CTCAE 4.03 2010-0

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CTCAE 4.03 2010-0
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Common Terminology Criteria for Adverse Events Version 4.03 June 2010
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1. CTCAE 4.03 Common Terminology Criteria forAdverse Events (CTCAE) Version 4.0 Published: May 28, 2009 (v4.03: June 14, 2010) U.S.DEPARTMENT OF HEALTH AND HUMAN SERVICES National Institutes of HealthNational Cancer Institute

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CONTENTS SOC Page Blood and lymphatic system disorders 3 Cardiac disorders 4 Congenital, familial and genetic disorders 7 Ear and labyrinth disorders 8 Endocrine disorders 9 Eye disorders 10 Gastrointestinal disorders 12 General disorders and administration site conditions 22 Hepatobiliary disorders 24 Immune system disorders 26 Infections and infestations 27 Injury, poisoning and procedural complications 34 Investigations 41 Metabolism and nutrition disorders 44 Musculoskeletal and connective tissue disorders 46 Neoplasms benign, malignant and unspecified (incl cysts and polyps) 50 Nervous system disorders 51 Pregnancy, puerperium and perinatal conditions 56 Psychiatric disorders 57 Renal and urinary disorders 59 Reproductive system and breast disorders 61 Respiratory, thoracic and mediastinal disorders 65 Skin and subcutaneous tissue disorders 71 Social circumstances 75 Surgical and medical procedures 76 Vascular disorders 77

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CTCAE 4.03 June 14, 2010 : Blood and lymphatic system disorders 3 2. Blood and lymphatic system disorders Blood and lymphatic system disorders Grade Adverse Event 1 2 3 4 5 Anemia Hemoglobin (Hgb) 25 -<50% reduction from normalcellularity for age Severely hypocellular or >50 -<=75% reduction cellularity fromnormal for age Aplastic persistent for longerthan 2 weeks Death Definition: A disorder characterized by the inability of the bone marrow to produce hematopoietic elements. Disseminated intravascularcoagulation Laboratory findings with nobleeding Laboratory findings andbleeding Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by systemic pathological activation of blood clotting mechanisms which results in clot formation throughout the body. There is an increase in therisk of hemorrhage as the body is depleted of platelets and coagulation factors. Febrile neutropenia ANC <1000/mm3 with a singletemperature of >38.3 degrees C(101 degrees F) or a sustainedtemperature of >=38 degrees C(100.4 degrees F) for more thanone hour. Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by an ANC <1000/mm3 and a single temperature of >38.3 degrees C (101 degrees F) or a sustained temperature of >=38 degrees C (100.4degrees F) for more than one hour. Hemolysis Laboratory evidence ofhemolysis only (e.g., directantiglobulin test; DAT; Coombs';schistocytes; decreasedhaptoglobin) Evidence of hemolysis and >=2gm decrease in hemoglobin. Transfusion or medicalintervention indicated (e.g.,steroids) Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by laboratory test results that indicate widespread erythrocyte cell membrane destruction. Hemolytic uremic syndrome Evidence of RBC destruction(schistocytosis) without clinicalconsequences Laboratory findings with clinicalconsequences (e.g., renalinsufficiency, petechiae) Life-threatening consequences,(e.g., CNS hemorrhage orthrombosis/embolism or renalfailure) Death Definition: A disorder characterized by a form of thrombotic microangiopathy with renal failure, hemolytic anemia, and severe thrombocytopenia. Leukocytosis >100,000/mm3 Clinical manifestations ofleucostasis; urgent interventionindicated Death Definition: A disorder characterized by laboratory test results that indicate an increased number of white blood cells in the blood. Lymph node pain Mild pain Moderate pain; limitinginstrumental ADL Severe pain; limiting self careADL Definition: A disorder characterized by a sensation of marked discomfort in a lymph node. Spleen disorder Incidental findings (e.g., Howell-Jolly bodies); mild degree ofthrombocytosis andleukocytosis Prophylactic antibioticsindicated Life-threatening consequences;urgent intervention indicated Death Definition: A disorder of the spleen. Thrombotic thrombocytopenicpurpura Evidence of RBC destruction(schistocytosis) without clinicalconsequences Laboratory findings with clinicalconsequences (e.g., renalinsufficiency, petechiae) Life-threatening consequences,(e.g., CNS hemorrhage orthrombosis/embolism or renalfailure) Death Definition: A disorder characterized by the presence of microangiopathic hemolytic anemia, thrombocytopenic purpura, fever, renal abnormalities and neurological abnormalities suchas seizures, hemiplegia, and visual disturbances. It is an acute or subacute condition. Blood and lymphatic systemdisorders Other, specify Asymptomatic or mildsymptoms; clinical or diagnosticobservations only; interventionnot indicated Moderate; minimal, local ornoninvasive interventionindicated; limiting age-appropriate instrumental ADL Severe or medically significantbut not immediately life-threatening; hospitalization orprolongation of existinghospitalization indicated;disabling; limiting self care ADL Life-threatening consequences;urgent intervention indicated Death

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CTCAE 4.03 June 14, 2010 : Cardiac disorders 4 3. Cardiac disorders Cardiac disorders Grade Adverse Event 1 2 3 4 5 Acute coronary syndrome Symptomatic, progressiveangina; cardiac enzymesnormal; hemodynamically stable Symptomatic, unstable anginaand/or acute myocardialinfarction, cardiac enzymesabnormal, hemodynamicallystable Symptomatic, unstable anginaand/or acute myocardialinfarction, cardiac enzymesabnormal, hemodynamicallyunstable Death Definition: A disorder characterized by signs and symptoms related to acute ischemia of the myocardium secondary to coronary artery disease. The clinical presentation covers aspectrum of heart diseases from unstable angina to myocardial infarction. Aortic valve disease Asymptomatic valvularthickening with or without mildvalvular regurgitation orstenosis by imaging Asymptomatic; moderateregurgitation or stenosis byimaging Symptomatic; severeregurgitation or stenosis byimaging; symptoms controlledwith medical intervention Life-threatening consequences;urgent intervention indicated(e.g., valve replacement,valvuloplasty) Death Definition: A disorder characterized by a defect in aortic valve function or structure. Asystole Periods of asystole; non-urgentmedical management indicated Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by a dysrhythmia without cardiac electrical activity. Typically, this is accompanied by cessation of the pumping function of the heart. Atrial fibrillation Asymptomatic, intervention notindicated Non-urgent medical interventionindicated Symptomatic and incompletelycontrolled medically, orcontrolled with device (e.g.,pacemaker), or ablation Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by a dysrhythmia without discernible P waves and an irregular ventricular response due to multiple reentry circuits. The rhythm disturbanceoriginates above the ventricles. Atrial flutter Asymptomatic, intervention notindicated Non-urgent medical interventionindicated Symptomatic and incompletelycontrolled medically, orcontrolled with device (e.g.,pacemaker), or ablation Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by a dysrhythmia with organized rhythmic atrial contractions with a rate of 200-300 beats per minute. The rhythm disturbance originates in theatria. Atrioventricular block complete Non-urgent interventionindicated Symptomatic and incompletelycontrolled medically, orcontrolled with device (e.g.,pacemaker) Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by a dysrhythmia with complete failure of atrial electrical impulse conduction through the AV node to the ventricles. Atrioventricular block firstdegree Asymptomatic, intervention notindicated Non-urgent interventionindicated Definition: A disorder characterized by a dysrhythmia with a delay in the time required for the conduction of an electrical impulse through the atrioventricular (AV) node beyond 0.2seconds; prolongation of the PR interval greater than 200 milliseconds. Cardiac arrest Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by cessation of the pumping function of the heart. Chest pain cardiac Mild pain Moderate pain; limitinginstrumental ADL Pain at rest; limiting self careADL Definition: A disorder characterized by substernal discomfort due to insufficient myocardial oxygenation. Conduction disorder Mild symptoms; intervention notindicated Moderate symptoms Severe symptoms; interventionindicated Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by pathological irregularities in the cardiac conduction system. Constrictive pericarditis Symptomatic heart failure orother cardiac symptoms,responsive to intervention Refractory heart failure or otherpoorly controlled cardiacsymptoms Death Definition: A disorder characterized by a thickened and fibrotic pericardial sac; these fibrotic changes impede normal myocardial function by restricting myocardial muscle action. Heart failure Asymptomatic with laboratory(e.g., BNP [B-NatriureticPeptide ]) or cardiac imagingabnormalities Symptoms with mild tomoderate activity or exertion Severe with symptoms at rest orwith minimal activity or exertion;intervention indicated Life-threatening consequences;urgent intervention indicated(e.g., continuous IV therapy ormechanical hemodynamicsupport) Death Definition: A disorder characterized by the inability of the heart to pump blood at an adequate volume to meet tissue metabolic requirements, or, the ability to do so only at an elevationin the filling pressure.

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CTCAE 4.03 June 14, 2010 : Cardiac disorders 5 Cardiac disorders Grade Adverse Event 1 2 3 4 5 Left ventricular systolicdysfunction Symptomatic due to drop inejection fraction responsive tointervention Refractory or poorly controlledheart failure due to drop inejection fraction; interventionsuch as ventricular assistdevice, intravenous vasopressorsupport, or heart transplantindicated Death Definition: A disorder characterized by failure of the left ventricle to produce adequate output despite an increase in distending pressure and in end-diastolic volume. Clinicalmanifestations mayinclude dyspnea, orthopnea, and other signs and symptoms of pulmonary congestion and edema. Mitral valve disease Asymptomatic valvularthickening with or without mildvalvular regurgitation orstenosis by imaging Asymptomatic; moderateregurgitation or stenosis byimaging Symptomatic; severeregurgitation or stenosis byimaging; symptoms controlledwith medical intervention Life-threatening consequences;urgent intervention indicated(e.g., valve replacement,valvuloplasty) Death Definition: A disorder characterized by a defect in mitral valve function or structure. Mobitz (type) II atrioventricularblock Asymptomatic, intervention notindicated Symptomatic; medicalintervention indicated Symptomatic and incompletelycontrolled medically, orcontrolled with device (e.g.,pacemaker) Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by a dysrhythmia with relatively constant PR interval prior to the block of an atrial impulse. This is the result of intermittent failure of atrial electricalimpulse conduction through the atrioventricular (AV) node to the ventricles. Mobitz type I Asymptomatic, intervention notindicated Symptomatic; medicalintervention indicated Symptomatic and incompletelycontrolled medically, orcontrolled with device (e.g.,pacemaker) Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by a dysrhythmia with a progressively lengthening PR interval prior to the blocking of an atrial impulse. This is the result of intermittent failure ofatrial electrical impulse conduction through the atrioventricular (AV) node to the ventricles. Myocardial infarction Asymptomatic and cardiacenzymes minimally abnormaland no evidence of ischemicECG changes Severe symptoms; cardiacenzymes abnormal;hemodynamically stable; ECGchanges consistent withinfarction Life-threatening consequences;hemodynamically unstable Death Definition: A disorder characterized by gross necrosis of the myocardium; this is due to an interruption of blood supply to the area. Myocarditis Asymptomatic with laboratory(e.g., BNP [B-NatriureticPeptide ]) or cardiac imagingabnormalities Symptoms with mild tomoderate activity or exertion Severe with symptoms at rest orwith minimal activity or exertion;intervention indicated Life-threatening consequences;urgent intervention indicated(e.g., continuous IV therapy ormechanical hemodynamicsupport) Death Definition: A disorder characterized by inflammation of the muscle tissue of the heart. Palpitations Mild symptoms; intervention notindicated Intervention indicated Definition: A disorder characterized by an unpleasant sensation of irregular and/or forceful beating of the heart. Paroxysmal atrial tachycardia Asymptomatic, intervention notindicated Symptomatic; medicalmanagement indicated IV medication indicated Life-threatening consequences;incompletely controlledmedically; cardioversionindicated Death Definition: A disorder characterized by a dysrhythmia with abrupt onset and sudden termination of atrial contractions with a rate of 150-250 beats per minute. The rhythm disturbanceoriginates in the atria. Pericardial effusion Asymptomatic effusion sizesmall to moderate Effusion with physiologicconsequences Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by fluid collection within the pericardial sac, usually due to inflammation. Pericardial tamponade Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by an increase in intrapericardial pressure due to the collection of blood or fluid in the pericardium. Pericarditis Asymptomatic, ECG or physicalfindings (e.g., rub) consistentwith pericarditis Symptomatic pericarditis (e.g.,chest pain) Pericarditis with physiologicconsequences (e.g., pericardialconstriction) Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by irritation to the layers of the pericardium (the protective sac around the heart).

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CTCAE 4.03 June 14, 2010 : Cardiac disorders 6 Cardiac disorders Grade Adverse Event 1 2 3 4 5 Pulmonary valve disease Asymptomatic valvularthickening with or without mildvalvular regurgitation orstenosis by imaging Asymptomatic; moderateregurgitation or stenosis byimaging Symptomatic; severeregurgitation or stenosis byimaging; symptoms controlledwith medical intervention Life-threatening consequences;urgent intervention indicated(e.g., valve replacement,valvuloplasty) Death Definition: A disorder characterized by a defect in pulmonary valve function or structure. Restrictive cardiomyopathy Symptomatic heart failure orother cardiac symptoms,responsive to intervention Refractory heart failure or otherpoorly controlled cardiacsymptoms Death Definition: A disorder characterized by an inability of the ventricles to fill with blood because the myocardium (heart muscle) stiffens and loses its flexibility. Right ventricular dysfunction Asymptomatic with laboratory(e.g., BNP [B-NatriureticPeptide ]) or cardiac imagingabnormalities Symptoms with mild tomoderate activity or exertion Severe symptoms, associatedwith hypoxemia, right heartfailure; oxygen indicated Life-threatening consequences;urgent intervention indicated(e.g., ventricular assist device);heart transplant indicated Death Definition: A disorder characterized by impairment of right ventricular function associated with low ejection fraction and a decrease in motility of the right ventricular wall. Sick sinus syndrome Asymptomatic, intervention notindicated Non-urgent interventionindicated Severe, medically significant;medical intervention indicated Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by a dysrhythmia with alternating periods of bradycardia and atrial tachycardia accompanied by syncope, fatigue and dizziness. Sinus bradycardia Asymptomatic, intervention notindicated Symptomatic, medicalintervention indicated Severe, medically significant,medical intervention indicated Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by a dysrhythmia with a heart rate less than 60 beats per minute that originates in the sinus node. Sinus tachycardia Asymptomatic, intervention notindicated Symptomatic; non-urgentmedical intervention indicated Urgent medical interventionindicated Definition: A disorder characterized by a dysrhythmia with a heart rate greater than 100 beats per minute that originates in the sinus node. Supraventricular tachycardia Asymptomatic, intervention notindicated Non-urgent medical interventionindicated Medical intervention indicated Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by a dysrhythmia with a heart rate greater than 100 beats per minute that originates above the ventricles. Tricuspid valve disease Asymptomatic valvularthickening with or without mildvalvular regurgitation orstenosis Asymptomatic; moderateregurgitation or stenosis byimaging Symptomatic; severeregurgitation or stenosis;symptoms controlled withmedical intervention Life-threatening consequences;urgent intervention indicated(e.g., valve replacement,valvuloplasty) Death Definition: A disorder characterized by a defect in tricuspid valve function or structure. Ventricular arrhythmia Asymptomatic, intervention notindicated Non-urgent medical interventionindicated Medical intervention indicated Life-threatening consequences;hemodynamic compromise;urgent intervention indicated Death Definition: A disorder characterized by a dysrhythmia that originates in the ventricles. Ventricular fibrillation Life-threatening consequences;hemodynamic compromise;urgent intervention indicated Death Definition: A disorder characterized by a dysrhythmia without discernible QRS complexes due to rapid repetitive excitation of myocardial fibers without coordinated contraction of theventricles. Ventricular tachycardia Non-urgent medical interventionindicated Medical intervention indicated Life-threatening consequences;hemodynamic compromise;urgent intervention indicated Death Definition: A disorder characterized by a dysrhythmia with a heart rate greater than 100 beats per minute that originates distal to the bundle of His. Wolff-Parkinson-Whitesyndrome Asymptomatic, intervention notindicated Non-urgent medical interventionindicated Symptomatic and incompletelycontrolled medically orcontrolled with procedure Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by the presence of an accessory conductive pathway between the atria and the ventricles that causes premature ventricular activation. Cardiac disorders Other,specify Asymptomatic or mildsymptoms; clinical or diagnosticobservations only; interventionnot indicated Moderate; minimal, local ornoninvasive interventionindicated; limiting age-appropriate instrumental ADL Severe or medically significantbut not immediately life-threatening; hospitalization orprolongation of existinghospitalization indicated;disabling; limiting self care ADL Life-threatening consequences;urgent intervention indicated Death

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CTCAE 4.03 June 14, 2010 : Congenital, familial and genetic disorders 7 4. Congenital, familial and genetic disorders Congenital, familial and genetic disorders Grade Adverse Event 1 2 3 4 5 Congenital, familial and geneticdisorders Other, specify Asymptomatic or mildsymptoms; clinical or diagnosticobservations only; interventionnot indicated Moderate; minimal, local ornoninvasive interventionindicated; limiting age-appropriate instrumental ADL Severe or medically significantbut not immediately life-threatening; hospitalization orprolongation of existinghospitalization indicated;disabling; limiting self care ADL Life-threatening consequences;urgent intervention indicated Death

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CTCAE 4.03 June 14, 2010 : Ear and labyrinth disorders 8 5. Ear and labyrinth disorders Ear and labyrinth disorders Grade Adverse Event 1 2 3 4 5 Ear pain Mild pain Moderate pain; limitinginstrumental ADL Severe pain; limiting self careADL Definition: A disorder characterized by a sensation of marked discomfort in the ear. External ear inflammation External otitis with erythema ordry desquamation External otitis with moistdesquamation, edema,enhanced cerumen ordischarge; tympanic membraneperforation; tympanostomy External otitis with mastoiditis;stenosis or osteomyelitis;necrosis of soft tissue or bone Urgent operative interventionindicated Death Definition: A disorder characterized by inflammation, swelling and redness to the outer ear and ear canal. External ear pain Mild pain Moderate pain; limitinginstrumental ADL Severe pain; limiting self careADL Definition: A disorder characterized by a sensation of marked discomfort in the external ear region. Hearing impaired Adults enrolled on a MonitoringProgram (on a 1, 2, 3, 4, 6 and8 kHz audiogram): Thresholdshift of 15 25 dB averaged at 2contiguous test frequencies in atleast one ear.Adults not enrolled in MonitoringProgram: subjective change inhearing in the absence ofdocumented hearing loss.Pediatric (on a 1, 2, 3, 4, 6 and8 kHz audiogram): Thresholdshift >20 dB at 8 kHz in at leastone ear. Adults enrolled in MonitoringProgram (on a 1, 2, 3, 4, 6 and8 kHz audiogram): Thresholdshift of >25 dB averaged at 2contiguous test frequencies in atleast one ear.Adults not enrolled in MonitoringProgram: hearing loss buthearing aid or intervention notindicated; limiting instrumentalADL.Pediatric (on a 1, 2, 3, 4, 6 and8 kHz audiogram): Thresholdshift >20 dB at 4 kHz and abovein at least one ear. Adults enrolled in MonitoringProgram (on a 1, 2, 3, 4, 6 and8 kHz audiogram): Thresholdshift of >25 dB averaged at 3contiguous test frequencies in atleast one ear; therapeuticintervention indicated.Adults not enrolled in MonitoringProgram: hearing loss withhearing aid or interventionindicated; limiting self care ADL.Pediatric (on a 1, 2, 3, 4, 6 and8 kHz audiogram): hearing losssufficient to indicate therapeuticintervention, including hearingaids; threshold shift >20 dB at 3kHz and above in at least oneear; additional speech-languagerelated services indicated. Adults: Decrease in hearing toprofound bilateral loss (absolutethreshold >80 dB HL at 2 kHzand above); non-servicablehearing.Pediatric: Audiologic indicationfor cochlear implant andadditional speech-languagerelated services indicated. Definition: A disorder characterized by partial or complete loss of the ability to detect or understand sounds resulting from damage to ear structures. Middle ear inflammation Serous otitis Serous otitis, medicalintervention indicated Mastoiditis; necrosis of canalsoft tissue or bone Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by inflammation (physiologic response to irritation), swelling and redness to the middle ear. Tinnitus Mild symptoms; intervention notindicated Moderate symptoms; limitinginstrumental ADL Severe symptoms; limiting selfcare ADL Definition: A disorder characterized by noise in the ears, such as ringing, buzzing, roaring or clicking. Vertigo Mild symptoms Moderate symptoms; limitinginstrumental ADL Severe symptoms; limiting selfcare ADL Definition: A disorder characterized by a sensation as if the external world were revolving around the patient (objective vertigo) or as if he himself were revolving in space (subjectivevertigo). Vestibular disorder Symptomatic; limitinginstrumental ADL Severe symptoms; limiting selfcare ADL Definition: A disorder characterized by dizziness, imbalance, nausea, and vision problems. Ear and labyrinth disorders -Other, specify Asymptomatic or mildsymptoms; clinical or diagnosticobservations only; interventionnot indicated Moderate; minimal, local ornoninvasive interventionindicated; limiting age-appropriate instrumental ADL Severe or medically significantbut not immediately life-threatening; hospitalization orprolongation of existinghospitalization indicated;disabling; limiting self care ADL Life-threatening consequences;urgent intervention indicated Death

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CTCAE 4.03 June 14, 2010 : Endocrine disorders 9 6. Endocrine disorders Endocrine disorders Grade Adverse Event 1 2 3 4 5 Adrenal insufficiency Asymptomatic; clinical ordiagnostic observations only;intervention not indicated Moderate symptoms; medicalintervention indicated Severe symptoms;hospitalization indicated Life-threatening consequences;urgent intervention indicated Death Definition: A disorder that occurs when the adrenal cortex does not produce enough of the hormone cortisol and in some cases, the hormone aldosterone. It may be due to a disorderof the adrenal cortex as in Addison's disease or primary adrenal insufficiency. Cushingoid Mild symptoms; intervention notindicated Moderate symptoms; medicalintervention indicated Severe symptoms, medicalintervention or hospitalizationindicated Definition: A disorder characterized by signs and symptoms that resemble Cushing's disease or syndrome: buffalo hump obesity, striations, adiposity, hypertension, diabetes, andosteoporosis, usually due to exogenous corticosteroids. Delayed puberty No breast development by age13 yrs for females; testesvolume of <3 cc or no TannerStage 2 development by age14.5 yrs for males No breast development by age14 yrs for females; no increasein testes volume or no TannerStage 2 by age 16 yrs formales; hormone replacementindicated Definition: A disorder characterized by unusually late sexual maturity. Growth accelerated >= +2 SD (standard deviation)above mid parental height ortarget height Definition: A disorder characterized by greater growth than expected for age. Hyperparathyroidism Mild symptoms; intervention notindicated Moderate symptoms; medicalintervention indicated Definition: A disorder characterized by an increase in production of parathyroid hormone by the parathyroid glands. This results in hypercalcemia (abnormally high levels of calcium inthe blood). Hyperthyroidism Asymptomatic; clinical ordiagnostic observations only;intervention not indicated Symptomatic; thyroidsuppression therapy indicated;limiting instrumental ADL Severe symptoms; limiting selfcare ADL; hospitalizationindicated Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by excessive levels of thyroid hormone in the body. Common causes include an overactive thyroid gland or thyroid hormone overdose. Hypoparathyroidism Asymptomatic; clinical ordiagnostic observations only;intervention not indicated Moderate symptoms; medicalintervention indicated Severe symptoms; medicalintervention or hospitalizationindicated Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by a decrease in production of parathyroid hormone by the parathyroid glands. Hypothyroidism Asymptomatic; clinical ordiagnostic observations only;intervention not indicated Symptomatic; thyroidreplacement indicated; limitinginstrumental ADL Severe symptoms; limiting selfcare ADL; hospitalizationindicated Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by a decrease in production of thyroid hormone by the thyroid gland. Precocious puberty Physical signs of puberty withno biochemical markers forfemales <8 years and males <9years Physical signs and biochemicalmarkers of puberty for females<8 years and males <9 years Definition: A disorder characterized by unusually early development of secondary sexual features; the onset of sexual maturation begins usually before age 8 for girls and before age9 for boys. Virilization Mild symptoms; intervention notindicated Moderate symptoms; medicalintervention indicated Definition: A disorder characterized by inappropriate masculinization occurring in a female or prepubertal male. Endocrine disorders Other,specify Asymptomatic or mildsymptoms; clinical or diagnosticobservations only; interventionnot indicated Moderate; minimal, local ornoninvasive interventionindicated; limiting age-appropriate instrumental ADL Severe or medically significantbut not immediately life-threatening; hospitalization orprolongation of existinghospitalization indicated;disabling; limiting self care ADL Life-threatening consequences;urgent intervention indicated Death

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CTCAE 4.03 June 14, 2010 : Eye disorders 10 7. Eye disorders Eye disorders Grade Adverse Event 1 2 3 4 5 Blurred vision Intervention not indicated Symptomatic; limitinginstrumental ADL Limiting self care ADL Definition: A disorder characterized by visual perception of unclear or fuzzy images. Cataract Asymptomatic; clinical ordiagnostic observations only;intervention not indicated Symptomatic; moderatedecrease in visual acuity(20/40 or better) Symptomatic with markeddecrease in visual acuity(worse than 20/40 but betterthan 20/200); operativeintervention indicated (e.g.,cataract surgery) Blindness (20/200 or worse)in the affected eye Definition: A disorder characterized by partial or complete opacity of the crystalline lens of one or both eyes. This results in a decrease in visual acuity and eventual blindness ifuntreated. Conjunctivitis Asymptomatic or mildsymptoms; intervention notindicated Symptomatic; topicalintervention indicated (e.g.,antibiotics); limitinginstrumental ADL Limiting self care ADL Definition: A disorder characterized by inflammation, swelling and redness to the conjunctiva of the eye. Corneal ulcer Symptomatic; medicalintervention indicated (e.g.,topical agents); limitinginstrumental ADL Limiting self care ADL;declining vision (worse than20/40 but better than 20/200) Perforation or blindness(20/200 or worse) in theaffected eye Definition: A disorder characterized by an area of epithelial tissue loss on the surface of the cornea. It is associated with inflammatory cells in the cornea and anterior chamber. Dry eye Asymptomatic; clinical ordiagnostic observations only;mild symptoms relieved bylubricants Symptomatic; multipleagents indicated; limitinginstrumental ADL Decrease in visual acuity(<20/40); limiting self careADL Definition: A disorder characterized by dryness of the cornea and conjunctiva. Extraocular muscle paresis Asymptomatic; clinical ordiagnostic observations only Symptomatic; limitinginstrumental ADL Limiting self care ADL;disabling Definition: A disorder characterized by incomplete paralysis of an extraocular muscle. Eye pain Mild pain Moderate pain; limitinginstrumental ADL Severe pain; limiting selfcare ADL Definition: A disorder characterized by a sensation of marked discomfort in the eye. Eyelid function disorder Asymptomatic; clinical ordiagnostic observations only;intervention not indicated Symptomatic; nonoperativeintervention indicated;limiting instrumental ADL Limiting self care ADL;operative interventionindicated Definition: A disorder characterized by impaired eyelid function. Flashing lights Symptomatic but not limitingADL Limiting instrumental ADL Limiting self care ADL Definition: A disorder characterized by a sudden or brief burst of light. Floaters Symptomatic but not limitingADL Limiting instrumental ADL Limiting self care ADL Definition: A disorder characterized by an individual seeing spots before their eyes. The spots are shadows of opaque cell fragments in the vitreous humor or lens. Glaucoma Elevated intraocularpressure (EIOP) with singletopical agent for intervention;no visual field deficit EIOP causing early visualfield deficits; multiple topicalor oral agents indicated;limiting instrumental ADL EIOP causing marked visualfield deficits (e.g., involvingboth superior and inferiorvisual fields); operativeintervention indicated;limiting self care ADL Blindness (20/200 or worse)in the affected eye Definition: A disorder characterized by an increase in pressure in the eyeball due to obstruction of the aqueous humor outflow. Keratitis Symptomatic; medicalintervention indicated (e.g.,topical agents); limitinginstrumental ADL Decline in vision (worse than20/40 but better than20/200); limiting self careADL Perforation or blindness(20/200 or worse) in theaffected eye Definition: A disorder characterized by inflammation to the cornea of the eye. Night blindness Symptomatic but not limitingADL Limiting instrumental ADL Limiting self care ADL Blindness (20/200 or worse)in the affected eye Definition: A disorder characterized by an inability to see clearly in dim light.

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CTCAE 4.03 June 14, 2010 : Eye disorders 11 Eye disorders Grade Adverse Event 1 2 3 4 5 Optic nerve disorder Asymptomatic; clinical ordiagnostic observations only Limiting vision of the affectedeye (20/40 or better) Limiting vision in the affectedeye (worse than 20/40 butbetter than 20/200) Blindness (20/200 or worse)in the affected eye Definition: A disorder characterized by involvement of the optic nerve (second cranial nerve). Papilledema Asymptomatic; no visual fielddefects Symptomatic decline invision; visual field defectpresent sparing the central20 degrees Marked visual field defect(worse than 20/40 but betterthan 20/200) Blindness (20/200 or worse)in the affected eye Definition: A disorder characterized by swelling around the optic disc. Photophobia Symptomatic but not limitingADL Limiting instrumental ADL Limiting self care ADL Definition: A disorder characterized by fear and avoidance of light. Retinal detachment Asymptomatic Exudative and visual acuity20/40 or better Rhegmatogenous orexudative detachment;operative interventionindicated; decline in vision(worse than 20/40 but betterthan 20/200) Blindness (20/200 or worse)in the affected eye Definition: A disorder characterized by the separation of the inner retina layers from the underlying pigment epithelium. Retinal tear Laser therapy orpneumopexy indicated Vitroretinal surgical repairindicated Blindness (20/200 or worse)in the affected eye Definition: A disorder characterized by a small laceration of the retina, this occurs when the vitreous separates from the retina. Symptoms include flashes and floaters. Retinal vascular disorder Topical medication indicated Intravitreal medication;operative interventionindicated Definition: A disorder characterized by pathological retinal blood vessels that adversely affects vision. Retinopathy Asymptomatic; clinical ordiagnostic observations only Symptomatic with moderatedecrease in visual acuity(20/40 or better); limitinginstrumental ADL Symptomatic with markeddecrease in visual acuity(worse than 20/40);disabling; limiting self careADL Blindness (20/200 or worse)in the affected eye Definition: A disorder involving the retina. Scleral disorder Asymptomatic; clinical ordiagnostic observations only Symptomatic, limitinginstrumental ADL; moderatedecrease in visual acuity(20/40 or better) Symptomatic, limiting selfcare ADL; marked decreasein visual acuity (worse than20/40) Blindness (20/200 or worse)in the affected eye Definition: A disorder characterized by involvement of the sclera of the eye. Uveitis Asymptomatic; clinical ordiagnostic observations only Anterior uveitis; medicalintervention indicated Posterior or pan-uveitis Blindness (20/200 or worse)in the affected eye Definition: A disorder characterized by inflammation to the uvea of the eye. Vitreous hemorrhage Asymptomatic or mildsymptoms; clinical ordiagnostic observations only Symptomatic; limitinginstrumental ADL Limiting self care ADL;vitrectomy indicated Blindness (20/200 or worse)in the affected eye Definition: A disorder characterized by blood extravasation into the vitreous humor. Watering eyes Intervention not indicated Intervention indicated Operative interventionindicated Definition: A disorder of excessive tearing in the eyes; it can be caused by overproduction of tears or impaired drainage of the tear duct. Eye disorders Other,specify Asymptomatic or mildsymptoms; clinical ordiagnostic observations only;intervention not indicated Moderate; minimal, local ornoninvasive interventionindicated; limiting age-appropriate instrumentalADL Severe or medicallysignificant but notimmediately sight-threatening; hospitalizationor prolongation of existinghospitalization indicated;disabling; limiting self careADL Sight-threateningconsequences; urgentintervention indicated;blindness (20/200 or worse)in the affected eye -

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CTCAE 4.03 June 14, 2010 : Gastrointestinal disorders 12 8. Gastrointestinal disorders Gastrointestinal disorders Grade Adverse Event 1 2 3 4 5 Abdominal distension Asymptomatic; clinical ordiagnostic observations only;intervention not indicated Symptomatic; limitinginstrumental ADL Severe discomfort; limiting selfcare ADL Definition: A disorder characterized by swelling of the abdomen. Abdominal pain Mild pain Moderate pain; limitinginstrumental ADL Severe pain; limiting self careADL Definition: A disorder characterized by a sensation of marked discomfort in the abdominal region. Anal fistula Asymptomatic; clinical ordiagnostic observations only;intervention not indicated Symptomatic; altered GIfunction Severely altered GI function;tube feeding, TPN orhospitalization indicated;elective operative interventionindicated Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by an abnormal communication between the opening in the anal canal to the perianal skin. Anal hemorrhage Mild; intervention not indicated Moderate symptoms; medicalintervention or minorcauterization indicated Transfusion, radiologic,endoscopic, or electiveoperative intervention indicated Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by bleeding from the anal region. Anal mucositis Asymptomatic or mildsymptoms; intervention notindicated Symptomatic; medicalintervention indicated; limitinginstrumental ADL Severe symptoms; limiting selfcare ADL Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by inflammation of the mucous membrane of the anus. Anal necrosis TPN or hospitalization indicated;radiologic, endoscopic, oroperative intervention indicated Life-threatening consequences;urgent operative interventionindicated Death Definition: A disorder characterized by a necrotic process occurring in the anal region. Anal pain Mild pain Moderate pain; limitinginstrumental ADL Severe pain; limiting self careADL Definition: A disorder characterized by a sensation of marked discomfort in the anal region. Anal stenosis Asymptomatic; clinical ordiagnostic observations only;intervention not indicated Symptomatic; altered GIfunction Symptomatic and severelyaltered GI function; non-emergent operative interventionindicated; TPN or hospitalizationindicated Life-threatening consequences;urgent operative interventionindicated Death Definition: A disorder characterized by a narrowing of the lumen of the anal canal. Anal ulcer Asymptomatic; clinical ordiagnostic observations only;intervention not indicated Symptomatic; altered GIfunction Severely altered GI function;TPN indicated; electiveoperative or endoscopicintervention indicated; disabling Life-threatening consequences;urgent operative interventionindicated Death Definition: A disorder characterized by a circumscribed, inflammatory and necrotic erosive lesion on the mucosal surface of the anal canal. Ascites Asymptomatic; clinical ordiagnostic observations only;intervention not indicated Symptomatic; medicalintervention indicated Severe symptoms; invasiveintervention indicated Life-threatening consequences;urgent operative interventionindicated Death Definition: A disorder characterized by accumulation of serous or hemorrhagic fluid in the peritoneal cavity. Bloating No change in bowel function ororal intake Symptomatic, decreased oralintake; change in bowel function Definition: A disorder characterized by subject-reported feeling of uncomfortable fullness of the abdomen. Cecal hemorrhage Mild; intervention not indicated Moderate symptoms; medicalintervention or minorcauterization indicated Transfusion, radiologic,endoscopic, or electiveoperative intervention indicated Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by bleeding from the cecum. Cheilitis Asymptomatic; clinical ordiagnostic observations only;intervention not indicated Moderate symptoms; limitinginstrumental ADL Severe symptoms; limiting selfcare ADL; intervention indicated Definition: A disorder characterized by inflammation of the lip.

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CTCAE 4.03 June 14, 2010 : Gastrointestinal disorders 13 Gastrointestinal disorders Grade Adverse Event 1 2 3 4 5 Colitis Asymptomatic; clinical ordiagnostic observations only;intervention not indicated Abdominal pain; mucus or bloodin stool Severe abdominal pain; changein bowel habits; medicalintervention indicated;peritoneal signs Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by inflammation of the colon. Colonic fistula Asymptomatic; clinical ordiagnostic observations only;intervention not indicated Symptomatic; altered GIfunction Severely altered GI function;bowel rest, TPN orhospitalization indicated;elective operative interventionindicated Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by an abnormal communication between the large intestine and another organ or anatomic site. Colonic hemorrhage Mild; intervention not indicated Moderate symptoms; medicalintervention or minorcauterization indicated Transfusion, radiologic,endoscopic, or electiveoperative intervention indicated Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by bleeding from the colon. Colonic obstruction Asymptomatic; clinical ordiagnostic observations only;intervention not indicated Symptomatic; altered GIfunction Hospitalization indicated;elective operative interventionindicated; disabling Life-threatening consequences;urgent operative interventionindicated Death Definition: A disorder characterized by blockage of the normal flow of the intestinal contents in the colon. Colonic perforation Symptomatic; medicalintervention indicated Severe symptoms; electiveoperative intervention indicated Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by a rupture in the colonic wall. Colonic stenosis Asymptomatic; clinical ordiagnostic observations only;intervention not indicated Symptomatic; altered GIfunction Severely altered GI function;tube feeding or hospitalizationindicated; elective operativeintervention indicated Life-threatening consequences;urgent operative interventionindicated Death Definition: A disorder characterized by a narrowing of the lumen of the colon. Colonic ulcer Asymptomatic; clinical ordiagnostic observations only;intervention not indicated Symptomatic; altered GIfunction Severely altered GI function;TPN indicated; electiveoperative or endoscopicintervention indicated; disabling Life-threatening consequences;urgent operative interventionindicated Death Definition: A disorder characterized by a circumscribed, inflammatory and necrotic erosive lesion on the mucosal surface of the colon. Constipation Occasional or intermittentsymptoms; occasional use ofstool softeners, laxatives,dietary modification, or enema Persistent symptoms withregular use of laxatives orenemas; limiting instrumentalADL Obstipation with manualevacuation indicated; limitingself care ADL Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by irregular and infrequent or difficult evacuation of the bowels. Dental caries One or more dental caries, notinvolving the root Dental caries involving the root Dental caries resulting in pulpitisor periapical abscess orresulting in tooth loss Definition: A disorder characterized by the decay of a tooth, in which it becomes softened, discolored and/or porous. Diarrhea Increase of <4 stools per dayover baseline; mild increase inostomy output compared tobaseline Increase of 4 6 stools per dayover baseline; moderateincrease in ostomy outputcompared to baseline Increase of >=7 stools per dayover baseline; incontinence;hospitalization indicated; severeincrease in ostomy outputcompared to baseline; limitingself care ADL Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by frequent and watery bowel movements. Dry mouth Symptomatic (e.g., dry or thicksaliva) without significant dietaryalteration; unstimulated salivaflow >0.2 ml/min Moderate symptoms; oral intakealterations (e.g., copious water,other lubricants, diet limited topurees and/or soft, moist foods);unstimulated saliva 0.1 to 0.2ml/min Inability to adequately alimentorally; tube feeding or TPNindicated; unstimulated saliva<0.1 ml/min Definition: A disorder characterized by reduced salivary flow in the oral cavity.

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CTCAE 4.03 June 14, 2010 : Gastrointestinal disorders 14 Gastrointestinal disorders Grade Adverse Event 1 2 3 4 5 Duodenal fistula Asymptomatic; clinical ordiagnostic observations only;intervention not indicated Symptomatic; altered GIfunction Severely altered GI function;tube feeding, TPN orhospitalization indicated;elective operative interventionindicated Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by an abnormal communication between the duodenum and another organ or anatomic site. Duodenal hemorrhage Mild; intervention not indicated Moderate symptoms; medicalintervention or minorcauterization indicated Transfusion, radiologic,endoscopic, or electiveoperative intervention indicated Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by bleeding from the duodenum. Duodenal obstruction Asymptomatic; clinical ordiagnostic observations only;intervention not indicated Symptomatic; altered GIfunction Hospitalization or electiveoperative intervention indicated;disabling Life-threatening consequences;urgent operative interventionindicated Death Definition: A disorder characterized by blockage of the normal flow of stomach contents through the duodenum. Duodenal perforation Symptomatic; medicalintervention indicated Severe symptoms; electiveoperative intervention indicated Life-threatening consequences;urgent operative interventionindicated Death Definition: A disorder characterized by a rupture in the duodenal wall. Duodenal stenosis Asymptomatic; clinical ordiagnostic observations only;intervention not indicated Symptomatic; altered GIfunction Severely altered GI function;tube feeding; hospitalizationindicated; elective operativeintervention indicated Life-threatening consequences;urgent operative interventionindicated Death Definition: A disorder characterized by a narrowing of the lumen of the duodenum. Duodenal ulcer Asymptomatic; clinical ordiagnostic observations only;intervention not indicated Moderate symptoms; medicalintervention indicated; limitinginstrumental ADL Severely altered GI function;TPN indicated; electiveoperative or endoscopicintervention indicated; limitingself care ADL; disabling Life-threatening consequences;urgent operative interventionindicated Death Definition: A disorder characterized by a circumscribed, inflammatory and necrotic erosive lesion on the mucosal surface of the duodenal wall. Dyspepsia Mild symptoms; intervention notindicated Moderate symptoms; medicalintervention indicated Severe symptoms; surgicalintervention indicated Definition: A disorder characterized by an uncomfortable, often painful feeling in the stomach, resulting from impaired digestion. Symptoms include burning stomach, bloating,heartburn, nausea and vomiting. Dysphagia Symptomatic, able to eatregular diet Symptomatic and alteredeating/swallowing Severely alteredeating/swallowing; tube feedingor TPN or hospitalizationindicated Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by difficulty in swallowing. Enterocolitis Asymptomatic; clinical ordiagnostic observations only;intervention not indicated Abdominal pain; mucus or bloodin stool Severe or persistent abdominalpain; fever; ileus; peritonealsigns Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by inflammation of the small and large intestines. Enterovesical fistula Asymptomatic; clinical ordiagnostic observations only;intervention not indicated Symptomatic; noninvasiveintervention indicated Severe, medically significant;medical intervention indicated Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by an abnormal communication between the urinary bladder and the intestine. Esophageal fistula Asymptomatic; clinical ordiagnostic observations only;intervention not indicated Symptomatic; altered GIfunction Severely altered GI function;tube feeding, TPN orhospitalization indicated;elective operative interventionindicated Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by an abnormal communication between the esophagus and another organ or anatomic site. Esophageal hemorrhage Mild; intervention not indicated Moderate symptoms; medicalintervention or minorcauterization indicated Transfusion, radiologic,endoscopic, or electiveoperative intervention indicated Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by bleeding from the esophagus.

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CTCAE 4.03 June 14, 2010 : Gastrointestinal disorders 15 Gastrointestinal disorders Grade Adverse Event 1 2 3 4 5 Esophageal necrosis Inability to aliment adequatelyby GI tract; radiologic,endoscopic, or operativeintervention indicated Life-threatening consequences;urgent operative interventionindicated Death Definition: A disorder characterized by a necrotic process occurring in the esophageal wall. Esophageal obstruction Asymptomatic; clinical ordiagnostic observations only;intervention not indicated Symptomatic; altered GIfunction; limiting instrumentalADL Hospitalization indicated;elective operative interventionindicated; limiting self care ADL;disabling Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by blockage of the normal flow of the contents in the esophagus. Esophageal pain Mild pain Moderate pain; limitinginstrumental ADL Severe pain; limiting self careADL Definition: A disorder characterized by a sensation of marked discomfort in the esophageal region. Esophageal perforation Symptomatic; medicalintervention indicated Severe symptoms; electiveoperative intervention indicated Life-threatening consequences;urgent operative interventionindicated Death Definition: A disorder characterized by a rupture in the wall of the esophagus. Esophageal stenosis Asymptomatic; clinical ordiagnostic observations only;intervention not indicated Symptomatic; altered GIfunction Severely altered GI function;tube feeding; hospitalizationindicated; elective operativeintervention indicated Life-threatening consequences;urgent operative interventionindicated Death Definition: A disorder characterized by a narrowing of the lumen of the esophagus. Esophageal ulcer Asymptomatic; clinical ordiagnostic observations only;intervention not indicated Symptomatic; altered GIfunction; limiting instrumentalADL Severely altered GI function;TPN indicated; electiveoperative or endoscopicintervention indicated; limitingself care ADL; disabling Life-threatening consequences;urgent operative interventionindicated Death Definition: A disorder characterized by a circumscribed, inflammatory and necrotic erosive lesion on the mucosal surface of the esophageal wall. Esophageal variceshemorrhage Self-limited; intervention notindicated Transfusion, radiologic,endoscopic, or electiveoperative intervention indicated Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by bleeding from esophageal varices. Esophagitis Asymptomatic; clinical ordiagnostic observations only;intervention not indicated Symptomatic; alteredeating/swallowing; oralsupplements indicated Severely alteredeating/swallowing; tube feeding,TPN or hospitalization indicated Life-threatening consequences;urgent operative interventionindicated Death Definition: A disorder characterized by inflammation of the esophageal wall. Fecal incontinence Occasional use of pads required Daily use of pads required Severe symptoms; electiveoperative intervention indicated Definition: A disorder characterized by inability to control the escape of stool from the rectum. Flatulence Mild symptoms; intervention notindicated Moderate; persistent;psychosocial sequelae Definition: A disorder characterized by a state of excessive gas in the alimentary canal. Gastric fistula Asymptomatic; clinical ordiagnostic observations only;intervention not indicated Symptomatic; altered GIfunction Severely altered GI function;bowel rest; tube feeding, TPN orhospitalization indicated;elective operative interventionindicated Life-threatening consequences;urgent operative interventionindicated Death Definition: A disorder characterized by an abnormal communication between the stomach and another organ or anatomic site. Gastric hemorrhage Mild; intervention not indicated Moderate symptoms; medicalintervention or minorcauterization indicated Transfusion, radiologic,endoscopic, or electiveoperative intervention indicated Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by bleeding from the gastric wall. Gastric necrosis Inability to aliment adequatelyby GI tract; radiologic,endoscopic, or operativeintervention indicated Life-threatening consequences;urgent operative interventionindicated Death Definition: A disorder characterized by a necrotic process occurring in the gastric wall.

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CTCAE 4.03 June 14, 2010 : Gastrointestinal disorders 16 Gastrointestinal disorders Grade Adverse Event 1 2 3 4 5 Gastric perforation Symptomatic; medicalintervention indicated Severe symptoms; electiveoperative intervention indicated Life-threatening consequences;urgent operative interventionindicated Death Definition: A disorder characterized by a rupture in the stomach wall. Gastric stenosis Asymptomatic; clinical ordiagnostic observations only;intervention not indicated Symptomatic; altered GIfunction Severely altered GI function;tube feeding; hospitalizationindicated; elective operativeintervention indicated Life-threatening consequences;urgent operative interventionindicated Death Definition: A disorder characterized by a narrowing of the lumen of the stomach. Gastric ulcer Asymptomatic; clinical ordiagnostic observations only;intervention not indicated Symptomatic; altered GIfunction; medical interventionindicated; limiting instrumentalADL Severely altered GI function;TPN indicated; electiveoperative or endoscopicintervention indicated; limitingself care ADL; disabling Life-threatening consequences;urgent operative interventionindicated Death Definition: A disorder characterized by a circumscribed, inflammatory and necrotic erosive lesion on the mucosal surface of the stomach. Gastritis Asymptomatic; clinical ordiagnostic observations only;intervention not indicated Symptomatic; altered GIfunction; medical interventionindicated Severely altered eating orgastric function; TPN orhospitalization indicated Life-threatening consequences;urgent operative interventionindicated Death Definition: A disorder characterized by inflammation of the stomach. Gastroesophageal refluxdisease Mild symptoms; intervention notindicated Moderate symptoms; medicalintervention indicated Severe symptoms; surgicalintervention indicated Definition: A disorder characterized by reflux of the gastric and/or duodenal contents into the distal esophagus. It is chronic in nature and usually caused by incompetence of the loweresophageal sphincter, and may result in injury to the esophageal mucosal. Symptoms include heartburn and acid indigestion. Gastrointestinal fistula Asymptomatic; clinical ordiagnostic observations only;intervention not indicated Symptomatic; altered GIfunction Severely altered GI function;tube feeding, TPN orhospitalization indicated Life-threatening consequences;urgent operative interventionindicated Death Definition: A disorder characterized by an abnormal communication between any part of the gastrointestinal system and another organ or anatomic site. Gastrointestinal pain Mild pain Moderate pain; limitinginstrumental ADL Severe pain; limiting self careADL Definition: A disorder characterized by a sensation of marked discomfort in the gastrointestinal region. Gastroparesis Mild nausea, early satiety andbloating, able to maintain caloricintake on regular diet Moderate symptoms; able tomaintain nutrition with dietaryand lifestyle modifications; mayneed pharmacologicintervention Weight loss; refractory tomedical intervention; unable tomaintain nutrition orally Definition: A disorder characterized by an incomplete paralysis of the muscles of the stomach wall resulting in delayed emptying of the gastric contents into the small intestine. Gingival pain Mild pain Moderate pain interfering withoral intake Severe pain; inability to alimentorally Definition: A disorder characterized by a sensation of marked discomfort in the gingival region. Hemorrhoidal hemorrhage Mild; intervention not indicated Moderate symptoms; medicalintervention or minorcauterization indicated Transfusion, radiologic,endoscopic, or electiveoperative intervention indicated Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by bleeding from the hemorrhoids. Hemorrhoids Asymptomatic; clinical ordiagnostic observations only;intervention not indicated Symptomatic; banding ormedical intervention indicated Severe symptoms; radiologic,endoscopic or elective operativeintervention indicated Definition: A disorder characterized by the presence of dilated veins in the rectum and surrounding area. Ileal fistula Asymptomatic; clinical ordiagnostic observations only;intervention not indicated Symptomatic; altered GIfunction Severely altered GI function;TPN or hospitalization indicated;elective operative interventionindicated Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by an abnormal communication between the ileum and another organ or anatomic site. Ileal hemorrhage Mild; intervention not indicated Moderate symptoms; medicalintervention or minorcauterization indicated Transfusion, radiologic,endoscopic, or electiveoperative intervention indicated Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by bleeding from the ileal wall.

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CTCAE 4.03 June 14, 2010 : Gastrointestinal disorders 17 Gastrointestinal disorders Grade Adverse Event 1 2 3 4 5 Ileal obstruction Asymptomatic; clinical ordiagnostic observations only;intervention not indicated Symptomatic; altered GIfunction; limiting instrumentalADL Hospitalization indicated;elective operative interventionindicated; limiting self care ADL;disabling Life-threatening consequences;urgent operative interventionindicated Death Definition: A disorder characterized by blockage of the normal flow of the intestinal contents in the ileum. Ileal perforation Symptomatic; medicalintervention indicated Severe symptoms; electiveoperative intervention indicated Life-threatening consequences;urgent operative interventionindicated Death Definition: A disorder characterized by a rupture in the ileal wall. Ileal stenosis Asymptomatic; clinical ordiagnostic observations only;intervention not indicated Symptomatic; altered GIfunction Severely altered GI function;tube feeding or hospitalizationindicated; elective operativeintervention indicated Life-threatening consequences;urgent operative interventionindicated Death Definition: A disorder characterized by a narrowing of the lumen of the ileum. Ileal ulcer Asymptomatic; clinical ordiagnostic observations only;intervention not indicated Symptomatic; altered GIfunction Severely altered GI function;TPN indicated; electiveoperative or endoscopicintervention indicated; disabling Life-threatening consequences;urgent operative interventionindicated Death Definition: A disorder characterized by a circumscribed, inflammatory and necrotic erosive lesion on the mucosal surface of the ileum. Ileus Symptomatic; altered GIfunction; bowel rest indicated Severely altered GI function;TPN indicated Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by failure of the ileum to transport intestinal contents. Intra-abdominal hemorrhage Medical intervention or minorcauterization indicated Transfusion, radiologic,endoscopic, or electiveoperative intervention indicated Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by bleeding in the abdominal cavity. Jejunal fistula Asymptomatic; clinical ordiagnostic observations only;intervention not indicated Symptomatic; altered GIfunction Severely altered GI function;TPN or hospitalization indicated;elective operative interventionindicated Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by an abnormal communication between the jejunum and another organ or anatomic site. Jejunal hemorrhage Mild; intervention not indicated Moderate symptoms; medicalintervention or minorcauterization indicated Transfusion, radiologic,endoscopic, or electiveoperative intervention indicated Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by bleeding from the jejunal wall. Jejunal obstruction Asymptomatic; clinical ordiagnostic observations only;intervention not indicated Symptomatic; altered GIfunction; limiting instrumentalADL Hospitalization indicated;elective operative interventionindicated; limiting self care ADL;disabling Life-threatening consequences;urgent operative interventionindicated Death Definition: A disorder characterized by blockage of the normal flow of the intestinal contents in the jejunum. Jejunal perforation Symptomatic; medicalintervention indicated Severe symptoms; electiveoperative intervention indicated Life-threatening consequences;urgent operative interventionindicated Death Definition: A disorder characterized by a rupture in the jejunal wall. Jejunal stenosis Asymptomatic; clinical ordiagnostic observations only;intervention not indicated Symptomatic; altered GIfunction Severely altered GI function;tube feeding or hospitalizationindicated; elective operativeintervention indicated Life-threatening consequences;urgent operative interventionindicated Death Definition: A disorder characterized by a narrowing of the lumen of the jejunum. Jejunal ulcer Asymptomatic; clinical ordiagnostic observations only;intervention not indicated Symptomatic; altered GIfunction Severely altered GI function;TPN indicated; electiveoperative or endoscopicintervention indicated; disabling Life-threatening consequences;urgent operative interventionindicated Death Definition: A disorder characterized by a circumscribed, inflammatory and necrotic erosive lesion on the mucosal surface of the jejunum. Lip pain Mild pain Moderate pain; limitinginstrumental ADL Severe pain; limiting self careADL Definition: A disorder characterized by a sensation of marked discomfort of the lip.

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CTCAE 4.03 June 14, 2010 : Gastrointestinal disorders 18 Gastrointestinal disorders Grade Adverse Event 1 2 3 4 5 Lower gastrointestinalhemorrhage Mild; intervention not indicated Moderate symptoms; medicalintervention or minorcauterization indicated Transfusion, radiologic,endoscopic, or electiveoperative intervention indicated Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by bleeding from the lower gastrointestinal tract (small intestine, large intestine, and anus). Malabsorption Altered diet; oral interventionindicated Inability to aliment adequately;TPN indicated Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by inadequate absorption of nutrients in the small intestine. Symptoms include abdominal marked discomfort, bloating and diarrhea. Mucositis oral Asymptomatic or mildsymptoms; intervention notindicated Moderate pain; not interferingwith oral intake; modified dietindicated Severe pain; interfering with oralintake Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by inflammation of the oral mucosal. Nausea Loss of appetite withoutalteration in eating habits Oral intake decreased withoutsignificant weight loss,dehydration or malnutrition Inadequate oral caloric or fluidintake; tube feeding, TPN, orhospitalization indicated Definition: A disorder characterized by a queasy sensation and/or the urge to vomit. Obstruction gastric Asymptomatic; clinical ordiagnostic observations only;intervention not indicated Symptomatic; altered GIfunction; limiting instrumentalADL Hospitalization indicated;elective operative interventionindicated; limiting self care ADL;disabling Life-threatening consequences;urgent operative interventionindicated Death Definition: A disorder characterized by blockage of the normal flow of the contents in the stomach. Oral cavity fistula Asymptomatic; clinical ordiagnostic observations only;intervention not indicated Symptomatic; altered GIfunction Severely altered GI function;TPN or hospitalization indicated;elective operative interventionindicated Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by an abnormal communication between the oral cavity and another organ or anatomic site. Oral dysesthesia Mild discomfort; not interferingwith oral intake Moderate pain; interfering withoral intake Disabling pain; tube feeding orTPN indicated Definition: A disorder characterized by a burning or tingling sensation on the lips, tongue or entire mouth. Oral hemorrhage Mild; intervention not indicated Moderate symptoms; medicalintervention or minorcauterization indicated Transfusion, radiologic,endoscopic, or electiveoperative intervention indicated Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by bleeding from the mouth. Oral pain Mild pain Moderate pain; limitinginstrumental ADL Severe pain; limiting self careADL Definition: A disorder characterized by a sensation of marked discomfort in the mouth, tongue or lips. Pancreatic duct stenosis Asymptomatic; clinical ordiagnostic observations only;intervention not indicated Symptomatic; altered GIfunction Severely altered GI function;tube feeding or hospitalizationindicated; elective operativeintervention indicated Life-threatening consequences;urgent operative interventionindicated Death Definition: A disorder characterized by a narrowing of the lumen of the pancreatic duct. Pancreatic fistula Asymptomatic; clinical ordiagnostic observations only;intervention not indicated Symptomatic; altered GIfunction Severely altered GI function;tube feeding or TPN orhospitalization indicated;elective operative interventionindicated Life-threatening consequences;urgent operative interventionindicated Death Definition: A disorder characterized by an abnormal communication between the pancreas and another organ or anatomic site. Pancreatic hemorrhage Mild; intervention not indicated Moderate symptoms; medicalintervention or minorcauterization indicated Transfusion, radiologic,endoscopic, or electiveoperative intervention indicated Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by bleeding from the pancreas. Pancreatic necrosis Tube feeding or TPN indicated;radiologic, endoscopic, oroperative intervention indicated Life-threatening consequences;urgent operative interventionindicated Death Definition: A disorder characterized by a necrotic process occurring in the pancreas. Pancreatitis Enzyme elevation or radiologicfindings only Severe pain; vomiting; medicalintervention indicated (e.g.,analgesia, nutritional support) Life-threatening consequences;urgent intervention indicated Death

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CTCAE 4.03 June 14, 2010 : Gastrointestinal disorders 19 Gastrointestinal disorders Grade Adverse Event 1 2 3 4 5 Definition: A disorder characterized by inflammation of the pancreas. Periodontal disease Gingival recession or gingivitis;limited bleeding on probing; mildlocal bone loss Moderate gingival recession orgingivitis; multiple sites ofbleeding on probing; moderatebone loss Spontaneous bleeding; severebone loss with or without toothloss; osteonecrosis of maxilla ormandible Definition: A disorder in the gingival tissue around the teeth. Peritoneal necrosis Tube feeding or TPN indicated;radiologic, endoscopic, oroperative intervention indicated Life-threatening consequences;urgent operative interventionindicated Death Definition: A disorder characterized by a necrotic process occurring in the peritoneum. Proctitis Rectal discomfort, interventionnot indicated Symptoms (e.g., rectaldiscomfort, passing blood ormucus); medical interventionindicated; limiting instrumentalADL Severe symptoms; fecalurgency or stool incontinence;limiting self care ADL Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by inflammation of the rectum. Rectal fistula Asymptomatic; clinical ordiagnostic observations only;intervention not indicated Symptomatic; altered GIfunction Severely altered GI function;TPN or hospitalization indicated;elective operative interventionindicated Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by an abnormal communication between the rectum and another organ or anatomic site. Rectal hemorrhage Mild; intervention not indicated Moderate symptoms; medicalintervention or minorcauterization indicated Transfusion, radiologic,endoscopic, or electiveoperative intervention indicated Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by bleeding from the rectal wall and discharged from the anus. Rectal mucositis Asymptomatic or mildsymptoms; intervention notindicated Symptomatic; medicalintervention indicated; limitinginstrumental ADL Severe symptoms; limiting selfcare ADL Life-threatening consequences;urgent operative interventionindicated Death Definition: A disorder characterized by inflammation of the mucous membrane of the rectum. Rectal necrosis Tube feeding or TPN indicated;radiologic, endoscopic, oroperative intervention indicated Life-threatening consequences;urgent operative interventionindicated Death Definition: A disorder characterized by a necrotic process occurring in the rectal wall. Rectal obstruction Asymptomatic; clinical ordiagnostic observations only;intervention not indicated Symptomatic; altered GIfunction; limiting instrumentalADL Hospitalization indicated;elective operative interventionindicated; limiting self care ADL;disabling Life-threatening consequences;urgent operative interventionindicated Death Definition: A disorder characterized by blockage of the normal flow of the intestinal contents in the rectum. Rectal pain Mild pain Moderate pain; limitinginstrumental ADL Severe pain; limiting self careADL Definition: A disorder characterized by a sensation of marked discomfort in the rectal region. Rectal perforation Symptomatic; medicalintervention indicated Severe symptoms; electiveoperative intervention indicated Life-threatening consequences;urgent operative interventionindicated Death Definition: A disorder characterized by a rupture in the rectal wall. Rectal stenosis Asymptomatic; clinical ordiagnostic observations only;intervention not indicated Symptomatic; altered GIfunction Severely altered GI function;tube feeding or hospitalizationindicated; elective operativeintervention indicated Life-threatening consequences;urgent operative interventionindicated Death Definition: A disorder characterized by a narrowing of the lumen of the rectum. Rectal ulcer Asymptomatic; clinical ordiagnostic observations only;intervention not indicated Symptomatic; altered GIfunction (e.g. altered dietaryhabits, vomiting, diarrhea) Severely altered GI function;TPN indicated; electiveoperative or endoscopicintervention indicated; disabling Life-threatening consequences;urgent operative interventionindicated Death Definition: A disorder characterized by a circumscribed, inflammatory and necrotic erosive lesion on the mucosal surface of the rectum.

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CTCAE 4.03 June 14, 2010 : Gastrointestinal disorders 20 Gastrointestinal disorders Grade Adverse Event 1 2 3 4 5 Retroperitoneal hemorrhage Self-limited; interventionindicated Transfusion, medical, radiologic,endoscopic, or electiveoperative intervention indicated Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by bleeding from the retroperitoneal area. Salivary duct inflammation Slightly thickened saliva; slightlyaltered taste (e.g., metallic) Thick, ropy, sticky saliva;markedly altered taste;alteration in diet indicated;secretion-induced symptoms;limiting instrumental ADL Acute salivary gland necrosis;severe secretion-inducedsymptoms (e.g., thick saliva/oralsecretions or gagging); tubefeeding or TPN indicated;limiting self care ADL; disabling Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by inflammation of the salivary duct. Salivary gland fistula Asymptomatic; clinical ordiagnostic observations only;intervention not indicated Symptomatic; altered GIfunction; tube feeding indicated Severely altered GI function;hospitalization indicated;elective operative interventionindicated Life-threatening consequences;urgent operative interventionindicated Death Definition: A disorder characterized by an abnormal communication between a salivary gland and another organ or anatomic site. Small intestinal mucositis Asymptomatic or mildsymptoms; intervention notindicated Symptomatic; medicalintervention indicated; limitinginstrumental ADL Severe pain; interfering with oralintake; tube feeding, TPN orhospitalization indicated; limitingself care ADL Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by inflammation of the mucous membrane of the small intestine. Small intestinal obstruction Asymptomatic; clinical ordiagnostic observations only;intervention not indicated Symptomatic; altered GIfunction; limiting instrumentalADL Hospitalization indicated;elective operative interventionindicated; limiting self care ADL;disabling Life-threatening consequences;urgent operative interventionindicated Death Definition: A disorder characterized by blockage of the normal flow of the intestinal contents. Small intestinal perforation Symptomatic; medicalintervention indicated Severe symptoms; electiveoperative intervention indicated Life-threatening consequences;urgent operative interventionindicated Death Definition: A disorder characterized by a rupture in the small intestine wall. Small intestinal stenosis Asymptomatic; clinical ordiagnostic observations only;intervention not indicated Symptomatic; altered GIfunction Symptomatic and severelyaltered GI function; tubefeeding, TPN or hospitalizationindicated; non-emergentoperative intervention indicated Life-threatening consequences;urgent operative interventionindicated Death Definition: A disorder characterized by a narrowing of the lumen of the small intestine. Small intestine ulcer Asymptomatic; clinical ordiagnostic observations only;intervention not indicated Symptomatic; altered GIfunction; limiting instrumentalADL Severely altered GI function;TPN indicated; electiveoperative or endoscopicintervention indicated; limitingself care ADL; disabling Life-threatening consequences;urgent operative interventionindicated Death Definition: A disorder characterized by a circumscribed, inflammatory and necrotic erosive lesion on the mucosal surface of the small intestine. Stomach pain Mild pain Moderate pain; limitinginstrumental ADL Severe pain; limiting self careADL Definition: A disorder characterized by a sensation of marked discomfort in the stomach. Tooth development disorder Asymptomatic; hypoplasia oftooth or enamel Impairment correctable with oralsurgery Maldevelopment withimpairment not surgicallycorrectable; disabling Definition: A disorder characterized by a pathological process of the teeth occurring during tooth development. Tooth discoloration Surface stains Definition: A disorder characterized by a change in tooth hue or tint. Toothache Mild pain Moderate pain; limitinginstrumental ADL Severe pain; limiting self careADL Definition: A disorder characterized by a sensation of marked discomfort in the tooth.

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CTCAE 4.03 June 14, 2010 : Gastrointestinal disorders 21 Gastrointestinal disorders Grade Adverse Event 1 2 3 4 5 Typhlitis Symptomatic (e.g., abdominalpain, fever, change in bowelhabits with ileus); peritonealsigns Life-threatening consequences;urgent operative interventionindicated Death Definition: A disorder characterized by inflammation of the cecum. Upper gastrointestinalhemorrhage Mild; intervention not indicated Moderate symptoms; medicalintervention or minorcauterization indicated Transfusion, radiologic,endoscopic, or electiveoperative intervention indicated Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by bleeding from the upper gastrointestinal tract (oral cavity, pharynx, esophagus, and stomach). Vomiting 1 2 episodes (separated by 5minutes) in 24 hrs 3 5 episodes (separated by 5minutes) in 24 hrs >=6 episodes (separated by 5minutes) in 24 hrs; tube feeding,TPN or hospitalization indicated Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by the reflexive act of ejecting the contents of the stomach through the mouth. Gastrointestinal disorders -Other, specify Asymptomatic or mildsymptoms; clinical or diagnosticobservations only; interventionnot indicated Moderate; minimal, local ornoninvasive interventionindicated; limiting age-appropriate instrumental ADL Severe or medically significantbut not immediately life-threatening; hospitalization orprolongation of existinghospitalization indicated;disabling; limiting self care ADL Life-threatening consequences;urgent intervention indicated Death

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CTCAE 4.03 June 14, 2010 : General disorders and administration site conditions 22 9. General disorders and administration site conditions General disorders and administration site conditions Grade Adverse Event 1 2 3 4 5 Chills Mild sensation of cold;shivering; chattering of teeth Moderate tremor of the entirebody; narcotics indicated Severe or prolonged, notresponsive to narcotics Definition: A disorder characterized by a sensation of cold that often marks a physiologic response to sweating after a fever. Death neonatal Death Definition: A disorder characterized by cessation of life occurring during the first 28 days of life. Death NOS Death Definition: A cessation of life that cannot be attributed to a CTCAE term associated with Grade 5. Edema face Localized facial edema Moderate localized facialedema; limiting instrumentalADL Severe swelling; limiting selfcare ADL Definition: A disorder characterized by swelling due to excessive fluid accumulation in facial tissues. Edema limbs 5 10% inter-limb discrepancyin volume or circumference atpoint of greatest visibledifference; swelling orobscuration of anatomicarchitecture on close inspection >10 30% inter-limbdiscrepancy in volume orcircumference at point ofgreatest visible difference;readily apparent obscuration ofanatomic architecture;obliteration of skin folds; readilyapparent deviation from normalanatomic contour; limitinginstrumental ADL >30% inter-limb discrepancy involume; gross deviation fromnormal anatomic contour;limiting self care ADL Definition: A disorder characterized by swelling due to excessive fluid accumulation in the upper or lower extremities. Edema trunk Swelling or obscuration ofanatomic architecture on closeinspection Readily apparent obscuration ofanatomic architecture;obliteration of skin folds; readilyapparent deviation from normalanatomic contour; limitinginstrumental ADL Gross deviation from normalanatomic contour; limiting selfcare ADL Definition: A disorder characterized by swelling due to excessive fluid accumulation in the trunk area. Facial pain Mild pain Moderate pain; limitinginstrumental ADL Severe pain; limiting self careADL Definition: A disorder characterized by a sensation of marked discomfort in the face. Fatigue Fatigue relieved by rest Fatigue not relieved by rest;limiting instrumental ADL Fatigue not relieved by rest,limiting self care ADL Definition: A disorder characterized by a state of generalized weakness with a pronounced inability to summon sufficient energy to accomplish daily activities. Fever 38.0 39.0 degrees C (100.4 -102.2 degrees F) >39.0 40.0 degrees C (102.3 -104.0 degrees F) >40.0 degrees C (>104.0degrees F) for <=24 hrs >40.0 degrees C (>104.0degrees F) for >24 hrs Death Definition: A disorder characterized by elevation of the body's temperature above the upper limit of normal. Flu like symptoms Mild flu-like symptoms present Moderate symptoms; limitinginstrumental ADL Severe symptoms; limiting selfcare ADL Definition: A disorder characterized by a group of symptoms similar to those observed in patients with the flu. It includes fever, chills, body aches, malaise, loss of appetite and drycough. Gait disturbance Mild change in gait (e.g., wide-based, limping or hobbling) Moderate change in gait (e.g.,wide-based, limping orhobbling); assistive deviceindicated; limiting instrumentalADL Disabling; limiting self care ADL Definition: A disorder characterized by walking difficulties. Hypothermia 35 >32 degrees C; 95 >89.6degrees F 32 >28 degrees C; 89.6 ->82.4 degrees F <=28 degrees C; 82.4 degreesF; life-threateningconsequences (e.g., coma,hypotension, pulmonary edema,acidemia, ventricular fibrillation) Death Definition: A disorder characterized by an abnormally low body temperature. Treatment is required when the body temperature is 35C (95F) or below.

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CTCAE 4.03 June 14, 2010 : General disorders and administration site conditions 23 General disorders and administration site conditions Grade Adverse Event 1 2 3 4 5 Infusion related reaction Mild transient reaction; infusioninterruption not indicated;intervention not indicated Therapy or infusion interruptionindicated but responds promptlyto symptomatic treatment (e.g.,antihistamines, NSAIDS,narcotics, IV fluids); prophylacticmedications indicated for <=24hrs Prolonged (e.g., not rapidlyresponsive to symptomaticmedication and/or briefinterruption of infusion);recurrence of symptomsfollowing initial improvement;hospitalization indicated forclinical sequelae Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by adverse reaction to the infusion of pharmacological or biological substances. Infusion site extravasation Erythema with associatedsymptoms (e.g., edema, pain,induration, phlebitis) Ulceration or necrosis; severetissue damage; operativeintervention indicated Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by leakage of a pharmacologic or a biologic substance from the infusion site into the surrounding tissue. Signs and symptoms include induration,erythema, swelling, burning sensation and marked discomfort at the infusion site. Injection site reaction Tenderness with or withoutassociated symptoms (e.g.,warmth, erythema, itching) Pain; lipodystrophy; edema;phlebitis Ulceration or necrosis; severetissue damage; operativeintervention indicated Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by an intense adverse reaction (usually immunologic) developing at the site of an injection. Irritability Mild; easily consolable Moderate; limiting instrumentalADL; increased attentionindicated Severe abnormal or excessiveresponse; limiting self care ADL;inconsolable Definition: A disorder characterized by an abnormal responsiveness to stimuli or physiological arousal; may be in response to pain, fright, a drug, an emotional situation or a medicalcondition. Localized edema Localized to dependent areas,no disability or functionalimpairment Moderate localized edema andintervention indicated; limitinginstrumental ADL Severe localized edema andintervention indicated; limitingself care ADL Definition: A disorder characterized by swelling due to excessive fluid accumulation at a specific anatomic site. Malaise Uneasiness or lack of well being Uneasiness or lack of wellbeing; limiting instrumental ADL Definition: A disorder characterized by a feeling of general discomfort or uneasiness, an out-of-sorts feeling. Multi-organ failure Shock with azotemia and acid-base disturbances; significantcoagulation abnormalities Life-threatening consequences(e.g., vasopressor dependentand oliguric or anuric orischemic colitis or lacticacidosis) Death Definition: A disorder characterized by progressive deterioration of the lungs, liver, kidney and clotting mechanisms. Neck edema Asymptomatic localized neckedema Moderate neck edema; slightobliteration of anatomiclandmarks; limiting instrumentalADL Generalized neck edema (e.g.,difficulty in turning neck);limiting self care ADL Definition: A disorder characterized by swelling due to an accumulation of excessive fluid in the neck. Non-cardiac chest pain Mild pain Moderate pain; limitinginstrumental ADL Severe pain; limiting self careADL Definition: A disorder characterized by discomfort in the chest unrelated to a heart disorder. Pain Mild pain Moderate pain; limitinginstrumental ADL Severe pain; limiting self careADL Definition: A disorder characterized by the sensation of marked discomfort, distress or agony. Sudden death NOS Death Definition: An unexpected cessation of life that cannot be attributed to a CTCAE term associated with Grade 5. General disorders andadministration site conditions -Other, specify Asymptomatic or mildsymptoms; clinical or diagnosticobservations only; interventionnot indicated Moderate; minimal, local ornoninvasive interventionindicated; limiting age-appropriate instrumental ADL Severe or medically significantbut not immediately life-threatening; hospitalization orprolongation of existinghospitalization indicated;disabling; limiting self care ADL Life-threatening consequences;urgent intervention indicated Death

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CTCAE 4.03 June 14, 2010 : Hepatobiliary disorders 24 10. Hepatobiliary disorders Hepatobiliary disorders Grade Adverse Event 1 2 3 4 5 Bile duct stenosis Asymptomatic; clinical ordiagnostic observations only;intervention not indicated Symptomatic; altered GIfunction; IV fluids indicated <24hrs Severely altered GI function;radiologic, endoscopic orelective operative interventionindicated Life-threatening consequences;urgent operative interventionindicated Death Definition: A disorder characterized by a narrowing of the lumen of the bile duct. Biliary fistula Symptomatic and interventionnot indicated Severely altered GI function;TPN indicated; endoscopicintervention indicated; electiveoperative intervention indicated Life-threatening consequences;urgent operative interventionindicated Death Definition: A disorder characterized by an abnormal communication between the bile ducts and another organ or anatomic site. Cholecystitis Symptomatic; medicalintervention indicated Severe symptoms; radiologic,endoscopic or elective operativeintervention indicated Life-threatening consequences;urgent operative interventionindicated Death Definition: A disorder characterized by inflammation involving the gallbladder. It may be associated with the presence of gallstones. Gallbladder fistula Asymptomatic clinical ordiagnostic observations only;intervention not indicated Symptomatic and interventionnot indicated Symptomatic or severely alteredGI function; TPN indicated;radiologic, endoscopic orelective operative interventionindicated Life-threatening consequences;urgent operative interventionindicated Death Definition: A disorder characterized by an abnormal communication between the gallbladder and another organ or anatomic site. Gallbladder necrosis Life-threatening consequences;urgent radiologic or operativeintervention indicated Death Definition: A disorder characterized by a necrotic process occurring in the gallbladder. Gallbladder obstruction Asymptomatic; clinical ordiagnostic observations only;intervention not indicated Symptomatic; altered GIfunction; IV fluids indicated <24hrs Symptomatic and severelyaltered GI function; tubefeeding, TPN or hospitalizationindicated; non-emergentoperative intervention indicated Life-threatening consequences;urgent operative interventionindicated Death Definition: A disorder characterized by blockage of the normal flow of the contents of the gallbladder. Gallbladder pain Mild pain Moderate pain; limitinginstrumental ADL Severe pain; limiting self careADL Definition: A disorder characterized by a sensation of marked discomfort in the gallbladder region. Gallbladder perforation Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by a rupture in the gallbladder wall. Hepatic failure Asterixis; mild encephalopathy;limiting self care ADL Moderate to severeencephalopathy; coma; life-threatening consequences Death Definition: A disorder characterized by the inability of the liver to metabolize chemicals in the body. Laboratory test results reveal abnormal plasma levels of ammonia, bilirubin, lacticdehydrogenase, and alkaline phosphatase. Hepatic hemorrhage Mild; intervention not indicated Symptomatic; medicalintervention indicated Transfusion indicated Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by bleeding from the liver. Hepatic necrosis Life-threatening consequences;urgent radiologic or operativeintervention indicated Death Definition: A disorder characterized by a necrotic process occurring in the hepatic parenchyma. Hepatic pain Mild pain Moderate pain; limitinginstrumental ADL Severe pain; limiting self careADL Definition: A disorder characterized by a sensation of marked discomfort in the liver region. Perforation bile duct Radiologic, endoscopic orelective operative interventionindicated Life-threatening consequences;urgent operative interventionindicated Death Definition: A disorder characterized by a rupture in the wall of the extrahepatic or intrahepatic bile duct.

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CTCAE 4.03 June 14, 2010 : Hepatobiliary disorders 25 Hepatobiliary disorders Grade Adverse Event 1 2 3 4 5 Portal hypertension Decreased portal vein flow Reversal/retrograde portal veinflow; associated with varicesand/or ascites Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by an increase in blood pressure in the portal venous system. Portal vein thrombosis Intervention not indicated Medical intervention indicated Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by the formation of a thrombus (blood clot) in the portal vein. Hepatobiliary disorders Other,specify Asymptomatic or mildsymptoms; clinical or diagnosticobservations only; interventionnot indicated Moderate; minimal, local ornoninvasive interventionindicated; limiting age-appropriate instrumental ADL Severe or medically significantbut not immediately life-threatening; hospitalization orprolongation of existinghospitalization indicated;disabling; limiting self care ADL Life-threatening consequences;urgent intervention indicated Death

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CTCAE 4.03 June 14, 2010 : Immune system disorders 26 11. Immune system disorders Immune system disorders Grade Adverse Event 1 2 3 4 5 Allergic reaction Transient flushing or rash, drugfever <38 degrees C (<100.4degrees F); intervention notindicated Intervention or infusioninterruption indicated; respondspromptly to symptomatictreatment (e.g., antihistamines,NSAIDS, narcotics);prophylactic medicationsindicated for <=24 hrs Prolonged (e.g., not rapidlyresponsive to symptomaticmedication and/or briefinterruption of infusion);recurrence of symptomsfollowing initial improvement;hospitalization indicated forclinical sequelae (e.g., renalimpairment, pulmonaryinfiltrates) Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by an adverse local or general response from exposure to an allergen. Anaphylaxis Symptomatic bronchospasm,with or without urticaria;parenteral interventionindicated; allergy-relatededema/angioedema;hypotension Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by an acute inflammatory reaction resulting from the release of histamine and histamine-like substances from mast cells, causing a hypersensitivityimmune response. Clinically, it presents with breathing difficulty, dizziness, hypotension, cyanosis and loss of consciousness and may lead to death. Autoimmune disorder Asymptomatic; serologic orother evidence of autoimmunereaction, with normal organfunction; intervention notindicated Evidence of autoimmunereaction involving a non-essential organ or function (e.g.,hypothyroidism) Autoimmune reactions involvingmajor organ (e.g., colitis,anemia, myocarditis, kidney) Life-threatening consequences;urgent intervention indicated Death Definition: A disorder resulting from loss of function or tissue destruction of an organ or multiple organs, arising from humoral or cellular immune responses of the individual to his owntissue constituents. Cytokine release syndrome Mild reaction; infusioninterruption not indicated;intervention not indicated Therapy or infusion interruptionindicated but responds promptlyto symptomatic treatment (e.g.,antihistamines, NSAIDS,narcotics, IV fluids); prophylacticmedications indicated for <=24hrs Prolonged (e.g., not rapidlyresponsive to symptomaticmedication and/or briefinterruption of infusion);recurrence of symptomsfollowing initial improvement;hospitalization indicated forclinical sequelae (e.g., renalimpairment, pulmonaryinfiltrates) Life-threatening consequences;pressor or ventilatory supportindicated Death Definition: A disorder characterized by nausea, headache, tachycardia, hypotension, rash, and shortness of breath; it is caused by the release of cytokines from the cells. Serum sickness Asymptomatic; clinical ordiagnostic observations only;intervention not indicated Moderate arthralgia; fever, rash,urticaria, antihistaminesindicated Severe arthralgia or arthritis;extensive rash; steroids or IVfluids indicated Life-threatening consequences;pressor or ventilatory supportindicated Death Definition: A disorder characterized by a delayed-type hypersensitivity reaction to foreign proteins derived from an animal serum. It occurs approximately six to twenty-one daysfollowing the administration of the foreign antigen. Symptoms include fever, arthralgias, myalgias, skin eruptions, lymphadenopathy, chest marked discomfort and dyspnea. Immune system disorders -Other, specify Asymptomatic or mildsymptoms; clinical or diagnosticobservations only; interventionnot indicated Moderate; minimal, local ornoninvasive interventionindicated; limiting age-appropriate instrumental ADL Severe or medically significantbut not immediately life-threatening; hospitalization orprolongation of existinghospitalization indicated;disabling; limiting self care ADL Life-threatening consequences;urgent intervention indicated Death

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CTCAE 4.03 June 14, 2010 : Infections and infestations 27 12. Infections and infestations Infections and infestations Grade Adverse Event 1 2 3 4 5 Abdominal infection IV antibiotic, antifungal, orantiviral intervention indicated;radiologic or operativeintervention indicated Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by an infectious process involving the abdominal cavity. Anorectal infection Localized; local interventionindicated Oral intervention indicated (e.g.,antibiotic, antifungal, antiviral) IV antibiotic, antifungal, orantiviral intervention indicated;radiologic, endoscopic, oroperative intervention indicated Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by an infectious process involving the anal area and the rectum. Appendicitis IV antibiotic, antifungal, orantiviral intervention indicated;radiologic or operativeintervention indicated Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by acute inflammation to the vermiform appendix caused by a pathogenic agent. Appendicitis perforated Symptomatic; medicalintervention indicated Severe symptoms; electiveoperative intervention indicated Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by acute inflammation to the vermiform appendix caused by a pathogenic agent with gangrenous changes resulting in the rupture of theappendiceal wall. The appendiceal wall rupture causes the release of inflammatory and bacterial contents from the appendiceal lumen into the abdominal cavity. Arteritis infective IV antibiotic, antifungal, orantiviral intervention indicated;radiologic or operativeintervention indicated Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by an infectious process involving an artery. Biliary tract infection IV antibiotic, antifungal, orantiviral intervention indicated;radiologic or operativeintervention indicated Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by an infectious process involving the biliary tract. Bladder infection Oral intervention indicated (e.g.,antibiotic, antifungal, antiviral) IV antibiotic, antifungal, orantiviral intervention indicated;radiologic, endoscopic, oroperative intervention indicated Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by an infectious process involving the bladder. Bone infection IV antibiotic, antifungal, orantiviral intervention indicated;radiologic or operativeintervention indicated Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by an infectious process involving the bones. Breast infection Local infection with moderatesymptoms; oral interventionindicated (e.g., antibiotic,antifungal, antiviral) Severe infection; axillaryadenitis; IV antibacterial,antifungal, or antiviralintervention indicated Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by an infectious process involving the breast. Bronchial infection Moderate symptoms; oralintervention indicated (e.g.,antibiotic, antifungal, antiviral) IV antibiotic, antifungal, orantiviral intervention indicated;radiologic, endoscopic, oroperative intervention indicated Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by an infectious process involving the bronchi. Catheter related infection Localized; local interventionindicated; oral interventionindicated (e.g., antibiotic,antifungal, antiviral) IV antibiotic, antifungal, orantiviral intervention indicated;radiologic or operativeintervention indicated Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by an infectious process that arises secondary to catheter use. Cecal infection IV antibiotic, antifungal, orantiviral intervention indicated;radiologic, endoscopic, oroperative intervention indicated Life-threatening consequences;urgent intervention indicated Death

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CTCAE 4.03 June 14, 2010 : Infections and infestations 28 Infections and infestations Grade Adverse Event 1 2 3 4 5 Definition: A disorder characterized by an infectious process involving the cecum. Cervicitis infection Localized; local interventionindicated (e.g., topical antibiotic,antifungal, or antiviral) IV antibiotic, antifungal, orantiviral intervention indicated;radiologic or operativeintervention indicated Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by an infectious process involving the uterine cervix. Conjunctivitis infective Localized; local interventionindicated (e.g., topical antibiotic,antifungal, or antiviral) IV antibiotic, antifungal, orantiviral intervention indicated;radiologic or operativeintervention indicated Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by an infectious process involving the conjunctiva. Clinical manifestations include pink or red color in the eyes. Corneal infection Localized; local interventionindicated (e.g., topical antibiotic,antifungal, or antiviral) IV antibiotic, antifungal, orantiviral intervention indicated;radiologic or operativeintervention indicated Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by an infectious process involving the cornea. Cranial nerve infection IV antibiotic, antifungal, orantiviral intervention indicated;radiologic or operativeintervention indicated Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by an infectious process involving a cranial nerve. Device related infection IV antibiotic, antifungal, orantiviral intervention indicated;radiologic or operativeintervention indicated Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by an infectious process involving the use of a medical device. Duodenal infection Moderate symptoms; medicalintervention indicated (e.g., oralantibiotics) IV antibiotic, antifungal, orantiviral intervention indicated;radiologic or operativeintervention indicated Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by an infectious process involving the duodenum. Encephalitis infection IV antibiotic, antifungal, orantiviral intervention indicated;severe changes in mentalstatus; self-limited seizureactivity; focal neurologicabnormalities Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by an infectious process involving the brain tissue. Encephalomyelitis infection IV antibiotic, antifungal, orantiviral intervention indicated;radiologic or operativeintervention indicated Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by an infectious process involving the brain and spinal cord tissues. Endocarditis infective IV antibiotic, antifungal, orantiviral intervention indicated;radiologic or operativeintervention indicated Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by an infectious process involving the endocardial layer of the heart. Endophthalmitis Local intervention indicated Systemic intervention orhospitalization indicated Blindness (20/200 or worse) Definition: A disorder characterized by an infectious process involving the internal structures of the eye.

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CTCAE 4.03 June 14, 2010 : Infections and infestations 29 Infections and infestations Grade Adverse Event 1 2 3 4 5 Enterocolitis infectious Passage of >3 unformed stoolsper 24 hrs or duration of illness>48 hrs; moderate abdominalpain IV antibiotic, antifungal, orantiviral intervention indicated;radiologic, endoscopic, oroperative intervention indicated;profuse watery diarrhea withsigns of hypovolemia; bloodydiarrhea; fever; severeabdominal pain; hospitalizationindicated Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by an infectious process involving the small and large intestines. Esophageal infection Local intervention indicated(e.g., oral antibiotic, antifungal,antiviral) IV antibiotic, antifungal, orantiviral intervention indicated;radiologic or operativeintervention indicated Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by an infectious process involving the esophagus. Eye infection Localized; local interventionindicated (e.g., topical antibiotic,antifungal, or antiviral) IV antibiotic, antifungal, orantiviral intervention indicated;radiologic or operativeintervention indicated Life-threatening consequences;urgent intervention indicated;enucleation Death Definition: A disorder characterized by an infectious process involving the eye. Gallbladder infection IV antibiotic, antifungal, orantiviral intervention indicated;radiologic, endoscopic, oroperative intervention indicated Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by an infectious process involving the gallbladder. Gum infection Local therapy indicated (swishand swallow) Moderate symptoms; oralintervention indicated (e.g.,antibiotic, antifungal, antiviral) IV antibiotic, antifungal, orantiviral intervention indicated;radiologic or operativeintervention indicated Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by an infectious process involving the gums. Hepatic infection IV antibiotic, antifungal, orantiviral intervention indicated;radiologic or operativeintervention indicated Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by an infectious process involving the liver. Hepatitis viral Asymptomatic, treatment notindicated Symptomatic liver dysfunction;fibrosis by biopsy; compensatedcirrhosis; reactivation of chronichepatitis Decompensated liver function(e.g., ascites, coagulopathy,encephalopathy, coma) Death Definition: A disorder characterized by a viral pathologic process involving the liver parenchyma. Infective myositis Localized; local interventionindicated (e.g., topical antibiotic,antifungal, or antiviral) IV antibiotic, antifungal, orantiviral intervention indicated;radiologic or operativeintervention indicated Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by an infectious process involving the skeletal muscles. Joint infection Localized; local interventionindicated; oral interventionindicated (e.g., antibiotic,antifungal, antiviral); needleaspiration indicated (single ormultiple) Arthroscopic interventionindicated (e.g., drainage) orarthrotomy (e.g., open surgicaldrainage) Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by an infectious process involving a joint. Kidney infection IV antibiotic, antifungal, orantiviral intervention indicated;radiologic, endoscopic, oroperative intervention indicated Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by an infectious process involving the kidney.

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CTCAE 4.03 June 14, 2010 : Infections and infestations 30 Infections and infestations Grade Adverse Event 1 2 3 4 5 Laryngitis Moderate symptoms; oralintervention indicated (e.g.,antibiotic, antifungal, antiviral) IV antibiotic, antifungal, orantiviral intervention indicated;radiologic or operativeintervention indicated Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by an inflammatory process involving the larynx. Lip infection Localized, local interventionindicated Oral intervention indicated (e.g.,antibiotic, antifungal, antiviral) IV antibiotic, antifungal, orantiviral intervention indicated;radiologic or operativeintervention indicated Definition: A disorder characterized by an infectious process involving the lips. Lung infection Moderate symptoms; oralintervention indicated (e.g.,antibiotic, antifungal, antiviral) IV antibiotic, antifungal, orantiviral intervention indicated;radiologic, endoscopic, oroperative intervention indicated Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by an infectious process involving the lungs. Lymph gland infection Localized; local interventionindicated (e.g., topical antibiotic,antifungal, or antiviral) IV antibiotic, antifungal, orantiviral intervention indicated;radiologic or operativeintervention indicated Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by an infectious process involving the lymph nodes. Mediastinal infection IV antibiotic, antifungal, orantiviral intervention indicated;radiologic or operativeintervention indicated Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by an infectious process involving the mediastinum. Meningitis IV antibiotic, antifungal, orantiviral intervention indicated;radiologic or operativeintervention indicated; focalneurologic deficit Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by acute inflammation of the meninges of the brain and/or spinal cord. Mucosal infection Localized, local interventionindicated Oral intervention indicated (e.g.,antibiotic, antifungal, antiviral) IV antibiotic, antifungal, orantiviral intervention indicated;radiologic or operativeintervention indicated Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by an infectious process involving a mucosal surface. Nail infection Localized, local interventionindicated Oral intervention indicated (e.g.,antibiotic, antifungal, antiviral) IV antibiotic, antifungal, orantiviral intervention indicated;radiologic or operativeintervention indicated Definition: A disorder characterized by an infectious process involving the nail. Otitis externa Localized; local interventionindicated (e.g., topical antibiotic,antifungal, or antiviral) IV antibiotic, antifungal, orantiviral intervention indicated;radiologic or operativeintervention indicated Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by an infectious process involving the outer ear and ear canal. Contributory factors include excessive water exposure (swimmer's ear infection)and cuts in the ear canal. Symptoms include fullness, itching, swelling and marked discomfort in the ear and ear drainage. Otitis media Localized; local interventionindicated (e.g., topical antibiotic,antifungal, or antiviral) IV antibiotic, antifungal, orantiviral intervention indicated;radiologic or operativeintervention indicated Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by an infectious process involving the middle ear. Ovarian infection Localized; local interventionindicated (e.g., topical antibiotic,antifungal, or antiviral) IV antibiotic, antifungal, orantiviral intervention indicated;radiologic or operativeintervention indicated Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by an infectious process involving the ovary.

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CTCAE 4.03 June 14, 2010 : Infections and infestations 31 Infections and infestations Grade Adverse Event 1 2 3 4 5 Pancreas infection IV antibiotic, antifungal, orantiviral intervention indicated;radiologic or operativeintervention indicated Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by an infectious process involving the pancreas. Papulopustular rash Papules and/or pustulescovering <10% BSA, which mayor may not be associated withsymptoms of pruritus ortenderness Papules and/or pustulescovering 10-30% BSA, whichmay or may not be associatedwith symptoms of pruritus ortenderness; associated withpsychosocial impact; limitinginstrumental ADL Papules and/or pustulescovering >30% BSA, which mayor may not be associated withsymptoms of pruritus ortenderness; limiting self-careADL; associated with localsuperinfection with oralantibiotics indicated Papules and/or pustulescovering any % BSA, whichmay or may not be associatedwith symptoms of pruritus ortenderness and are associatedwith extensive superinfectionwith IV antibiotics indicated; life-threatening consequences Death Definition: A disorder characterized by an eruption consisting of papules (a small, raised pimple) and pustules (a small pus filled blister), typically appearing in face, scalp, and upperchest and back Unlike acne, this rash does not present with whiteheads or blackheads, and can be symptomatic, with itchy or tender lesions. Paronychia Nail fold edema or erythema;disruption of the cuticle Localized intervention indicated;oral intervention indicated (e.g.,antibiotic, antifungal, antiviral);nail fold edema or erythemawith pain; associated withdischarge or nail plateseparation; limiting instrumentalADL Surgical intervention or IVantibiotics indicated; limiting selfcare ADL Definition: A disorder characterized by an infectious process involving the soft tissues around the nail. Pelvic infection Moderate symptoms; oralintervention indicated (e.g.,antibiotic, antifungal, antiviral) IV antibiotic, antifungal, orantiviral intervention indicated;radiologic or operativeintervention indicated Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by an infectious process involving the pelvic cavity. Penile infection Localized; local interventionindicated (e.g., topical antibiotic,antifungal, or antiviral) IV antibiotic, antifungal, orantiviral intervention indicated;radiologic or operativeintervention indicated Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by an infectious process involving the penis. Periorbital infection Localized; local interventionindicated (e.g., topical antibiotic,antifungal, or antiviral) IV antibiotic, antifungal, orantiviral intervention indicated;radiologic or operativeintervention indicated Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by an infectious process involving the orbit of the eye. Peripheral nerve infection Localized; local interventionindicated (e.g., topical antibiotic,antifungal, or antiviral) IV antibiotic, antifungal, orantiviral intervention indicated;radiologic or operativeintervention indicated Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by an infectious process involving the peripheral nerves. Peritoneal infection IV antibiotic, antifungal, orantiviral intervention indicated;radiologic, endoscopic, oroperative intervention indicated Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by an infectious process involving the peritoneum. Pharyngitis Localized; local interventionindicated (e.g., topical antibiotic,antifungal, or antiviral) IV antibiotic, antifungal, orantiviral intervention indicated;radiologic or operativeintervention indicated Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by inflammation of the throat. Phlebitis infective Localized; local interventionindicated (e.g., topical antibiotic,antifungal, or antiviral) IV antibiotic, antifungal, orantiviral intervention indicated;radiologic or operativeintervention indicated Life-threatening consequences;urgent intervention indicated Death

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CTCAE 4.03 June 14, 2010 : Infections and infestations 32 Infections and infestations Grade Adverse Event 1 2 3 4 5 Definition: A disorder characterized by an infectious process involving the vein. Clinical manifestations include erythema, marked discomfort, swelling, and induration along the courseof the infected vein. Pleural infection Localized; local interventionindicated (e.g., topical antibiotic,antifungal, or antiviral) IV antibiotic, antifungal, orantiviral intervention indicated;radiologic, endoscopic, oroperative intervention indicated Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by an infectious process involving the pleura. Prostate infection Moderate symptoms; oralintervention indicated (e.g.,antibiotic, antifungal, antiviral) IV antibiotic, antifungal, orantiviral intervention indicated;radiologic, endoscopic, oroperative intervention indicated Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by an infectious process involving the prostate gland. Rash pustular Localized; local interventionindicated (e.g., topical antibiotic,antifungal, or antiviral) IV antibiotic, antifungal, orantiviral intervention indicated;radiologic or operativeintervention indicated Definition: A disorder characterized by a circumscribed and elevated skin lesion filled with pus. Rhinitis infective Localized; local interventionindicated (e.g., topical antibiotic,antifungal, or antiviral) Definition: A disorder characterized by an infectious process involving the nasal mucosal. Salivary gland infection Moderate symptoms; oralintervention indicated (e.g.,antibiotic, antifungal, antiviral) IV antibiotic, antifungal, orantiviral intervention indicated;radiologic or operativeintervention indicated Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by an infectious process involving the salivary gland. Scrotal infection Localized; local interventionindicated (e.g., topical antibiotic,antifungal, or antiviral) IV antibiotic, antifungal, orantiviral intervention indicated;radiologic or operativeintervention indicated Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by an infectious process involving the scrotum. Sepsis Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by the presence of pathogenic microorganisms in the blood stream that cause a rapidly progressing systemic reaction that may lead to shock. Sinusitis Localized; local interventionindicated (e.g., topical antibiotic,antifungal, or antiviral) IV antibiotic, antifungal, orantiviral intervention indicated;radiologic, endoscopic, oroperative intervention indicated Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by an infectious process involving the mucous membranes of the paranasal sinuses. Skin infection Localized, local interventionindicated Oral intervention indicated (e.g.,antibiotic, antifungal, antiviral) IV antibiotic, antifungal, orantiviral intervention indicated;radiologic or operativeintervention indicated Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by an infectious process involving the skin. Small intestine infection Moderate symptoms; oralintervention indicated (e.g.,antibiotic, antifungal, antiviral) IV antibiotic, antifungal, orantiviral intervention indicated;radiologic or operativeintervention indicated Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by an infectious process involving the small intestine. Soft tissue infection Localized; local interventionindicated (e.g., topical antibiotic,antifungal, or antiviral) IV antibiotic, antifungal, orantiviral intervention indicated;radiologic or operativeintervention indicated Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by an infectious process involving soft tissues. Splenic infection IV antibiotic, antifungal, orantiviral intervention indicated;radiologic or operativeintervention indicated Life-threatening consequences;urgent intervention indicated Death

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CTCAE 4.03 June 14, 2010 : Infections and infestations 33 Infections and infestations Grade Adverse Event 1 2 3 4 5 Definition: A disorder characterized by an infectious process involving the spleen. Stoma site infection Localized, local interventionindicated Oral intervention indicated (e.g.,antibiotic, antifungal, antiviral) IV antibiotic, antifungal, orantiviral intervention indicated;radiologic, endoscopic, oroperative intervention indicated Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by an infectious process involving a stoma (surgically created opening on the surface of the body). Tooth infection Localized; local interventionindicated (e.g., topical antibiotic,antifungal, or antiviral) IV antibiotic, antifungal, orantiviral intervention indicated;radiologic or operativeintervention indicated Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by an infectious process involving a tooth. Tracheitis Moderate symptoms; oralintervention indicated (e.g.,antibiotic, antifungal, antiviral) IV antibiotic, antifungal, orantiviral intervention indicated;radiologic, endoscopic, oroperative intervention indicated Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by an infectious process involving the trachea. Upper respiratory infection Moderate symptoms; oralintervention indicated (e.g.,antibiotic, antifungal, antiviral) IV antibiotic, antifungal, orantiviral intervention indicated;radiologic, endoscopic, oroperative intervention indicated Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by an infectious process involving the upper respiratory tract (nose, paranasal sinuses, pharynx, larynx, or trachea). Urethral infection Localized; local interventionindicated (e.g., topical antibiotic,antifungal, or antiviral) IV antibiotic, antifungal, orantiviral intervention indicated;radiologic, endoscopic, oroperative intervention indicated Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by an infectious process involving the urethra. Urinary tract infection Localized; local interventionindicated (e.g., topical antibiotic,antifungal, or antiviral) IV antibiotic, antifungal, orantiviral intervention indicated;radiologic or operativeintervention indicated Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by an infectious process involving the urinary tract, most commonly the bladder and the urethra. Uterine infection Moderate symptoms; oralintervention indicated (e.g.,antibiotic, antifungal, antiviral) IV antibiotic, antifungal, orantiviral intervention indicated;radiologic or operativeintervention indicated Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by an infectious process involving the endometrium. It may extend to the myometrium and parametrial tissues. Vaginal infection Localized; local interventionindicated (e.g., topical antibiotic,antifungal, or antiviral) IV antibiotic, antifungal, orantiviral intervention indicated;radiologic or operativeintervention indicated Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by an infectious process involving the vagina. Vulval infection Localized, local interventionindicated Oral intervention indicated (e.g.,antibiotic, antifungal, antiviral) IV antibiotic, antifungal, orantiviral intervention indicated;radiologic or operativeintervention indicated Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by an infectious process involving the vulva. Wound infection Localized; local interventionindicated (e.g., topical antibiotic,antifungal, or antiviral) IV antibiotic, antifungal, orantiviral intervention indicated;radiologic or operativeintervention indicated Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by an infectious process involving the wound. Infections and infestations -Other, specify Asymptomatic or mildsymptoms; clinical or diagnosticobservations only; interventionnot indicated Moderate; minimal, local ornoninvasive interventionindicated; limiting age-appropriate instrumental ADL Severe or medically significantbut not immediately life-threatening; hospitalization orprolongation of existinghospitalization indicated;disabling; limiting self care ADL Life-threatening consequences;urgent intervention indicated Death

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CTCAE 4.03 June 14, 2010 : Injury, poisoning and procedural complications 34 13. Injury, poisoning and procedural complications Injury, poisoning and procedural complications Grade Adverse Event 1 2 3 4 5 Ankle fracture Mild; non-surgical interventionindicated Limiting instrumental ADL;operative intervention indicated Limiting self care ADL; electivesurgery indicated Definition: A finding of damage to the ankle joint characterized by a break in the continuity of the ankle bone. Symptoms include marked discomfort, swelling and difficulty moving theaffected leg and foot. Aortic injury Severe symptoms; limiting selfcare ADL; disabling; repair orrevision indicated Life-threatening consequences;evidence of end organ damage;urgent operative interventionindicated Death Definition: A finding of damage to the aorta. Arterial injury Asymptomatic diagnosticfinding; intervention notindicated Symptomatic (e.g.,claudication); repair or revisionnot indicated Severe symptoms; limiting selfcare ADL; disabling; repair orrevision indicated Life-threatening consequences;evidence of end organ damage;urgent operative interventionindicated Death Definition: A finding of damage to an artery. Biliary anastomotic leak Asymptomatic diagnosticobservations only; interventionnot indicated Symptomatic; medicalintervention indicated Severe symptoms; radiologic,endoscopic or elective operativeintervention indicated Life-threatening consequences;urgent operative interventionindicated Death Definition: A finding of leakage of bile due to breakdown of a biliary anastomosis (surgical connection of two separate anatomic structures). Bladder anastomotic leak Asymptomatic diagnosticobservations only; interventionnot indicated Symptomatic; medicalintervention indicated Severe symptoms; radiologic,endoscopic or elective operativeintervention indicated Life-threatening consequences;urgent operative interventionindicated Death Definition: A finding of leakage of urine due to breakdown of a bladder anastomosis (surgical connection of two separate anatomic structures). Bruising Localized or in a dependentarea Generalized Definition: A finding of injury of the soft tissues or bone characterized by leakage of blood into surrounding tissues. Burn Minimal symptoms; interventionnot indicated Medical intervention; minimaldebridement indicated Moderate to major debridementor reconstruction indicated Life-threatening consequences Death Definition: A finding of impaired integrity to the anatomic site of an adverse thermal reaction. Burns can be caused by exposure to chemicals, direct heat, electricity, flames andradiation. The extent of damage depends on the length and intensity of exposure and time until provision of treatment. Dermatitis radiation Faint erythema or drydesquamation Moderate to brisk erythema;patchy moist desquamation,mostly confined to skin foldsand creases; moderate edema Moist desquamation in areasother than skin folds andcreases; bleeding induced byminor trauma or abrasion Life-threatening consequences;skin necrosis or ulceration of fullthickness dermis; spontaneousbleeding from involved site; skingraft indicated Death Definition: A finding of cutaneous inflammatory reaction occurring as a result of exposure to biologically effective levels of ionizing radiation. Esophageal anastomotic leak Asymptomatic diagnosticobservations only; interventionnot indicated Symptomatic; medicalintervention indicated Severe symptoms; radiologic,endoscopic or elective operativeintervention indicated Life-threatening consequences;urgent operative interventionindicated Death Definition: A finding of leakage due to breakdown of an esophageal anastomosis (surgical connection of two separate anatomic structures). Fall Minor with no resultant injuries;intervention not indicated Symptomatic; noninvasiveintervention indicated Hospitalization indicated Definition: A finding of sudden movement downward, usually resulting in injury. Fallopian tube anastomotic leak Asymptomatic; clinical ordiagnostic observations only;intervention not indicated Symptomatic; medicalintervention indicated Severe symptoms; radiologic,endoscopic or elective operativeintervention indicated Life-threatening consequences;urgent operative interventionindicated Death Definition: A finding of leakage due to breakdown of a fallopian tube anastomosis (surgical connection of two separate anatomic structures). Fallopian tube perforation Asymptomatic diagnosticobservations only; interventionnot indicated Symptomatic and interventionnot indicated Severe symptoms; electiveoperative intervention indicated Life-threatening consequences;urgent operative interventionindicated (e.g., organ resection) Death Definition: A finding of rupture of the fallopian tube wall. Fracture Asymptomatic; clinical ordiagnostic observations only;intervention not indicated Symptomatic but non-displaced;immobilization indicated Severe symptoms; displaced oropen wound with boneexposure; disabling; operativeintervention indicated Life-threatening consequences;urgent intervention indicated Death Definition: A finding of traumatic injury to the bone in which the continuity of the bone is broken.

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CTCAE 4.03 June 14, 2010 : Injury, poisoning and procedural complications 35 Injury, poisoning and procedural complications Grade Adverse Event 1 2 3 4 5 Gastric anastomotic leak Asymptomatic diagnosticobservations only; interventionnot indicated Symptomatic; medicalintervention indicated Severe symptoms; radiologic,endoscopic or elective operativeintervention indicated Life-threatening consequences;urgent operative interventionindicated Death Definition: A finding of leakage due to breakdown of a gastric anastomosis (surgical connection of two separate anatomic structures). Gastrointestinal anastomoticleak Asymptomatic diagnosticobservations only; interventionnot indicated Symptomatic; medicalintervention indicated Severe symptoms; radiologic,endoscopic or elective operativeintervention indicated Life-threatening consequences;urgent operative interventionindicated Death Definition: A finding of leakage due to breakdown of a gastrointestinal anastomosis (surgical connection of two separate anatomic structures). Gastrointestinal stoma necrosis Superficial necrosis;intervention not indicated Severe symptoms;hospitalization or electiveoperative intervention indicated Life-threatening consequences;urgent intervention indicated Death Definition: A finding of a necrotic process occurring in the gastrointestinal tract stoma. Hip fracture Hairline fracture; mild pain;limiting instrumental ADL; non-surgical intervention indicated Severe pain; hospitalization orintervention indicated for paincontrol (e.g., traction); operativeintervention indicated Life-threatening consequences;symptoms associated withneurovascular compromise Definition: A finding of traumatic injury to the hip in which the continuity of either the femoral head, femoral neck, intertrochanteric or subtrochanteric regions is broken. Injury to carotid artery Severe symptoms; limiting selfcare ADL (e.g., transientcerebral ischemia); repair orrevision indicated Life-threatening consequences;urgent intervention indicated Death Definition: A finding of damage to the carotid artery. Injury to inferior vena cava Life-threatening consequences;urgent intervention indicated Death Definition: A finding of damage to the inferior vena cava. Injury to jugular vein Symptomatic limiting self careADL; disabling; repair orrevision indicated Life-threatening consequences;urgent intervention indicated Death Definition: A finding of damage to the jugular vein. Injury to superior vena cava Asymptomatic diagnosticfinding; intervention notindicated Symptomatic; repair or revisionnot indicated Severe symptoms; limiting selfcare ADL; disabling; repair orrevision indicated Life-threatening consequences;evidence of end organ damage;urgent operative interventionindicated Death Definition: A finding of damage to the superior vena cava. Intestinal stoma leak Asymptomatic diagnosticobservations only; interventionnot indicated Symptomatic; medicalintervention indicated Severe symptoms; radiologic,endoscopic or elective operativeintervention indicated Life-threatening consequences;urgent operative interventionindicated Death Definition: A finding of leakage of contents from an intestinal stoma (surgically created opening on the surface of the body). Intestinal stoma obstruction Self-limited; intervention notindicated Severe symptoms; IV fluids,tube feeding, or TPN indicated>=24 hrs; elective operativeintervention indicated Life-threatening consequences;urgent operative interventionindicated Death Definition: A finding of blockage of the normal flow of the contents of the intestinal stoma. Intestinal stoma site bleeding Minimal bleeding identified onclinical exam; intervention notindicated Moderate bleeding; medicalintervention indicated Severe bleeding; transfusionindicated; radiologic orendoscopic interventionindicated Life-threatening consequences;urgent intervention indicated Death Definition: A finding of blood leakage from the intestinal stoma. Intraoperative arterial injury Primary repair of injuredorgan/structure indicated Partial resection of injuredorgan/structure indicated Complete resection orreconstruction of injuredorgan/structure indicated;disabling Life-threatening consequences;urgent intervention indicated Death Definition: A finding of damage to an artery during a surgical procedure. Intraoperative breast injury Primary repair of injuredorgan/structure indicated Partial resection of injuredorgan/structure indicated Complete resection orreconstruction of injuredorgan/structure indicated;disabling Life-threatening consequences;urgent intervention indicated Death

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CTCAE 4.03 June 14, 2010 : Injury, poisoning and procedural complications 36 Injury, poisoning and procedural complications Grade Adverse Event 1 2 3 4 5 Definition: A finding of damage to the breast parenchyma during a surgical procedure. Intraoperative cardiac injury Primary repair of injuredorgan/structure indicated Life-threatening consequences;urgent intervention indicated Death Definition: A finding of damage to the heart during a surgical procedure. Intraoperative ear injury Primary repair of injuredorgan/structure indicated Partial resection of injuredorgan/structure indicated Complete resection of injuredorgan/structure indicated;disabling (e.g., impairedhearing; impaired balance) Life-threatening consequences;urgent intervention indicated Death Definition: A finding of damage to the ear during a surgical procedure. Intraoperative endocrine injury Primary repair of injuredorgan/structure indicated Partial resection of injuredorgan/structure indicated Complete resection orreconstruction of injuredorgan/structure indicated;disabling Life-threatening consequences;urgent intervention indicated Death Definition: A finding of damage to the endocrine gland during a surgical procedure. Intraoperative gastrointestinalinjury Primary repair of injuredorgan/structure indicated Partial resection of injuredorgan/structure indicated Complete resection orreconstruction of injuredorgan/structure indicated;disabling Life-threatening consequences;urgent intervention indicated Death Definition: A finding of damage to the gastrointestinal system during a surgical procedure. Intraoperative head and neckinjury Primary repair of injuredorgan/structure indicated Partial resection of injuredorgan/structure indicated Complete resection orreconstruction of injuredorgan/structure indicated;disabling Life-threatening consequences;urgent intervention indicated Death Definition: A finding of damage to the head and neck during a surgical procedure. Intraoperative hemorrhage Postoperative radiologic,endoscopic, or operativeintervention indicated Life-threatening consequences;urgent intervention indicated Death Definition: A finding of uncontrolled bleeding during a surgical procedure. Intraoperative hepatobiliaryinjury Primary repair of injuredorgan/structure indicated Partial resection of injuredorgan/structure indicated Complete resection orreconstruction of injuredorgan/structure indicated;disabling Life-threatening consequences;urgent intervention indicated Death Definition: A finding of damage to the hepatic parenchyma and/or biliary tract during a surgical procedure. Intraoperative musculoskeletalinjury Primary repair of injuredorgan/structure indicated Partial resection of injuredorgan/structure indicated Complete resection orreconstruction of injuredorgan/structure indicated;disabling Life-threatening consequences;urgent intervention indicated Death Definition: A finding of damage to the musculoskeletal system during a surgical procedure. Intraoperative neurologicalinjury Primary repair of injuredorgan/structure indicated Partial resection of injuredorgan/structure indicated Complete resection orreconstruction of injuredorgan/structure indicated;disabling Life-threatening consequences;urgent intervention indicated Death Definition: A finding of damage to the nervous system during a surgical procedure. Intraoperative ocular injury Primary repair of injuredorgan/structure indicated Partial resection of injuredorgan/structure indicated Complete resection orreconstruction of injuredorgan/structure indicated;disabling Life-threatening consequences;urgent intervention indicated Death Definition: A finding of damage to the eye during a surgical procedure. Intraoperative renal injury Primary repair of injuredorgan/structure indicated Partial resection of injuredorgan/structure indicated Complete resection orreconstruction of injuredorgan/structure indicated;disabling Life-threatening consequences;urgent intervention indicated Death Definition: A finding of damage to the kidney during a surgical procedure. Intraoperative reproductive tractinjury Primary repair of injuredorgan/structure indicated Partial resection of injuredorgan/structure indicated Complete resection orreconstruction of injuredorgan/structure indicated;disabling Life-threatening consequences;urgent intervention indicated Death

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CTCAE 4.03 June 14, 2010 : Injury, poisoning and procedural complications 37 Injury, poisoning and procedural complications Grade Adverse Event 1 2 3 4 5 Definition: A finding of damage to the reproductive organs during a surgical procedure. Intraoperative respiratory injury Primary repair of injuredorgan/structure indicated Partial resection of injuredorgan/structure indicated Complete resection orreconstruction of injuredorgan/structure indicated;disabling Life-threatening consequences;urgent intervention indicated Death Definition: A finding of damage to the respiratory system during a surgical procedure. Intraoperative skin injury Primary repair of injuredorgan/structure indicated Partial resection of injuredorgan/structure indicated Complete resection orreconstruction of injuredorgan/structure indicated;disabling Life-threatening consequences;urgent intervention indicated Death Definition: A finding of damage to the skin during a surgical procedure. Intraoperative splenic injury Primary repair of injuredorgan/structure indicated Resection or reconstruction ofinjured organ/structureindicated; disabling Life-threatening consequences;urgent intervention indicated Death Definition: A finding of damage to the spleen during a surgical procedure. Intraoperative urinary injury Primary repair of injuredorgan/structure indicated Partial resection of injuredorgan/structure indicated Complete resection orreconstruction of injuredorgan/structure indicated;disabling Life-threatening consequences;urgent intervention indicated Death Definition: A finding of damage to the urinary system during a surgical procedure. Intraoperative venous injury Primary repair of injuredorgan/structure indicated Partial resection of injuredorgan/structure indicated Complete resection orreconstruction of injuredorgan/structure indicated;disabling Life-threatening consequences;urgent intervention indicated Death Definition: A finding of damage to a vein during a surgical procedure. Kidney anastomotic leak Asymptomatic diagnosticobservations only; interventionnot indicated Symptomatic; medicalintervention indicated Severe symptoms; radiologic,endoscopic or elective operativeintervention indicated Life-threatening consequences;urgent operative interventionindicated Death Definition: A finding of leakage of urine due to breakdown of a kidney anastomosis (surgical connection of two separate anatomic structures). Large intestinal anastomoticleak Asymptomatic diagnosticobservations only; interventionnot indicated Symptomatic; medicalintervention indicated Severe symptoms; radiologic,endoscopic or elective operativeintervention indicated Life-threatening consequences;urgent operative interventionindicated Death Definition: A finding of leakage due to breakdown of an anastomosis (surgical connection of two separate anatomic structures) in the large intestine. Pancreatic anastomotic leak Asymptomatic diagnosticobservations only; interventionnot indicated Symptomatic; medicalintervention indicated Severe symptoms; radiologic,endoscopic or elective operativeintervention indicated Life-threatening consequences;urgent operative interventionindicated Death Definition: A finding of leakage due to breakdown of a pancreatic anastomosis (surgical connection of two separate anatomic structures). Pharyngeal anastomotic leak Asymptomatic diagnosticobservations only; interventionnot indicated Symptomatic; medicalintervention indicated Severe symptoms; radiologic,endoscopic or elective operativeintervention indicated Life-threatening consequences;urgent operative interventionindicated Death Definition: A finding of leakage due to breakdown of a pharyngeal anastomosis (surgical connection of two separate anatomic structures). Postoperative hemorrhage Minimal bleeding identified onclinical exam; intervention notindicated Moderate bleeding; radiologic,endoscopic, or operativeintervention indicated Transfusion indicated of >=2units (10 cc/kg for pediatrics)pRBCs beyond protocolspecification; urgent radiologic,endoscopic, or operativeintervention indicated Life-threatening consequences;urgent intervention indicated Death Definition: A finding of bleeding occurring after a surgical procedure. Postoperative thoracicprocedure complication Extubated within 24 72 hrspostoperatively Extubated >72 hrspostoperatively, but beforetracheostomy indicated Life-threatening airwaycompromise; urgent interventionindicated (e.g., tracheotomy orintubation) Death Definition: A finding of a previously undocumented problem that occurs after a thoracic procedure. Prolapse of intestinal stoma Asymptomatic; reducible Recurrent after manualreduction; local irritation or stoolleakage; difficulty to fitappliance; limiting instrumentalADL Severe symptoms; electiveoperative intervention indicated;limiting self care ADL Life-threatening consequences;urgent operative interventionindicated Death

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CTCAE 4.03 June 14, 2010 : Injury, poisoning and procedural complications 38 Injury, poisoning and procedural complications Grade Adverse Event 1 2 3 4 5 Definition: A finding of protrusion of the intestinal stoma (surgically created opening on the surface of the body) above the abdominal surface. Prolapse of urostomy Asymptomatic; clinical ordiagnostic observations only;intervention not indicated Local care or maintenance;minor revision indicated Dysfunctional stoma; electiveoperative intervention or majorstomal revision indicated Life-threatening consequences;urgent intervention indicated Death Definition: A finding of displacement of the urostomy. Radiation recall reaction(dermatologic) Faint erythema or drydesquamation Moderate to brisk erythema;patchy moist desquamation,mostly confined to skin foldsand creases; moderate edema Moist desquamation in areasother than skin folds andcreases; bleeding induced byminor trauma or abrasion Life-threatening consequences;skin necrosis or ulceration of fullthickness dermis; spontaneousbleeding from involved site; skingraft indicated Death Definition: A finding of acute skin inflammatory reaction caused by drugs, especially chemotherapeutic agents, for weeks or months following radiotherapy. The inflammatory reactionis confined to the previously irradiated skin and the symptoms disappear after the removal of the pharmaceutical agent. Rectal anastomotic leak Asymptomatic diagnosticobservations only; interventionnot indicated Symptomatic; medicalintervention indicated Severe symptoms; radiologic,endoscopic or elective operativeintervention indicated Life-threatening consequences;urgent operative interventionindicated Death Definition: A finding of leakage due to breakdown of a rectal anastomosis (surgical connection of two separate anatomic structures). Seroma Asymptomatic; clinical ordiagnostic observations only;intervention not indicated Symptomatic; simple aspirationindicated Symptomatic, elective radiologicor operative interventionindicated Definition: A finding of tumor-like collection of serum in the tissues. Small intestinal anastomoticleak Asymptomatic diagnosticobservations only; interventionnot indicated Symptomatic; medicalintervention indicated Severe symptoms; radiologic,endoscopic or elective operativeintervention indicated Life-threatening consequences;urgent operative interventionindicated Death Definition: A finding of leakage due to breakdown of an anastomosis (surgical connection of two separate anatomic structures) in the small bowel. Spermatic cord anastomoticleak Asymptomatic diagnosticobservations only; interventionnot indicated Symptomatic; medicalintervention indicated Severe symptoms; radiologic,endoscopic or elective operativeintervention indicated Life-threatening consequences;urgent operative interventionindicated Death Definition: A finding of leakage due to breakdown of a spermatic cord anastomosis (surgical connection of two separate anatomic structures). Spinal fracture Mild back pain; nonprescriptionanalgesics indicated Moderate back pain;prescription analgesicsindicated; limiting instrumentalADL Severe back pain;hospitalization or interventionindicated for pain control (e.g.,vertebroplasty); limiting self careADL; disability Life-threatening consequences;symptoms associated withneurovascular compromise Death Definition: A finding of traumatic injury to the spine in which the continuity of a vertebral bone is broken. Stenosis of gastrointestinalstoma Symptomatic; IV fluids indicated<24 hrs; manual dilation atbedside Severely altered GI function;tube feeding, TPN orhospitalization indicated;elective operative interventionindicated Life-threatening consequences;urgent operative interventionindicated Death Definition: A finding of narrowing of the gastrointestinal stoma (surgically created opening on the surface of the body). Stomal ulcer Asymptomatic; clinical ordiagnostic observations only;intervention not indicated Symptomatic; medicalintervention indicated Severe symptoms; electiveoperative intervention indicated Definition: A disorder characterized by a circumscribed, inflammatory and necrotic erosive lesion on the jejunal mucosal surface close to the anastomosis site following agastroenterostomy procedure. Tracheal hemorrhage Minimal bleeding identified onclinical or diagnostic exam;intervention not indicated Moderate bleeding; medicalintervention indicated Severe bleeding; transfusionindicated; radiologic orendoscopic interventionindicated Life-threatening consequences;urgent intervention indicated Death Definition: A finding of bleeding from the trachea. Tracheal obstruction Partial asymptomaticobstruction on examination(e.g., visual, radiologic orendoscopic) Symptomatic (e.g., noisy airwaybreathing), no respiratorydistress; medical interventionindicated (e.g., steroids); limitinginstrumental ADL Stridor; radiologic or endoscopicintervention indicated (e.g.,stent, laser); limiting self careADL Life-threatening airwaycompromise; urgent interventionindicated (e.g., tracheotomy orintubation) Death Definition: A finding of blockage of the lumen of the trachea.

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CTCAE 4.03 June 14, 2010 : Injury, poisoning and procedural complications 39 Injury, poisoning and procedural complications Grade Adverse Event 1 2 3 4 5 Tracheostomy site bleeding Minimal bleeding identified onclinical exam; intervention notindicated Moderate bleeding; medicalintervention indicated Severe bleeding; transfusionindicated; radiologic orendoscopic interventionindicated Life-threatening consequences;urgent intervention indicated Death Definition: A finding of blood leakage from the tracheostomy site. Ureteric anastomotic leak Asymptomatic diagnosticobservations only; interventionnot indicated Symptomatic; medicalintervention indicated Severe symptoms; radiologic,endoscopic or elective operativeintervention indicated Life-threatening consequences;urgent operative interventionindicated Death Definition: A finding of leakage due to breakdown of a ureteral anastomosis (surgical connection of two separate anatomic structures). Urethral anastomotic leak Asymptomatic diagnosticobservations only; interventionnot indicated Symptomatic; medicalintervention indicated Severe symptoms; radiologic,endoscopic or elective operativeintervention indicated Life-threatening consequences;urgent operative interventionindicated Death Definition: A finding of leakage due to breakdown of a urethral anastomosis (surgical connection of two separate anatomic structures). Urostomy leak Asymptomatic diagnosticobservations only; interventionnot indicated Symptomatic; medicalintervention indicated Severe symptoms; radiologic,endoscopic or elective operativeintervention indicated Life-threatening consequences;urgent operative interventionindicated Death Definition: A finding of leakage of contents from a urostomy. Urostomy obstruction Asymptomatic diagnosticobservations only; interventionnot indicated Symptomatic; dilation orendoscopic repair or stentplacement indicated Altered organ function (e.g.,sepsis or hydronephrosis, orrenal dysfunction); electiveoperative intervention indicated Life-threatening consequences;organ failure; urgent operativeintervention indicated Death Definition: A finding of blockage of the urostomy. Urostomy site bleeding Minimal bleeding identified onclinical exam; intervention notindicated Moderate bleeding; medicalintervention indicated Severe bleeding; transfusionindicated; radiologic orendoscopic interventionindicated Life-threatening consequences;urgent intervention indicated Death Definition: A finding of bleeding from the urostomy site. Urostomy stenosis Symptomatic but nohydronephrosis, no sepsis or norenal dysfunction; dilation orendoscopic repair or stentplacement indicated Symptomatic (e.g.,hydronephrosis, or renaldysfunction); elective operativeintervention indicated Life-threatening consequences;urgent operative interventionindicated Death Definition: A finding of narrowing of the opening of a urostomy. Uterine anastomotic leak Asymptomatic diagnosticobservations only; interventionnot indicated Symptomatic; medicalintervention indicated Severe symptoms; radiologic,endoscopic or elective operativeintervention indicated Life-threatening consequences;urgent operative interventionindicated Death Definition: A finding of leakage due to breakdown of a uterine anastomosis (surgical connection of two separate anatomic structures). Uterine perforation Asymptomatic diagnosticobservations only; interventionnot indicated Symptomatic and interventionnot indicated Severe symptoms; electiveoperative intervention indicated Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by a rupture in the uterine wall. Vaginal anastomotic leak Asymptomatic diagnosticobservations only; interventionnot indicated Symptomatic; medicalintervention indicated Severe symptoms; radiologic,endoscopic or elective operativeintervention indicated Life-threatening consequences;urgent operative interventionindicated Death Definition: A finding of leakage due to breakdown of a vaginal anastomosis (surgical connection of two separate anatomic structures). Vas deferens anastomotic leak Asymptomatic diagnosticobservations only; interventionnot indicated Symptomatic; medicalintervention indicated Severe symptoms; radiologic,endoscopic or elective operativeintervention indicated Life-threatening consequences;urgent operative interventionindicated Death Definition: A finding of leakage due to breakdown of a vas deferens anastomosis (surgical connection of two separate anatomic structures). Vascular access complication Device dislodgement, blockage,leak, or malposition; devicereplacement indicated Deep vein or cardiacthrombosis; interventionindicated (e.g., anticoagulation,lysis, filter, invasive procedure) Embolic event includingpulmonary embolism or life-threatening thrombus Death Definition: A finding of a previously undocumented problem related to the vascular access site.

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CTCAE 4.03 June 14, 2010 : Injury, poisoning and procedural complications 40 Injury, poisoning and procedural complications Grade Adverse Event 1 2 3 4 5 Venous injury Asymptomatic diagnosticfinding; intervention notindicated Symptomatic (e.g.,claudication); repair or revisionnot indicated Severe symptoms; limiting selfcare ADL; repair or revisionindicated; disabling Life-threatening consequences;evidence of end organ damage;urgent operative interventionindicated Death Definition: A finding of damage to a vein. Wound complication Incisional separation of <=25%of wound, no deeper thansuperficial fascia Incisional separation >25% ofwound; local care indicated Hernia without evidence ofstrangulation; fascialdisruption/dehiscence; primarywound closure or revision byoperative intervention indicated Hernia with evidence ofstrangulation; majorreconstruction flap, grafting,resection, or amputationindicated Death Definition: A finding of development of a new problem at the site of an existing wound. Wound dehiscence Incisional separation of <=25%of wound, no deeper thansuperficial fascia Incisional separation >25% ofwound with local care;asymptomatic hernia orsymptomatic hernia withoutevidence of strangulation Fascial disruption or dehiscencewithout evisceration; primarywound closure or revision byoperative intervention indicated Life-threatening consequences;symptomatic hernia withevidence of strangulation;fascial disruption withevisceration; majorreconstruction flap, grafting,resection, or amputationindicated Death Definition: A finding of separation of the approximated margins of a surgical wound. Wrist fracture Mild; non-surgical interventionindicated Limiting instrumental ADL;operative intervention indicated Limiting self care ADL; electivesurgery indicated Definition: A finding of traumatic injury to the wrist joint in which the continuity of a wrist bone is broken. Injury, poisoning and proceduralcomplications Other, specify Asymptomatic or mildsymptoms; clinical or diagnosticobservations only; interventionnot indicated Moderate; minimal, local ornoninvasive interventionindicated; limiting age-appropriate instrumental ADL Severe or medically significantbut not immediately life-threatening; hospitalization orprolongation of existinghospitalization indicated;disabling; limiting self care ADL Life-threatening consequences;urgent intervention indicated Death

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CTCAE 4.03 June 14, 2010 : Investigations 41 14. Investigations Investigations Grade Adverse Event 1 2 3 4 5 Activated partial thromboplastintime prolonged >ULN 1.5 x ULN >1.5 2.5 x ULN >2.5 x ULN; hemorrhage Definition: An abnormal laboratory test result in which the partial thromboplastin time is found to be greater than the control value. As a possible indicator of coagulopathy, a prolongedpartial thromboplastin time (PTT) may occur in a variety of diseases and disorders, both primary and related to treatment. Alanine aminotransferaseincreased >ULN 3.0 x ULN >3.0 5.0 x ULN >5.0 20.0 x ULN >20.0 x ULN Definition: A finding based on laboratory test results that indicate an increase in the level of alanine aminotransferase (ALT or SGPT) in the blood specimen. Alkaline phosphatase increased >ULN 2.5 x ULN >2.5 5.0 x ULN >5.0 20.0 x ULN >20.0 x ULN Definition: A finding based on laboratory test results that indicate an increase in the level of alkaline phosphatase in a blood specimen. Aspartate aminotransferaseincreased >ULN 3.0 x ULN >3.0 5.0 x ULN >5.0 20.0 x ULN >20.0 x ULN Definition: A finding based on laboratory test results that indicate an increase in the level of aspartate aminotransferase (AST or SGOT) in a blood specimen. Blood antidiuretic hormoneabnormal Asymptomatic; clinical ordiagnostic observations only;intervention not indicated Symptomatic; medicalintervention indicated Hospitalization indicated Definition: A finding based on laboratory test results that indicate abnormal levels of antidiuretic hormone in the blood specimen. Blood bilirubin increased >ULN 1.5 x ULN >1.5 3.0 x ULN >3.0 10.0 x ULN >10.0 x ULN Definition: A finding based on laboratory test results that indicate an abnormally high level of bilirubin in the blood. Excess bilirubin is associated with jaundice. Blood corticotrophin decreased Asymptomatic; clinical ordiagnostic observations only;intervention not indicated Symptomatic; medicalintervention indicated Hospitalization indicated Definition: A finding based on laboratory test results that indicate an decrease in levels of corticotrophin in a blood specimen. Blood gonadotrophin abnormal Asymptomatic; clinical ordiagnostic observations only;intervention not indicated Symptomatic; medicalintervention indicated; limitinginstrumental ADL Severe symptoms; limiting selfcare ADL Definition: A finding based on laboratory test results that indicate abnormal levels of gonadotrophin hormone in a blood specimen. Blood prolactin abnormal Asymptomatic; clinical ordiagnostic observations only;intervention not indicated Moderate symptoms; limitinginstrumental ADL Definition: A finding based on laboratory test results that indicate abnormal levels of prolactin hormone in a blood specimen. Carbon monoxide diffusingcapacity decreased 3 5 units below LLN; for follow-up, a decrease of 3 5 units(ml/min/mm Hg) below thebaseline value 6 8 units below LLN; for follow-up, an asymptomatic decreaseof >5 8 units (ml/min/mm Hg)below the baseline value Asymptomatic decrease of >8units drop; >5 units drop alongwith the presence of pulmonarysymptoms (e.g. >Grade 2hypoxia or >Grade 2 or higherdyspnea) Definition: A finding based on lung function test results that indicate a decrease in the lung capacity to absorb carbon monoxide. Cardiac troponin I increased Levels above the upper limit ofnormal and below the level ofmyocardial infarction as definedby the manufacturer Levels consistent withmyocardial infarction as definedby the manufacturer Definition: A laboratory test result which indicates increased levels of cardiac troponin I in a biological specimen. Cardiac troponin T increased Levels above the upper limit ofnormal and below the level ofmyocardial infarction as definedby the manufacturer Levels consistent withmyocardial infarction as definedby the manufacturer Definition: A laboratory test result which indicates increased levels of cardiac troponin T in a biological specimen. CD4 lymphocytes decreased ULN 300 mg/dL; >ULN 7.75mmol/L >300 400 mg/dL; >7.75 10.34mmol/L >400 500 mg/dL; >10.34 -12.92 mmol/L >500 mg/dL; >12.92 mmol/L Definition: A finding based on laboratory test results that indicate higher than normal levels of cholesterol in a blood specimen. CPK increased >ULN 2.5 x ULN >2.5 x ULN 5 x ULN >5 x ULN 10 x ULN >10 x ULN Definition: A finding based on laboratory test results that indicate an increase in levels of creatine phosphokinase in a blood specimen.

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CTCAE 4.03 June 14, 2010 : Investigations 42 Investigations Grade Adverse Event 1 2 3 4 5 Creatinine increased >1 1.5 x baseline; >ULN 1.5x ULN >1.5 3.0 x baseline; >1.5 3.0x ULN >3.0 baseline; >3.0 6.0 x ULN >6.0 x ULN Definition: A finding based on laboratory test results that indicate increased levels of creatinine in a biological specimen. Ejection fraction decreased Resting ejection fraction (EF) 5040%; 10 19% drop frombaseline Resting ejection fraction (EF) 3920%; >20% drop from baseline Resting ejection fraction (EF)<20% Definition: The percentage computed when the amount of blood ejected during a ventricular contraction of the heart is compared to the amount that was present prior to thecontraction. Electrocardiogram QT correctedinterval prolonged QTc 450 480 ms QTc 481 500 ms QTc >= 501 ms on at least twoseparate ECGs QTc >= 501 or >60 ms changefrom baseline and Torsade depointes or polymorphicventricular tachycardia orsigns/symptoms of seriousarrhythmia Definition: A finding of a cardiac dysrhythmia characterized by an abnormally long corrected QT interval. Fibrinogen decreased <1.0 0.75 x LLN or <25%decrease from baseline <0.75 0.5 x LLN or 25 <50%decrease from baseline <0.5 0.25 x LLN or 50 <75%decrease from baseline <0.25 x LLN or 75% decreasefrom baseline or absolute value<50 mg/dL Definition: A finding based on laboratory test results that indicate an decrease in levels of fibrinogen in a blood specimen. Forced expiratory volumedecreased FEV1% (percentages ofobserved FEV1 and FVCrelated to their respectivepredicted values) 99 70%predicted FEV1 60 69% 50 59% <= 49% Definition: A finding based on test results that indicate a relative decrease in the fraction of the forced vital capacity that is exhaled in a specific number of seconds. GGT increased >ULN 2.5 x ULN >2.5 5.0 x ULN >5.0 20.0 x ULN >20.0 x ULN Definition: A finding based on laboratory test results that indicate higher than normal levels of the enzyme gamma-glutamyltransferase in the blood specimen. GGT (gamma-glutamyltransferase ) catalyzes the transfer of a gamma glutamyl group from a gamma glutamyl peptide to another peptide, amino acids or water. Growth hormone abnormal Asymptomatic; clinical ordiagnostic observations only;intervention not indicated Symptomatic; medicalintervention indicated; limitinginstrumental ADL Definition: A finding based on laboratory test results that indicate abnormal levels of growth hormone in a biological specimen. Haptoglobin decreased 0 2 gm/dL aboveULN or above baseline ifbaseline is above ULN Increase in >2 4 gm/dL aboveULN or above baseline ifbaseline is above ULN Increase in >4 gm/dL aboveULN or above baseline ifbaseline is above ULN Definition: A finding based on laboratory test results that indicate increased levels of hemoglobin in a biological specimen. INR increased >1 1.5 x ULN; >1 1.5 timesabove baseline if onanticoagulation >1.5 2.5 x ULN; >1.5 2.5times above baseline if onanticoagulation >2.5 x ULN; >2.5 times abovebaseline if on anticoagulation Definition: A finding based on laboratory test results that indicate an increase in the ratio of the patient's prothrombin time to a control sample in the blood. Lipase increased >ULN 1.5 x ULN >1.5 2.0 x ULN >2.0 5.0 x ULN >5.0 x ULN Definition: A finding based on laboratory test results that indicate an increase in the level of lipase in a biological specimen. Lymphocyte count decreased 4000/mm3 20,000/mm3 >20,000/mm3 Definition: A finding based on laboratory test results that indicate an abnormal increase in the number of lymphocytes in the blood, effusions or bone marrow. Neutrophil count decreased
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CTCAE 4.03 June 14, 2010 : Investigations 43 Investigations Grade Adverse Event 1 2 3 4 5 Platelet count decreased ULN 1.5 x ULN >1.5 2.0 x ULN >2.0 5.0 x ULN >5.0 x ULN Definition: A finding based on laboratory test results that indicate an increase in the levels of amylase in a serum specimen. Urine output decreased Oliguria (<80 ml in 8 hr) Anuria (<240 ml in 24 hr) Definition: A finding based on test results that indicate urine production is less relative to previous output. Vital capacity abnormal 90 75% of predicted value <75 50% of predicted value;limiting instrumental ADL <50% of predicted value;limiting self care ADL Definition: A finding based on pulmonary function test results that indicate an abnormal vital capacity (amount of exhaled after a maximum inhalation) when compared to the predictedvalue. Weight gain 5 <10% from baseline 10 <20% from baseline >=20% from baseline Definition: A finding characterized by an increase in overall body weight; for pediatrics, greater than the baseline growth curve. Weight loss 5 to <10% from baseline;intervention not indicated 10 <20% from baseline;nutritional support indicated >=20% from baseline; tubefeeding or TPN indicated Definition: A finding characterized by a decrease in overall body weight; for pediatrics, less than the baseline growth curve. White blood cell decreased
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CTCAE 4.03 June 14, 2010 : Metabolism and nutrition disorders 44 15. Metabolism and nutrition disorders Metabolism and nutrition disorders Grade Adverse Event 1 2 3 4 5 Acidosis pH =7.3 pH <7.3 Life-threatening consequences Death Definition: A disorder characterized by abnormally high acidity (high hydrogen-ion concentration) of the blood and other body tissues. Alcohol intolerance Present Severe symptoms; limiting selfcare ADL Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by an increase in sensitivity to the adverse effects of alcohol, which can include nasal congestion, skin flushes, heart dysrhythmias, nausea,vomiting, indigestion and headaches. Alkalosis pH >normal, but <=7.5 pH >7.5 Life-threatening consequences Death Definition: A disorder characterized by abnormally high alkalinity (low hydrogen-ion concentration) of the blood and other body tissues. Anorexia Loss of appetite withoutalteration in eating habits Oral intake altered withoutsignificant weight loss ormalnutrition; oral nutritionalsupplements indicated Associated with significantweight loss or malnutrition (e.g.,inadequate oral caloric and/orfluid intake); tube feeding orTPN indicated Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by a loss of appetite. Dehydration Increased oral fluids indicated;dry mucous membranes;diminished skin turgor IV fluids indicated <24 hrs IV fluids or hospitalizationindicated Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by excessive loss of water from the body. It is usually caused by severe diarrhea, vomiting or diaphoresis. Glucose intolerance Asymptomatic; clinical ordiagnostic observations only;intervention not indicated Symptomatic; dietarymodification or oral agentindicated Severe symptoms; insulinindicated Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by an inability to properly metabolize glucose. Hypercalcemia Corrected serum calcium of>ULN 11.5 mg/dL; >ULN 2.9mmol/L; Ionized calcium >ULN1.5 mmol/L Corrected serum calcium of>11.5 12.5 mg/dL; >2.9 3.1mmol/L; Ionized calcium >1.5 -1.6 mmol/L; symptomatic Corrected serum calcium of>12.5 13.5 mg/dL; >3.1 3.4mmol/L; Ionized calcium >1.6 -1.8 mmol/L; hospitalizationindicated Corrected serum calcium of>13.5 mg/dL; >3.4 mmol/L;Ionized calcium >1.8 mmol/L;life-threatening consequences Death Definition: A disorder characterized by laboratory test results that indicate an elevation in the concentration of calcium (corrected for albumin) in blood. Hyperglycemia Fasting glucose value >ULN -160 mg/dL; Fasting glucosevalue >ULN 8.9 mmol/L Fasting glucose value >160 -250 mg/dL; Fasting glucosevalue >8.9 13.9 mmol/L >250 500 mg/dL; >13.9 27.8mmol/L; hospitalizationindicated >500 mg/dL; >27.8 mmol/L; life-threatening consequences Death Definition: A disorder characterized by laboratory test results that indicate an elevation in the concentration of blood sugar. It is usually an indication of diabetes mellitus or glucoseintolerance. Hyperkalemia >ULN 5.5 mmol/L >5.5 6.0 mmol/L >6.0 7.0 mmol/L;hospitalization indicated >7.0 mmol/L; life-threateningconsequences Death Definition: A disorder characterized by laboratory test results that indicate an elevation in the concentration of potassium in the blood; associated with kidney failure or sometimes withthe use of diuretic drugs. Hypermagnesemia >ULN 3.0 mg/dL; >ULN 1.23mmol/L >3.0 8.0 mg/dL; >1.23 3.30mmol/L >8.0 mg/dL; >3.30 mmol/L; life-threatening consequences Death Definition: A disorder characterized by laboratory test results that indicate an elevation in the concentration of magnesium in the blood. Hypernatremia >ULN 150 mmol/L >150 155 mmol/L >155 160 mmol/L;hospitalization indicated >160 mmol/L; life-threateningconsequences Death Definition: A disorder characterized by laboratory test results that indicate an elevation in the concentration of sodium in the blood. Hypertriglyceridemia 150 mg/dL 300 mg/dL; 1.71mmol/L 3.42 mmol/L >300 mg/dL 500 mg/dL; >3.42mmol/L 5.7 mmol/L >500 mg/dL 1000 mg/dL; >5.7mmol/L 11.4 mmol/L >1000 mg/dL; >11.4 mmol/L;life-threatening consequences Death Definition: A disorder characterized by laboratory test results that indicate an elevation in the concentration of triglyceride concentration in the blood. Hyperuricemia >ULN 10 mg/dL (0.59 mmol/L)without physiologicconsequences >ULN 10 mg/dL (0.59 mmol/L)with physiologic consequences >10 mg/dL; >0.59 mmol/L; life-threatening consequences Death Definition: A disorder characterized by laboratory test results that indicate an elevation in the concentration of uric acid. Hypoalbuminemia
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CTCAE 4.03 June 14, 2010 : Metabolism and nutrition disorders 45 Metabolism and nutrition disorders Grade Adverse Event 1 2 3 4 5 Hypocalcemia Corrected serum calcium of=40 kg/m2 Definition: A disorder characterized by having a high amount of body fat. Tumor lysis syndrome Present Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by metabolic abnormalities that result from a spontaneous or therapy-related cytolysis of tumor cells. Metabolism and nutritiondisorders Other, specify Asymptomatic or mildsymptoms; clinical or diagnosticobservations only; interventionnot indicated Moderate; minimal, local ornoninvasive interventionindicated; limiting age-appropriate instrumental ADL Severe or medically significantbut not immediately life-threatening; hospitalization orprolongation of existinghospitalization indicated;disabling; limiting self care ADL Life-threatening consequences;urgent intervention indicated Death

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CTCAE 4.03 June 14, 2010 : Musculoskeletal and connective tissue disorders 46 16. Musculoskeletal and connective tissue disorders Musculoskeletal and connective tissue disorders Grade Adverse Event 1 2 3 4 5 Abdominal soft tissue necrosis Local wound care; medicalintervention indicated (e.g.,dressings or topicalmedications) Operative debridement or otherinvasive intervention indicated(e.g. tissue reconstruction, flapor grafting) Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by a necrotic process occurring in the soft tissues of the abdominal wall. Arthralgia Mild pain Moderate pain; limitinginstrumental ADL Severe pain; limiting self careADL Definition: A disorder characterized by a sensation of marked discomfort in a joint. Arthritis Mild pain with inflammation,erythema, or joint swelling Moderate pain associated withsigns of inflammation,erythema, or joint swelling;limiting instrumental ADL Severe pain associated withsigns of inflammation,erythema, or joint swelling;irreversible joint damage;disabling; limiting self care ADL Definition: A disorder characterized by inflammation involving a joint. Avascular necrosis Asymptomatic; clinical ordiagnostic observations only;intervention not indicated Symptomatic; limitinginstrumental ADL Severe symptoms; limiting selfcare ADL; elective operativeintervention indicated Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by necrotic changes in the bone tissue due to interruption of blood supply. Most often affecting the epiphysis of the long bones, the necroticchanges result in the collapse and the destruction of the bone structure. Back pain Mild pain Moderate pain; limitinginstrumental ADL Severe pain; limiting self careADL Definition: A disorder characterized by marked discomfort sensation in the back region. Bone pain Mild pain Moderate pain; limitinginstrumental ADL Severe pain; limiting self careADL Definition: A disorder characterized by marked discomfort sensation in the bones. Buttock pain Mild pain Moderate pain; limitinginstrumental ADL Severe pain; limiting self careADL Definition: A disorder characterized by marked discomfort sensation in the buttocks. Chest wall pain Mild pain Moderate pain; limitinginstrumental ADL Severe pain; limiting self careADL Definition: A disorder characterized by marked discomfort sensation in the chest wall region. Exostosis Asymptomatic; clinical ordiagnostic observations only;intervention not indicated Symptomatic; limitinginstrumental ADL Severe symptoms; limiting selfcare ADL; elective operativeintervention indicated Definition: A disorder characterized by non-neoplastic overgrowth of bone. Fibrosis deep connective tissue Mild induration, able to moveskin parallel to plane (sliding)and perpendicular to skin(pinching up) Moderate induration, able toslide skin, unable to pinch skin;limiting instrumental ADL Severe induration; unable toslide or pinch skin; limiting jointor orifice movement (e.g.mouth, anus); limiting self careADL Generalized; associated withsigns or symptoms of impairedbreathing or feeding Death Definition: A disorder characterized by fibrotic degeneration of the deep connective tissues. Flank pain Mild pain Moderate pain; limitinginstrumental ADL Severe pain; limiting self careADL Definition: A disorder characterized by marked discomfort sensation on the lateral side of the body in the region below the ribs and above the hip. Generalized muscle weakness Symptomatic; weaknessperceived by patient but notevident on physical exam Symptomatic; weakness evidenton physical exam; weaknesslimiting instrumental ADL Weakness limiting self careADL; disabling Definition: A disorder characterized by a reduction in the strength of muscles in multiple anatomic sites. Growth suppression Reduction in growth velocity by10 29% ideally measured overthe period of a year Reduction in growth velocity by30 49% ideally measured overthe period of a year or 0 49%reduction in growth from thebaseline growth curve Reduction in growth velocity of>=50% ideally measured overthe period of a year Definition: A disorder characterized by of stature that is smaller than normal as expected for age.

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CTCAE 4.03 June 14, 2010 : Musculoskeletal and connective tissue disorders 47 Musculoskeletal and connective tissue disorders Grade Adverse Event 1 2 3 4 5 Head soft tissue necrosis Local wound care; medicalintervention indicated (e.g.,dressings or topicalmedications) Operative debridement or otherinvasive intervention indicated(e.g., tissue reconstruction, flapor grafting) Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by a necrotic process occurring in the soft tissues of the head. Joint effusion Asymptomatic; clinical ordiagnostic observations only;intervention not indicated Symptomatic; limitinginstrumental ADL Severe symptoms; limiting selfcare ADL; elective operativeintervention indicated; disabling Definition: A disorder characterized by excessive fluid in a joint, usually as a result of joint inflammation. Joint range of motion decreased <=25% loss of ROM (range ofmotion); decreased ROMlimiting athletic activity >25 50% decrease in ROM;limiting instrumental ADL >50% decrease in ROM; limitingself care ADL; disabling Definition: A disorder characterized by a decrease in joint flexibility of any joint. Joint range of motion decreasedcervical spine Mild restriction of rotation orflexion between 60 70 degrees Rotation <60 degrees to right orleft; <60 degrees of flexion Ankylosed/fused over multiplesegments with no C-spinerotation Definition: A disorder characterized by a decrease in flexibility of a cervical spine joint. Joint range of motion decreasedlumbar spine Stiffness; difficulty bending tothe floor to pick up a very lightobject but able to do athleticactivity Pain with range of motion(ROM) in lumbar spine; requiresa reaching aid to pick up a verylight object from the floor <50% lumbar spine flexion;associated with symptoms ofankylosis or fused over multiplesegments with no L-spineflexion (e.g., unable to reach tofloor to pick up a very lightobject) Definition: A disorder characterized by a decrease in flexibility of a lumbar spine joint. Kyphosis Asymptomatic; clinical ordiagnostic observations only;intervention not indicated Moderate accentuation; limitinginstrumental ADL Severe accentuation; operativeintervention indicated; limitingself care ADL Definition: A disorder characterized by an abnormal increase in the curvature of the thoracic portion of the spine. Lordosis Asymptomatic; clinical ordiagnostic observations only;intervention not indicated Moderate accentuation; limitinginstrumental ADL Severe accentuation; operativeintervention indicated; limitingself care ADL Definition: A disorder characterized by an abnormal increase in the curvature of the lumbar portion of the spine. Muscle weakness left-sided Symptomatic; perceived bypatient but not evident onphysical exam Symptomatic; evident onphysical exam; limitinginstrumental ADL Limiting self care ADL; disabling Definition: A disorder characterized by a reduction in the strength of the muscles on the left side of the body. Muscle weakness lower limb Symptomatic; perceived bypatient but not evident onphysical exam Symptomatic; evident onphysical exam; limitinginstrumental ADL Limiting self care ADL; disabling Definition: A disorder characterized by a reduction in the strength of the lower limb muscles. Muscle weakness right-sided Symptomatic; perceived bypatient but not evident onphysical exam Symptomatic; evident onphysical exam; limitinginstrumental ADL Limiting self care ADL; disabling Definition: A disorder characterized by a reduction in the strength of the muscles on the right side of the body. Muscle weakness trunk Symptomatic; perceived bypatient but not evident onphysical exam Symptomatic; evident onphysical exam; limitinginstrumental ADL Limiting self care ADL; disabling Definition: A disorder characterized by a reduction in the strength of the trunk muscles. Muscle weakness upper limb Symptomatic; perceived bypatient but not evident onphysical exam Symptomatic; evident onphysical exam; limitinginstrumental ADL Limiting self care ADL; disabling Definition: A disorder characterized by a reduction in the strength of the upper limb muscles.

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CTCAE 4.03 June 14, 2010 : Musculoskeletal and connective tissue disorders 48 Musculoskeletal and connective tissue disorders Grade Adverse Event 1 2 3 4 5 Musculoskeletal deformity Cosmetically and functionallyinsignificant hypoplasia Deformity, hypoplasia, orasymmetry able to beremediated by prosthesis (e.g.,shoe insert) or covered byclothing Significant deformity,hypoplasia, or asymmetry,unable to be remediated byprosthesis or covered byclothing; disabling Definition: A disorder characterized by of a malformation of the musculoskeletal system. Myalgia Mild pain Moderate pain; limitinginstrumental ADL Severe pain; limiting self careADL Definition: A disorder characterized by marked discomfort sensation originating from a muscle or group of muscles. Myositis Mild pain Moderate pain associated withweakness; pain limitinginstrumental ADL Pain associated with severeweakness; limiting self careADL Definition: A disorder characterized by inflammation involving the skeletal muscles. Neck pain Mild pain Moderate pain; limitinginstrumental ADL Severe pain; limiting self careADL Definition: A disorder characterized by marked discomfort sensation in the neck area. Neck soft tissue necrosis Local wound care; medicalintervention indicated (e.g.,dressings or topicalmedications) Operative debridement or otherinvasive intervention indicated(e.g., tissue reconstruction, flapor grafting) Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by a necrotic process occurring in the soft tissues of the neck. Osteonecrosis of jaw Asymptomatic; clinical ordiagnostic observations only;intervention not indicated Symptomatic; medicalintervention indicated (e.g.,topical agents); limitinginstrumental ADL Severe symptoms; limiting selfcare ADL; elective operativeintervention indicated Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by a necrotic process occurring in the bone of the mandible. Osteoporosis Radiologic evidence ofosteoporosis or Bone MineralDensity (BMD) t-score -1 to -2.5(osteopenia); no loss of heightor intervention indicated BMD t-score <-2.5; loss ofheight <2 cm; anti-osteoporotictherapy indicated; limitinginstrumental ADL Loss of height >=2 cm;hospitalization indicated; limitingself care ADL Definition: A disorder characterized by reduced bone mass, with a decrease in cortical thickness and in the number and size of the trabeculae of cancellous bone (but normal chemicalcomposition), resulting in increased fracture incidence. Pain in extremity Mild pain Moderate pain; limitinginstrumental ADL Severe pain; limiting self careADL Definition: A disorder characterized by marked discomfort sensation in the upper or lower extremities. Pelvic soft tissue necrosis Local wound care; medicalintervention indicated (e.g.,dressings or topicalmedications) Operative debridement or otherinvasive intervention indicated(e.g., tissue reconstruction, flapor grafting) Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by a necrotic process occurring in the soft tissues of the pelvis. Scoliosis <20 degrees; clinicallyundetectable >20 45 degrees; visible byforward flexion; limitinginstrumental ADL >45 degrees; scapularprominence in forward flexion;operative intervention indicated;limiting self care ADL; disabling Definition: A disorder characterized by a malformed, lateral curvature of the spine. Soft tissue necrosis lower limb Local wound care; medicalintervention indicated (e.g.,dressings or topicalmedications) Operative debridement or otherinvasive intervention indicated(e.g., tissue reconstruction, flapor grafting) Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by a necrotic process occurring in the soft tissues of the lower extremity. Soft tissue necrosis upper limb Local wound care; medicalintervention indicated (e.g.,dressings or topicalmedications) Operative debridement or otherinvasive intervention indicated(e.g., tissue reconstruction, flapor grafting) Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by a necrotic process occurring in the soft tissues of the upper extremity.

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CTCAE 4.03 June 14, 2010 : Musculoskeletal and connective tissue disorders 49 Musculoskeletal and connective tissue disorders Grade Adverse Event 1 2 3 4 5 Superficial soft tissue fibrosis Mild induration, able to moveskin parallel to plane (sliding)and perpendicular to skin(pinching up) Moderate induration, able toslide skin, unable to pinch skin;limiting instrumental ADL Severe induration; unable toslide or pinch skin; limiting jointor orifice movement (e.g.,mouth, anus); limiting self careADL Generalized; associated withsigns or symptoms of impairedbreathing or feeding Death Definition: A disorder characterized by fibrotic degeneration of the superficial soft tissues. Trismus Decreased ROM (range ofmotion) without impaired eating Decreased ROM requiring smallbites, soft foods or purees Decreased ROM with inability toadequately aliment or hydrateorally Definition: A disorder characterized by lack of ability to open the mouth fully due to a decrease in the range of motion of the muscles of mastication. Unequal limb length Mild length discrepancy <2 cm Moderate length discrepancy 2 -5 cm; shoe lift indicated; limitinginstrumental ADL Severe length discrepancy >5cm; limiting self care ADL;disabling; operative interventionindicated Definition: A disorder characterized by of a discrepancy between the lengths of the lower or upper extremities. Musculoskeletal and connectivetissue disorder Other, specify Asymptomatic or mildsymptoms; clinical or diagnosticobservations only; interventionnot indicated Moderate; minimal, local ornoninvasive interventionindicated; limiting age-appropriate instrumental ADL Severe or medically significantbut not immediately life-threatening; hospitalization orprolongation of existinghospitalization indicated;disabling; limiting self care ADL Life-threatening consequences;urgent intervention indicated Death

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CTCAE 4.03 June 14, 2010 : Neoplasms benign, malignant and unspecified (incl cysts and polyps) 50 17. Neoplasms benign, malignant and unspecified (incl cysts and polyps) Neoplasms benign, malignant and unspecified (incl cysts and polyps) Grade Adverse Event 1 2 3 4 5 Leukemia secondary tooncology chemotherapy Present Death Definition: A disorder characterized by leukemia arising as a result of the mutagenic effect of chemotherapy agents. Myelodysplastic syndrome Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by insufficiently healthy hematapoietic cell production by the bone marrow. Treatment related secondarymalignancy Non life-threatening secondarymalignancy Acute life-threatening secondarymalignancy; blast crisis inleukemia Death Definition: A disorder characterized by development of a malignancy most probably as a result of treatment for a previously existing malignancy. Tumor pain Mild pain Moderate pain; limitinginstrumental ADL Severe pain; limiting self careADL Definition: A disorder characterized by marked discomfort from a neoplasm that may be pressing on a nerve, blocking blood vessels, inflamed or fractured from metastasis. Neoplasms benign, malignantand unspecified (incl cysts andpolyps) Other, specify Asymptomatic or mildsymptoms; clinical or diagnosticobservations only; interventionnot indicated Moderate; minimal, local ornoninvasive interventionindicated; limiting age-appropriate instrumental ADL Severe or medically significantbut not immediately life-threatening; hospitalization orprolongation of existinghospitalization indicated;disabling; limiting self care ADL Life-threatening consequences;urgent intervention indicated Death

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CTCAE 4.03 June 14, 2010 : Nervous system disorders 51 18. Nervous system disorders Nervous system disorders Grade Adverse Event 1 2 3 4 5 Abducens nerve disorder Asymptomatic; clinical ordiagnostic observations only;intervention not indicated Moderate symptoms; limitinginstrumental ADL Severe symptoms; limiting selfcare ADL Definition: A disorder characterized by involvement of the abducens nerve (sixth cranial nerve). Accessory nerve disorder Asymptomatic; clinical ordiagnostic observations only;intervention not indicated Moderate symptoms; limitinginstrumental ADL Severe symptoms; limiting selfcare ADL Definition: A disorder characterized by involvement of the accessory nerve (eleventh cranial nerve). Acoustic nerve disorder NOS Asymptomatic; clinical ordiagnostic observations only;intervention not indicated Moderate symptoms; limitinginstrumental ADL Severe symptoms; limiting selfcare ADL Definition: A disorder characterized by involvement of the acoustic nerve (eighth cranial nerve). Akathisia Mild restlessness or increasedmotor activity Moderate restlessness orincreased motor activity; limitinginstrumental ADL Severe restlessness orincreased motor activity; limitingself care ADL Definition: A disorder characterized by an uncomfortable feeling of inner restlessness and inability to stay still; this is a side effect of some psychotropic drugs. Amnesia Mild; transient memory loss Moderate; short term memoryloss; limiting instrumental ADL Severe; long term memory loss;limiting self care ADL Definition: A disorder characterized by systematic and extensive loss of memory. Aphonia Voicelessness; unable to speak Definition: A disorder characterized by the inability to speak. It may result from injuries to the vocal cords or may be functional (psychogenic). Arachnoiditis Mild symptoms Moderate symptoms; limitinginstrumental ADL Severe symptoms; limiting selfcare ADL Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by inflammation of the arachnoid membrane and adjacent subarachnoid space. Ataxia Asymptomatic; clinical ordiagnostic observations only;intervention not indicated Moderate symptoms; limitinginstrumental ADL Severe symptoms; limiting selfcare ADL; mechanicalassistance indicated Definition: A disorder characterized by lack of coordination of muscle movements resulting in the impairment or inability to perform voluntary activities. Brachial plexopathy Asymptomatic; clinical ordiagnostic observations only;intervention not indicated Moderate symptoms; limitinginstrumental ADL Severe symptoms; limiting selfcare ADL Definition: A disorder characterized by regional paresthesia of the brachial plexus, marked discomfort and muscle weakness, and limited movement in the arm or hand. Central nervous systemnecrosis Asymptomatic; clinical ordiagnostic observations only;intervention not indicated Moderate symptoms;corticosteroids indicated Severe symptoms; medicalintervention indicated Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by a necrotic process occurring in the brain and/or spinal cord. Cerebrospinal fluid leakage Post-craniotomy: asymptomatic;Post-lumbar puncture: transientheadache; postural careindicated Post-craniotomy: moderatesymptoms; medical interventionindicated; Post-lumbarpuncture: persistent moderatesymptoms; blood patchindicated Severe symptoms; medicalintervention indicated Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by loss of cerebrospinal fluid into the surrounding tissues. Cognitive disturbance Mild cognitive disability; notinterfering with work/school/lifeperformance; specializededucational services/devicesnot indicated Moderate cognitive disability;interfering with work/school/lifeperformance but capable ofindependent living; specializedresources on part time basisindicated Severe cognitive disability;significant impairment ofwork/school/life performance Definition: A disorder characterized by a conspicuous change in cognitive function. Concentration impairment Mild inattention or decreasedlevel of concentration Moderate impairment inattention or decreased level ofconcentration; limitinginstrumental ADL Severe impairment in attentionor decreased level ofconcentration; limiting self careADL Definition: A disorder characterized by a deterioration in the ability to concentrate.

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CTCAE 4.03 June 14, 2010 : Nervous system disorders 52 Nervous system disorders Grade Adverse Event 1 2 3 4 5 Depressed level ofconsciousness Decreased level of alertness Sedation; slow response tostimuli; limiting instrumentalADL Difficult to arouse Life-threatening consequences Death Definition: A disorder characterized by a decrease in ability to perceive and respond. Dizziness Mild unsteadiness or sensationof movement Moderate unsteadiness orsensation of movement; limitinginstrumental ADL Severe unsteadiness orsensation of movement; limitingself care ADL Definition: A disorder characterized by a disturbing sensation of lightheadedness, unsteadiness, giddiness, spinning or rocking. Dysarthria Mild slurred speech Moderate impairment ofarticulation or slurred speech Severe impairment ofarticulation or slurred speech Definition: A disorder characterized by slow and slurred speech resulting from an inability to coordinate the muscles used in speech. Dysesthesia Mild sensory alteration Moderate sensory alteration;limiting instrumental ADL Severe sensory alteration;limiting self care ADL Definition: A disorder characterized by distortion of sensory perception, resulting in an abnormal and unpleasant sensation. Dysgeusia Altered taste but no change indiet Altered taste with change in diet(e.g., oral supplements);noxious or unpleasant taste;loss of taste Definition: A disorder characterized by abnormal sensual experience with the taste of foodstuffs; it can be related to a decrease in the sense of smell. Dysphasia Awareness of receptive orexpressive characteristics; notimpairing ability to communicate Moderate receptive orexpressive characteristics;impairing ability to communicatespontaneously Severe receptive or expressivecharacteristics; impairing abilityto read, write or communicateintelligibly Definition: A disorder characterized by impairment of verbal communication skills, often resulting from brain damage. Edema cerebral Life-threatening consequences;urgent intervention indicated Definition: A disorder characterized by swelling due to an excessive accumulation of fluid in the brain. Encephalopathy Mild symptoms Moderate symptoms; limitinginstrumental ADL Severe symptoms; limiting selfcare ADL Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by a pathologic process involving the brain. Extrapyramidal disorder Mild involuntary movements Moderate involuntarymovements; limitinginstrumental ADL Severe involuntary movementsor torticollis; limiting self careADL Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by abnormal, repetitive, involuntary muscle movements, frenzied speech and extreme restlessness. Facial muscle weakness Asymptomatic; clinical ordiagnostic observations only;intervention not indicated Moderate symptoms; limitinginstrumental ADL Severe symptoms; limiting selfcare ADL Definition: A disorder characterized by a reduction in the strength of the facial muscles. Facial nerve disorder Asymptomatic; clinical ordiagnostic observations only;intervention not indicated Moderate symptoms; limitinginstrumental ADL Severe symptoms; limiting selfcare ADL Definition: A disorder characterized by involvement of the facial nerve (seventh cranial nerve). Glossopharyngeal nervedisorder Asymptomatic; clinical ordiagnostic observations only;intervention not indicated Moderate symptoms; limitinginstrumental ADL Severe symptoms; limiting selfcare ADL Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by involvement of the glossopharyngeal nerve (ninth cranial nerve). Headache Mild pain Moderate pain; limitinginstrumental ADL Severe pain; limiting self careADL Definition: A disorder characterized by a sensation of marked discomfort in various parts of the head, not confined to the area of distribution of any nerve. Hydrocephalus Asymptomatic; clinical ordiagnostic observations only;intervention not indicated Moderate symptoms;intervention not indicated Severe symptoms orneurological deficit; interventionindicated Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by an abnormal increase of cerebrospinal fluid in the ventricles of the brain. Hypersomnia Mild increased need for sleep Moderate increased need forsleep Severe increased need forsleep Definition: A disorder characterized by characterized by excessive sleepiness during the daytime.

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CTCAE 4.03 June 14, 2010 : Nervous system disorders 53 Nervous system disorders Grade Adverse Event 1 2 3 4 5 Hypoglossal nerve disorder Asymptomatic; clinical ordiagnostic observations only;intervention not indicated Moderate symptoms; limitinginstrumental ADL Severe symptoms; limiting selfcare ADL Definition: A disorder characterized by involvement of the hypoglossal nerve (twelfth cranial nerve). Intracranial hemorrhage Asymptomatic; clinical ordiagnostic observations only;intervention not indicated Moderate symptoms; medicalintervention indicated Ventriculostomy, ICPmonitoring, intraventricularthrombolysis, or operativeintervention indicated Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by bleeding from the cranium. Ischemia cerebrovascular Asymptomatic; clinical ordiagnostic observations only;intervention not indicated Moderate symptoms Definition: A disorder characterized by a decrease or absence of blood supply to the brain caused by obstruction (thrombosis or embolism) of an artery resulting in neurologicaldamage. IVth nerve disorder Asymptomatic; clinical ordiagnostic observations only;intervention not indicated Moderate symptoms; limitinginstrumental ADL Severe symptoms; limiting selfcare ADL Definition: A disorder characterized by involvement of the trochlear nerve (fourth cranial nerve). Lethargy Mild symptoms; reducedalertness and awareness Moderate symptoms; limitinginstrumental ADL Definition: A disorder characterized by a decrease in consciousness characterized by mental and physical inertness. Leukoencephalopathy Asymptomatic; small focalT2/FLAIR hyperintensities;involving periventricular whitematter or <1/3 of susceptibleareas of cerebrum +/mildincrease in subarachnoid space(SAS) and/or mildventriculomegaly Moderate symptoms; focalT2/FLAIR hyperintensities,involving periventricular whitematter extending into centrumsemiovale or involving 1/3 to 2/3of susceptible areas ofcerebrum +/moderate increasein SAS and/or moderateventriculomegaly Severe symptoms; extensiveT2/FLAIR hyperintensities,involving periventricular whitematter involving 2/3 or more ofsusceptible areas of cerebrum+/moderate to severe increasein SAS and/or moderate tosevere ventriculomegaly Life-threatening consequences;extensive T2/FLAIRhyperintensities, involvingperiventricular white matterinvolving most of susceptibleareas of cerebrum +/moderateto severe increase in SASand/or moderate to severeventriculomegaly Death Definition: A disorder characterized by diffuse reactive astrocytosis with multiple areas of necrotic foci without inflammation. Memory impairment Mild memory impairment Moderate memory impairment;limiting instrumental ADL Severe memory impairment;limiting self care ADL Definition: A disorder characterized by a deterioration in memory function. Meningismus Mild symptoms Moderate symptoms; limitinginstrumental ADL Severe symptoms; limiting selfcare ADL Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by neck stiffness, headache, and photophobia resulting from irritation of the cerebral meninges. Movements involuntary Mild symptoms Moderate symptoms; limitinginstrumental ADL Severe symptoms; limiting selfcare ADL Definition: A disorder characterized by uncontrolled and purposeless movements. Myelitis Asymptomatic; mild signs (e.g.,Babinski's reflex or Lhermitte'ssign) Moderate weakness or sensoryloss; limiting instrumental ADL Severe weakness or sensoryloss; limiting self care ADL Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by inflammation involving the spinal cord. Symptoms include weakness, paresthesia, sensory loss, marked discomfort and incontinence. Neuralgia Mild pain Moderate pain; limitinginstrumental ADL Severe pain; limiting self careADL Definition: A disorder characterized by intense painful sensation along a nerve or group of nerves. Nystagmus Moderate symptoms; limitinginstrumental ADL Severe symptoms; limiting selfcare ADL Definition: A disorder characterized by involuntary movements of the eyeballs. Oculomotor nerve disorder Asymptomatic; clinical ordiagnostic observations only;intervention not indicated Moderate symptoms; limitinginstrumental ADL Severe symptoms; limiting selfcare ADL Definition: A disorder characterized by involvement of the oculomotor nerve (third cranial nerve). Olfactory nerve disorder Moderate symptoms; limitinginstrumental ADL Severe symptoms; limiting selfcare ADL Definition: A disorder characterized by involvement of the olfactory nerve (first cranial nerve).

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CTCAE 4.03 June 14, 2010 : Nervous system disorders 54 Nervous system disorders Grade Adverse Event 1 2 3 4 5 Paresthesia Mild symptoms Moderate symptoms; limitinginstrumental ADL Severe symptoms; limiting selfcare ADL Definition: A disorder characterized by functional disturbances of sensory neurons resulting in abnormal cutaneous sensations of tingling, numbness, pressure, cold, and warmth thatare experienced in the absence of a stimulus. Peripheral motor neuropathy Asymptomatic; clinical ordiagnostic observations only;intervention not indicated Moderate symptoms; limitinginstrumental ADL Severe symptoms; limiting selfcare ADL; assistive deviceindicated Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by inflammation or degeneration of the peripheral motor nerves. Peripheral sensory neuropathy Asymptomatic; loss of deeptendon reflexes or paresthesia Moderate symptoms; limitinginstrumental ADL Severe symptoms; limiting selfcare ADL Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by inflammation or degeneration of the peripheral sensory nerves. Phantom pain Mild pain Moderate pain; limitinginstrumental ADL Severe pain; limiting self careADL Definition: A disorder characterized by marked discomfort related to a limb or an organ that is removed from or is not physically part of the body. Presyncope Present (e.g., near fainting) Definition: A disorder characterized by an episode of lightheadedness and dizziness which may precede an episode of syncope. Pyramidal tract syndrome Asymptomatic; clinical ordiagnostic observations only;intervention not indicated Moderate symptoms; limitinginstrumental ADL Severe symptoms; limiting selfcare ADL Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by dysfunction of the corticospinal (pyramidal) tracts of the spinal cord. Symptoms include an increase in the muscle tone in the lower extremities,hyperreflexia, positive Babinski and a decrease in fine motor coordination. Radiculitis Mild symptoms Moderate symptoms; limitinginstrumental ADL; medicalintervention indicated Severe symptoms; limiting selfcare ADL Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by inflammation involving a nerve root. Patients experience marked discomfort radiating along a nerve path because of spinal pressure on theconnecting nerve root. Recurrent laryngeal nerve palsy Asymptomatic; clinical ordiagnostic observations only;intervention not indicated Moderate symptoms Severe symptoms; medicalintervention indicated (e.g.,thyroplasty, vocal cord injection) Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by paralysis of the recurrent laryngeal nerve. Reversible posteriorleukoencephalopathy syndrome Asymptomatic; clinical ordiagnostic observations only;intervention not indicated Moderate symptoms; abnormalimaging studies; limitinginstrumental ADL Severe symptoms; veryabnormal imaging studies;limiting self care ADL Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by headaches, mental status changes, visual disturbances, and seizures associated with imaging findings of posterior leukoencephalopathy. It hasbeen observed in association with hypertensive encephalopathy, eclampsia, and immunosuppressive and cytotoxic drug treatment. It is an acute or subacute reversible condition. Seizure Brief partial seizure; no loss ofconsciousness Brief generalized seizure Multiple seizures despitemedical intervention Life-threatening; prolongedrepetitive seizures Death Definition: A disorder characterized by a sudden, involuntary skeletal muscular contractions of cerebral or brain stem origin. Sinus pain Mild pain Moderate pain; limitinginstrumental ADL Severe pain; limiting self careADL Definition: A disorder characterized by marked discomfort in the face, between the eyes, or upper teeth originating from the sinuses. Somnolence Mild but more than usualdrowsiness or sleepiness Moderate sedation; limitinginstrumental ADL Obtundation or stupor Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by characterized by excessive sleepiness and drowsiness. Spasticity Mild or slight increase in muscletone Moderate increase in muscletone and increase in resistancethrough range of motion Severe increase in muscle toneand increase in resistancethrough range of motion Life-threatening; unable to moveactive or passive range ofmotion Death Definition: A disorder characterized by increased involuntary muscle tone that affects the regions interfering with voluntary movement. It results in gait, movement, and speechdisturbances. Stroke Asymptomatic or mildneurologic deficit; radiographicfindings only Moderate neurologic deficit Severe neurologic deficit Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by a sudden loss of sensory function due to an intracranial vascular event. Syncope Fainting; orthostatic collapse Definition: A disorder characterized by spontaneous loss of consciousness caused by insufficient blood supply to the brain.

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CTCAE 4.03 June 14, 2010 : Nervous system disorders 55 Nervous system disorders Grade Adverse Event 1 2 3 4 5 Transient ischemic attacks Mild neurologic deficit with orwithout imaging confirmation Moderate neurologic deficit withor without imaging confirmation Definition: A disorder characterized by a brief attack (less than 24 hours) of cerebral dysfunction of vascular origin, with no persistent neurological deficit. Tremor Mild symptoms Moderate symptoms; limitinginstrumental ADL Severe symptoms; limiting selfcare ADL Definition: A disorder characterized by the uncontrolled shaking movement of the whole body or individual parts. Trigeminal nerve disorder Asymptomatic; clinical ordiagnostic observations only;intervention not indicated Moderate symptoms; limitinginstrumental ADL Severe symptoms; limiting selfcare ADL Definition: A disorder characterized by involvement of the trigeminal nerve (fifth cranial nerve). Vagus nerve disorder Asymptomatic; clinical ordiagnostic observations only;intervention not indicated Moderate symptoms; limitinginstrumental ADL Severe symptoms; limiting selfcare ADL Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by involvement of the vagus nerve (tenth cranial nerve). Vasovagal reaction Present Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by a sudden drop of the blood pressure, bradycardia, and peripheral vasodilation that may lead to loss of consciousness. It results from anincrease in the stimulation of the vagus nerve. Nervous system disorders -Other, specify Asymptomatic or mildsymptoms; clinical or diagnosticobservations only; interventionnot indicated Moderate; minimal, local ornoninvasive interventionindicated; limiting age-appropriate instrumental ADL Severe or medically significantbut not immediately life-threatening; hospitalization orprolongation of existinghospitalization indicated;disabling; limiting self care ADL Life-threatening consequences;urgent intervention indicated Death

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CTCAE 4.03 June 14, 2010 : Pregnancy, puerperium and perinatal conditions 56 19. Pregnancy, puerperium and perinatal conditions Pregnancy, puerperium and perinatal conditions Grade Adverse Event 1 2 3 4 5 Fetal death Fetal loss atanygestationalage Definition: A disorder characterized by death in utero; failure of the product of conception to show evidence of respiration, heartbeat, or definite movement of a voluntary muscle afterexpulsion from the uterus, without possibility of resuscitation. Fetal growth retardation <10% percentile of weight forgestational age <5% percentile of weight forgestational age <1% percentile of weight forgestational age Definition: A disorder characterized by inhibition of fetal growth resulting in the inability of the fetus to achieve its potential weight. Premature delivery Delivery of a liveborn infant at>34 to 37 weeks gestation Delivery of a liveborn infant at>28 to 34 weeks gestation Delivery of a liveborn infant at24 to 28 weeks gestation Delivery of a liveborn infant at24 weeks of gestation or less Definition: A disorder characterized by delivery of a viable infant before the normal end of gestation. Typically, viability is achievable between the twentieth and thirty-seventh week ofgestation. Unintended pregnancy Unintended pregnancy Definition: A disorder characterized by an unexpected pregnancy at the time of conception. Pregnancy, puerperium andperinatal conditions Other,specify Asymptomatic or mildsymptoms; clinical or diagnosticobservations only; interventionnot indicated Moderate, local or noninvasiveintervention indicated; limitinginstrumental ADL Severe or medically significantbut not immediately life-threatening; hospitalization orprolongation of existinghospitalization indicated;disabling; limiting self care ADL Life-threatening consequences;urgent intervention indicated Death

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CTCAE 4.03 June 14, 2010 : Psychiatric disorders 57 20. Psychiatric disorders Psychiatric disorders Grade Adverse Event 1 2 3 4 5 Agitation Mild mood alteration Moderate mood alteration Severe agitation; hospitalizationnot indicated Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by a state of restlessness associated with unpleasant feelings of irritability and tension. Anorgasmia Inability to achieve orgasm notadversely affecting relationship Inability to achieve orgasmadversely affecting relationship Definition: A disorder characterized by an inability to achieve orgasm. Anxiety Mild symptoms; intervention notindicated Moderate symptoms; limitinginstrumental ADL Severe symptoms; limiting selfcare ADL; hospitalization notindicated Life-threatening; hospitalizationindicated Death Definition: A disorder characterized by apprehension of danger and dread accompanied by restlessness, tension, tachycardia, and dyspnea unattached to a clearly identifiablestimulus. Confusion Mild disorientation Moderate disorientation; limitinginstrumental ADL Severe disorientation; limitingself care ADL Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by a lack of clear and orderly thought and behavior. Delayed orgasm Delay in achieving orgasm notadversely affecting relationship Delay in achieving orgasmadversely affecting relationship Definition: A disorder characterized by sexual dysfunction characterized by a delay in climax. Delirium Mild acute confusional state Moderate and acute confusionalstate; limiting instrumental ADL Severe and acute confusionalstate; limiting self care ADL;hospitalization indicated Life-threatening consequences,threats of harm to self or others;hospitalization indicated Death Definition: A disorder characterized by the acute and sudden development of confusion, illusions, movement changes, inattentiveness, agitation, and hallucinations. Usually, it is areversible condition. Delusions Moderate delusional symptoms Severe delusional symptoms;hospitalization not indicated Life-threatening consequences,threats of harm to self or others;hospitalization indicated Death Definition: A disorder characterized by false personal beliefs held contrary to reality, despite contradictory evidence and common sense. Depression Mild depressive symptoms Moderate depressivesymptoms; limiting instrumentalADL Severe depressive symptoms;limiting self care ADL;hospitalization not indicated Life-threatening consequences,threats of harm to self or others;hospitalization indicated Death Definition: A disorder characterized by melancholic feelings of grief or unhappiness. Euphoria Mild mood elevation Moderate mood elevation Severe mood elevation (e.g.,hypomania) Definition: A disorder characterized by an exaggerated feeling of well-being which is disproportionate to events and stimuli. Hallucinations Mild hallucinations (e.g.,perceptual distortions) Moderate hallucinations Severe hallucinations;hospitalization not indicated Life-threatening consequences,threats of harm to self or others;hospitalization indicated Death Definition: A disorder characterized by a false sensory perception in the absence of an external stimulus. Insomnia Mild difficulty falling asleep,staying asleep or waking upearly Moderate difficulty fallingasleep, staying asleep orwaking up early Severe difficulty in fallingasleep, staying asleep orwaking up early Definition: A disorder characterized by difficulty in falling asleep and/or remaining asleep. Libido decreased Decrease in sexual interest notadversely affecting relationship Decrease in sexual interestadversely affecting relationship Definition: A disorder characterized by a decrease in sexual desire. Libido increased Mild increase in sexual interestnot adversely affectingrelationship Moderate increase in sexualinterest adversely affectingrelationship Severe increase in sexualinterest leading to dangerousbehavior Definition: A disorder characterized by an increase in sexual desire. Mania Mild manic symptoms (e.g.,elevated mood, rapid thoughts,rapid speech, decreased needfor sleep) Moderate manic symptoms(e.g., relationship and workdifficulties; poor hygiene) Severe manic symptoms (e.g.,hypomania; major sexual orfinancial indiscretions);hospitalization not indicated Life-threatening consequences,threats of harm to self or others;hospitalization indicated Death Definition: A disorder characterized by excitement of psychotic proportions manifested by mental and physical hyperactivity, disorganization of behavior and elevation of mood. Personality change Mild personality change Moderate personality change Severe personality change;hospitalization not indicated Life-threatening consequences,threats of harm to self or others;hospitalization indicated Death

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CTCAE 4.03 June 14, 2010 : Psychiatric disorders 58 Psychiatric disorders Grade Adverse Event 1 2 3 4 5 Definition: A disorder characterized by a conspicuous change in a person's behavior and thinking. Psychosis Mild psychotic symptoms Moderate psychotic symptoms(e.g., disorganized speech;impaired reality testing) Severe psychotic symptoms(e.g., paranoid; extremedisorganization); hospitalizationnot indicated Life-threatening consequences,threats of harm to self or others;hospitalization indicated Death Definition: A disorder characterized by personality change, impaired functioning, and loss of touch with reality. It may be a manifestation of schizophrenia, bipolar disorder or braintumor. Restlessness Mild symptoms; intervention notindicated Moderate symptoms; limitinginstrumental ADL Severe symptoms; limiting selfcare ADL Definition: A disorder characterized by an inability to rest, relax or be still. Suicidal ideation Increased thoughts of death butno wish to kill oneself Suicidal ideation with no specificplan or intent Specific plan to commit suicidewithout serious intent to diewhich may not requirehospitalization Specific plan to commit suicidewith serious intent to die whichrequires hospitalization Definition: A disorder characterized by thoughts of taking one's own life. Suicide attempt Suicide attempt or gesturewithout intent to die which maynot require hospitalization Suicide attempt with intent todie which requireshospitalization Death Definition: A disorder characterized by self-inflicted harm in an attempt to end one's own life. Psychiatric disorders Other,specify Asymptomatic or mildsymptoms; clinical or diagnosticobservations only; interventionnot indicated Moderate; minimal, local ornoninvasive interventionindicated; limiting age-appropriate instrumental ADL Severe or medically significantbut not immediately life-threatening; disabling; limitingself care ADL Life-threatening consequences;hospitalization or urgentintervention indicated Death

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CTCAE 4.03 June 14, 2010 : Renal and urinary disorders 59 21. Renal and urinary disorders Renal and urinary disorders Grade Adverse Event 1 2 3 4 5 Acute kidney injury Creatinine level increase of >0.3mg/dL; creatinine 1.5 2.0 xabove baseline Creatinine 2 3 x abovebaseline Creatinine >3 x baseline or >4.0mg/dL; hospitalization indicated Life-threatening consequences;dialysis indicated Death Definition: A disorder characterized by the acute loss of renal function and is traditionally classified as pre-renal (low blood flow into kidney), renal (kidney damage) and post-renalcauses (ureteral or bladder outflow obstruction). Bladder perforation Extraperitoneal perforation,indwelling catheter indicated Intraperitoneal perforation;elective radiologic, endoscopicor operative interventionindicated Life-threatening consequences;organ failure; urgent operativeintervention indicated Death Definition: A disorder characterized by a rupture in the bladder wall. Bladder spasm Intervention not indicated Antispasmodics indicated Hospitalization indicated Definition: A disorder characterized by a sudden and involuntary contraction of the bladder wall. Chronic kidney disease eGFR (estimated GlomerularFiltration Rate) or CrCl(creatinine clearance) 0.5 eGFR or CrCl 59 30ml/min/1.73 m2 eGFR or CrCl 29 15ml/min/1.73 m2 eGFR or CrCl <15 ml/min/1.73m2; dialysis or renal transplantindicated Death Definition: A disorder characterized by gradual and usually permanent loss of kidney function resulting in renal failure. Cystitis noninfective Microscopic hematuria; minimalincrease in frequency, urgency,dysuria, or nocturia; new onsetof incontinence Moderate hematuria; moderateincrease in frequency, urgency,dysuria, nocturia orincontinence; urinary catheterplacement or bladder irrigationindicated; limiting instrumentalADL Gross hematuria; transfusion, IVmedications or hospitalizationindicated; elective endoscopic,radiologic or operativeintervention indicated Life-threatening consequences;urgent radiologic or operativeintervention indicated Death Definition: A disorder characterized by inflammation of the bladder which is not caused by an infection of the urinary tract. Hematuria Asymptomatic; clinical ordiagnostic observations only;intervention not indicated Symptomatic; urinary catheteror bladder irrigation indicated;limiting instrumental ADL Gross hematuria; transfusion, IVmedications or hospitalizationindicated; elective endoscopic,radiologic or operativeintervention indicated; limitingself care ADL Life-threatening consequences;urgent radiologic or operativeintervention indicated Death Definition: A disorder characterized by laboratory test results that indicate blood in the urine. Hemoglobinuria Asymptomatic; clinical ordiagnostic observations only;intervention not indicated Definition: A disorder characterized by laboratory test results that indicate the presence of free hemoglobin in the urine. Proteinuria 1+ proteinuria; urinary protein<1.0 g/24 hrs Adults: 2+ proteinuria; urinaryprotein 1.0 3.4 g/24 hrs;Pediatric: urine P/C(Protein/Creatinine) ratio 0.5 -1.9 Adults: urinary protein >=3.5g/24 hrs;Pediatric: urine P/C >1.9 Definition: A disorder characterized by laboratory test results that indicate the presence of excessive protein in the urine. It is predominantly albumin, but also globulin. Renal calculi Asymptomatic or mildsymptoms; occasional use ofnonprescription analgesicsindicated Symptomatic; oral antiemeticsindicated; around the clocknonprescription analgesics orany oral narcotic analgesicsindicated Hospitalization indicated; IVintervention (e.g., analgesics,antiemetics); electiveendoscopic or radiologicintervention indicated Life-threatening consequences;urgent radiologic, endoscopic oroperative intervention indicated Death Definition: A disorder characterized by the formation of crystals in the pelvis of the kidney. Renal colic Mild pain not interfering withactivity; nonprescriptionmedication indicated Moderate pain; limitinginstrumental ADL; prescriptionmedication indicated Hospitalization indicated;limiting self care ADL Definition: A disorder characterized by paroxysmal and severe flank marked discomfort radiating to the inguinal area. Often, the cause is the passage of kidney stones.

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CTCAE 4.03 June 14, 2010 : Renal and urinary disorders 60 Renal and urinary disorders Grade Adverse Event 1 2 3 4 5 Renal hemorrhage Mild symptoms; intervention notindicated Analgesics and hematocritmonitoring indicated Transfusion, radiation, orhospitalization indicated;elective radiologic, endoscopicor operative interventionindicated Life-threatening consequences;urgent radiologic or operativeintervention indicated Death Definition: A disorder characterized by bleeding from the kidney. Urinary fistula Noninvasive interventionindicated; urinary or suprapubiccatheter placement indicated Limiting self care ADL; electiveradiologic, endoscopic oroperative intervention indicated;permanent urinary diversionindicated Life-threatening consequences;urgent radiologic or operativeintervention indicated Death Definition: A disorder characterized by an abnormal communication between any part of the urinary system and another organ or anatomic site. Urinary frequency Present Limiting instrumental ADL;medical management indicated Definition: A disorder characterized by urination at short intervals. Urinary incontinence Occasional (e.g., with coughing,sneezing, etc.), pads notindicated Spontaneous; pads indicated;limiting instrumental ADL Intervention indicated (e.g.,clamp, collagen injections);operative intervention indicated;limiting self care ADL Definition: A disorder characterized by inability to control the flow of urine from the bladder. Urinary retention Urinary, suprapubic orintermittent catheter placementnot indicated; able to void withsome residual Placement of urinary,suprapubic or intermittentcatheter placement indicated;medication indicated Elective operative or radiologicintervention indicated;substantial loss of affectedkidney function or mass Life-threatening consequences;organ failure; urgent operativeintervention indicated Death Definition: A disorder characterized by accumulation of urine within the bladder because of the inability to urinate. Urinary tract obstruction Asymptomatic; clinical ordiagnostic observations only Symptomatic but nohydronephrosis, sepsis or renaldysfunction; urethral dilation,urinary or suprapubic catheterindicated Symptomatic and altered organfunction (e.g., hydronephrosis,or renal dysfunction); electiveradiologic, endoscopic oroperative intervention indicated Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by blockage of the normal flow of contents of the urinary tract. Urinary tract pain Mild pain Moderate pain; limitinginstrumental ADL Severe pain; limiting self careADL Definition: A disorder characterized by a sensation of marked discomfort in the urinary tract. Urinary urgency Present Limiting instrumental ADL;medical management indicated Definition: A disorder characterized by a sudden compelling urge to urinate. Urine discoloration Present Definition: A disorder characterized by a change in the color of the urine. Renal and urinary disorders -Other, specify Asymptomatic or mildsymptoms; clinical or diagnosticobservations only; interventionnot indicated Moderate, local or noninvasiveintervention indicated; limitinginstrumental ADL Severe or medically significantbut not immediately life-threatening; hospitalization orprolongation of existinghospitalization indicated;disabling; limiting self care ADL Life-threatening consequences;urgent intervention indicated Death

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CTCAE 4.03 June 14, 2010 : Reproductive system and breast disorders 61 22. Reproductive system and breast disorders Reproductive system and breast disorders Grade Adverse Event 1 2 3 4 5 Azoospermia Absence of sperm in ejaculate Definition: A disorder characterized by laboratory test results that indicate complete absence of spermatozoa in the semen. Breast atrophy Minimal asymmetry; minimalatrophy Moderate asymmetry; moderateatrophy Asymmetry >1/3 of breastvolume; severe atrophy Definition: A disorder characterized by underdevelopment of the breast. Breast pain Mild pain Moderate pain; limitinginstrumental ADL Severe pain; limiting self careADL Definition: A disorder characterized by marked discomfort sensation in the breast region. Dysmenorrhea Mild symptoms; intervention notindicated Moderate symptoms; limitinginstrumental ADL Severe symptoms; limiting selfcare ADL Definition: A disorder characterized by abnormally painful abdominal cramps during menses. Dyspareunia Mild discomfort or painassociated with vaginalpenetration; discomfort relievedwith use of vaginal lubricants orestrogen Moderate discomfort or painassociated with vaginalpenetration; discomfort or painpartially relieved with use ofvaginal lubricants or estrogen Severe discomfort or painassociated with vaginalpenetration; discomfort or painunrelieved by vaginal lubricantsor estrogen Definition: A disorder characterized by painful or difficult coitus. Ejaculation disorder Diminished ejaculation Anejaculation or retrogradeejaculation Definition: A disorder characterized by problems related to ejaculation. This category includes premature, delayed, retrograde and painful ejaculation. Erectile dysfunction Decrease in erectile function(frequency or rigidity oferections) but intervention notindicated (e.g., medication oruse of mechanical device,penile pump) Decrease in erectile function(frequency/rigidity of erections),erectile intervention indicated,(e.g., medication or mechanicaldevices such as penile pump) Decrease in erectile function(frequency/rigidity of erections)but erectile intervention nothelpful (e.g., medication ormechanical devices such aspenile pump); placement of apermanent penile prosthesisindicated (not previouslypresent) Definition: A disorder characterized by the persistent or recurrent inability to achieve or to maintain an erection during sexual activity. Fallopian tube obstruction Diagnostic observations only;intervention not indicated Mild symptoms; electiveintervention indicated Severe symptoms; electiveoperative intervention indicated Definition: A disorder characterized by blockage of the normal flow of the contents in the fallopian tube. Fallopian tube stenosis Asymptomatic clinical ordiagnostic observations only;intervention not indicated Symptomatic and interventionnot indicated Severe symptoms; electiveoperative intervention indicated Life-threatening consequences;urgent operative interventionindicated (e.g., organ resection) Death Definition: A disorder characterized by a narrowing of the fallopian tube lumen. Female genital tract fistula Asymptomatic clinical ordiagnostic observations only;intervention not indicated Symptomatic and interventionnot indicated Severe symptoms; electiveoperative intervention indicated Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by an abnormal communication between a female reproductive system organ and another organ or anatomic site. Feminization acquired Mild symptoms; intervention notindicated Moderate symptoms; medicalintervention indicated Definition: A disorder characterized by the development of secondary female sex characteristics in males due to extrinsic factors. Genital edema Mild swelling or obscuration ofanatomic architecture on closeinspection Readily apparent obscuration ofanatomic architecture;obliteration of skin folds; readilyapparent deviation from normalanatomic contour Lymphorrhea; gross deviationfrom normal anatomic contour;limiting self care ADL Definition: A disorder characterized by swelling due to an excessive accumulation of fluid in the genitals. Gynecomastia Asymptomatic breastenlargement Symptomatic (e.g., pain orpsychosocial impact) Severe symptoms; electiveoperative intervention indicated Definition: A disorder characterized by excessive development of the breasts in males. Hematosalpinx Minimal bleeding identified onimaging study or laparoscopy;intervention not indicated Moderate bleeding; medicalintervention indicated Severe bleeding; transfusionindicated; radiologic orendoscopic interventionindicated Life-threatening consequences;urgent operative interventionindicated Death

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CTCAE 4.03 June 14, 2010 : Reproductive system and breast disorders 62 Reproductive system and breast disorders Grade Adverse Event 1 2 3 4 5 Definition: A disorder characterized by the presence of blood in a fallopian tube. Irregular menstruation Intermittent menses withskipped menses for no morethan 1 to 3 months Intermittent menses withskipped menses for more than 4to 6 months Persistent amenorrhea for morethan 6 months Definition: A disorder characterized by irregular cycle or duration of menses. Lactation disorder Mild changes in lactation, notsignificantly affecting productionor expression of breast milk Changes in lactation,significantly affecting breastproduction or expression ofbreast milk Definition: A disorder characterized by disturbances of milk secretion. It is not necessarily related to pregnancy that is observed in females and can be observed in males. Menorrhagia Mild; iron supplements indicated Moderate symptoms; medicalintervention indicated (e.g.,hormones) Severe; transfusion indicated;surgical intervention indicated(e.g., hysterectomy) Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by abnormally heavy vaginal bleeding during menses. Nipple deformity Asymptomatic; asymmetry withslight retraction and/orthickening of the nipple areolarcomplex Symptomatic; asymmetry ofnipple areolar complex withmoderate retraction and/orthickening of the nipple areolarcomplex Definition: A disorder characterized by a malformation of the nipple. Oligospermia Sperm concentration >48million/mL or motility >68% Sperm concentration 13 48million/mL or motility 32 68% Sperm concentration <13million/mL or motility <32% Definition: A disorder characterized by a decrease in the number of spermatozoa in the semen. Ovarian hemorrhage Minimal bleeding identified onimaging study or laproscopy;intervention not indicated Moderate bleeding; medicalintervention indicated Severe bleeding; transfusionindicated; radiologic orendoscopic interventionindicated Life-threatening consequences;urgent operative interventionindicated Death Definition: A disorder characterized by bleeding from the ovary. Ovarian rupture Asymptomatic clinical ordiagnostic observations only;intervention not indicated Symptomatic and interventionnot indicated Transfusion, radiologic,endoscopic, or electiveoperative intervention indicated Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by tearing or disruption of the ovarian tissue. Ovulation pain Mild pain Moderate pain; limitinginstrumental ADL Severe pain; limiting self careADL Definition: A disorder characterized by marked discomfort sensation in one side of the abdomen between menstrual cycles, around the time of the discharge of the ovum from theovarian follicle. Pelvic floor muscle weakness Asymptomatic; clinical ordiagnostic observations only;intervention not indicated Symptomatic, not interferingwith bladder, bowel, or vaginalfunction; limiting instrumentalADL Severe symptoms; limiting selfcare ADL Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by a reduction in the strength of the muscles of the pelvic floor. Pelvic pain Mild pain Moderate pain; limitinginstrumental ADL Severe pain; limiting self careADL Definition: A disorder characterized by marked discomfort sensation in the pelvis. Penile pain Mild pain Moderate pain; limitinginstrumental ADL Severe pain; limiting self careADL Definition: A disorder characterized by marked discomfort sensation in the penis. Perineal pain Mild pain Moderate pain; limitinginstrumental ADL Severe pain; limiting self careADL Definition: A disorder characterized by a sensation of marked discomfort in the area between the genital organs and the anus. Premature menopause Present Definition: A disorder characterized by ovarian failure before the age of 40. Symptoms include hot flashes, night sweats, mood swings and a decrease in sex drive. Prostatic hemorrhage Minimal bleeding identified onimaging study; intervention notindicated Moderate bleeding; medicalintervention indicated Severe bleeding; transfusionindicated; radiologic orendoscopic interventionindicated Life-threatening consequences;urgent operative interventionindicated Death

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CTCAE 4.03 June 14, 2010 : Reproductive system and breast disorders 63 Reproductive system and breast disorders Grade Adverse Event 1 2 3 4 5 Definition: A disorder characterized by bleeding from the prostate gland. Prostatic obstruction Diagnostic observations only;intervention not indicated Mild symptoms; electiveintervention indicated Severe symptoms; electiveoperative intervention indicated Definition: A disorder characterized by compression of the urethra secondary to enlargement of the prostate gland. This results in voiding difficulties (straining to void, slow urinestream, and incomplete emptying of the bladder). Prostatic pain Mild pain Moderate pain; limitinginstrumental ADL Severe pain; limiting self careADL Definition: A disorder characterized by a sensation of marked discomfort in the prostate gland. Scrotal pain Mild pain Moderate pain; limitinginstrumental ADL Severe pain; limiting self careADL Definition: A disorder characterized by marked discomfort sensation in the scrotal area. Spermatic cord hemorrhage Minimal bleeding identified onimaging study; intervention notindicated Moderate bleeding; medicalintervention indicated Severe bleeding; transfusionindicated; radiologic orendoscopic interventionindicated Life-threatening consequences;urgent operative interventionindicated Death Definition: A disorder characterized by bleeding from the spermatic cord. Spermatic cord obstruction Diagnostic observations only;intervention not indicated Mild symptoms; electiveintervention indicated Severe symptoms; electiveoperative intervention indicated Definition: A disorder characterized by blockage of the normal flow of the contents of the spermatic cord. Testicular disorder Asymptomatic; clinical ordiagnostic observations only;intervention not indicated Symptomatic but not interferingwith urination or sexualactivities; intervention notindicated; limiting instrumentalADL Severe symptoms; interferingwith urination or sexual function;limiting self care ADL;intervention indicated Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by involvement of the testis. Testicular hemorrhage Minimal bleeding identified onimaging study; intervention notindicated Moderate bleeding; medicalintervention indicated Severe bleeding; transfusionindicated; radiologic orendoscopic interventionindicated Life-threatening consequences;urgent operative interventionindicated Death Definition: A disorder characterized by bleeding from the testis. Testicular pain Mild pain Moderate pain; limitinginstrumental ADL Severe pain; limiting self careADL Definition: A disorder characterized by a sensation of marked discomfort in the testis. Uterine fistula Asymptomatic clinical ordiagnostic observations only;intervention not indicated Symptomatic and interventionnot indicated Severe symptoms; electiveoperative intervention indicated Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by an abnormal communication between the uterus and another organ or anatomic site. Uterine hemorrhage Minimal bleeding identified onimaging study; intervention notindicated Moderate bleeding; medicalintervention indicated Severe bleeding; transfusionindicated; radiologic orendoscopic interventionindicated Life-threatening consequences;urgent operative interventionindicated Death Definition: A disorder characterized by bleeding from the uterus. Uterine obstruction Diagnostic observations only;intervention not indicated Mild symptoms; electiveintervention indicated Severe symptoms; electiveoperative intervention indicated Definition: A disorder characterized by blockage of the uterine outlet. Uterine pain Mild pain Moderate pain; limitinginstrumental ADL Severe pain; limiting self careADL Definition: A disorder characterized by a sensation of marked discomfort in the uterus. Vaginal discharge Mild vaginal discharge (greaterthan baseline for patient) Moderate to heavy vaginaldischarge; use of perineal pador tampon indicated Definition: A disorder characterized by vaginal secretions. Mucus produced by the cervical glands is discharged from the vagina naturally, especially during the childbearing years. Vaginal dryness Mild vaginal dryness notinterfering with sexual function Moderate vaginal drynessinterfering with sexual functionor causing frequent discomfort Severe vaginal drynessresulting in dyspareunia orsevere discomfort Definition: A disorder characterized by an uncomfortable feeling of itching and burning in the vagina.

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CTCAE 4.03 June 14, 2010 : Reproductive system and breast disorders 64 Reproductive system and breast disorders Grade Adverse Event 1 2 3 4 5 Vaginal fistula Asymptomatic clinical ordiagnostic observations only;intervention not indicated Symptomatic and interventionnot indicated Severe symptoms; electiveoperative intervention indicated Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by an abnormal communication between the vagina and another organ or anatomic site. Vaginal hemorrhage Minimal bleeding identified onclinical exam or imaging study;intervention not indicated Moderate bleeding; medicalintervention indicated Severe bleeding; transfusionindicated; radiologic orendoscopic interventionindicated Life-threatening consequences;urgent operative interventionindicated Death Definition: A disorder characterized by bleeding from the vagina. Vaginal inflammation Mild discomfort or pain, edema,or redness Moderate discomfort or pain,edema, or redness; limitinginstrumental ADL Severe discomfort or pain,edema, or redness; limiting selfcare ADL; small areas ofmucosal ulceration Widespread areas of mucosalulceration; life-threateningconsequences; urgentintervention indicated Death Definition: A disorder characterized by inflammation involving the vagina. Symptoms may include redness, edema, marked discomfort and an increase in vaginal discharge. Vaginal obstruction Diagnostic observations only;intervention not indicated Mild symptoms; electiveintervention indicated Severe symptoms; electiveoperative intervention indicated Definition: A disorder characterized by blockage of vaginal canal. Vaginal pain Mild pain Moderate pain; limitinginstrumental ADL Severe pain; limiting self careADL Definition: A disorder characterized by a sensation of marked discomfort in the vagina. Vaginal perforation Asymptomatic clinical ordiagnostic observations only;intervention not indicated Symptomatic and interventionnot indicated Severe symptoms; electiveoperative intervention indicated Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by a rupture in the vaginal wall. Vaginal stricture Asymptomatic; mild vaginalshortening or narrowing Vaginal narrowing and/orshortening not interfering withphysical examination Vaginal narrowing and/orshortening interfering with theuse of tampons, sexual activityor physical examination Death Definition: A disorder characterized by a narrowing of the vaginal canal. Vaginismus Mild discomfort or painassociated with vaginalspasm/tightening; no impactupon sexual function or physicalexamination Moderate discomfort or painassociated with vaginalspasm/tightening; disruption insexual function and physicalexamination Severe discomfort or painassociated with vaginalspasm/tightening; unable totolerate vaginal penetration orphysical examination Definition: A disorder characterized by involuntary spasms of the pelvic floor muscles, resulting in pathologic tightness of the vaginal wall during penetration such as during sexualintercourse. Reproductive system and breastdisorders Other, specify Asymptomatic or mildsymptoms; clinical or diagnosticobservations only; interventionnot indicated Moderate; minimal, local ornoninvasive interventionindicated; limiting age-appropriate instrumental ADL Severe or medically significantbut not immediately life-threatening; hospitalization orprolongation of existinghospitalization indicated;disabling; limiting self care ADL Life-threatening consequences;urgent intervention indicated Death

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CTCAE 4.03 June 14, 2010 : Respiratory, thoracic and mediastinal disorders 65 23. Respiratory, thoracic and mediastinal disorders Respiratory, thoracic and mediastinal disorders Grade Adverse Event 1 2 3 4 5 Adult respiratory distresssyndrome Present with radiologic findings;intubation not indicated Life-threatening respiratory orhemodynamic compromise;intubation or urgent interventionindicated Death Definition: A disorder characterized by progressive and life-threatening pulmonary distress in the absence of an underlying pulmonary condition, usually following major trauma orsurgery. Allergic rhinitis Mild symptoms; intervention notindicated Moderate symptoms; medicalintervention indicated Definition: A disorder characterized by an inflammation of the nasal mucous membranes caused by an IgE-mediated response to external allergens. The inflammation may alsoinvolve the mucous membranes of the sinuses, eyes, middle ear, and pharynx. Symptoms include sneezing, nasal congestion, rhinorrhea and itching. Apnea Present; medical interventionindicated Life-threatening respiratory orhemodynamic compromise;intubation or urgent interventionindicated Death Definition: A disorder characterized by cessation of breathing. Aspiration Asymptomatic; clinical ordiagnostic observations only;intervention not indicated Altered eating habits; coughingor choking episodes after eatingor swallowing; medicalintervention indicated (e.g.,suction or oxygen) Dyspnea and pneumoniasymptoms (e.g., aspirationpneumonia); hospitalizationindicated; unable to alimentorally Life-threatening respiratory orhemodynamic compromise;intubation or urgent interventionindicated Death Definition: A disorder characterized by inhalation of solids or liquids into the lungs. Atelectasis Asymptomatic; clinical ordiagnostic observations only;intervention not indicated Symptomatic (e.g., dyspnea,cough); medical interventionindicated (e.g., chestphysiotherapy, suctioning);bronchoscopic suctioning Oxygen indicated;hospitalization or electiveoperative intervention indicated(e.g., stent, laser) Life-threatening respiratory orhemodynamic compromise;intubation or urgent interventionindicated Death Definition: A disorder characterized by the collapse of part or the entire lung. Bronchial fistula Asymptomatic; clinical ordiagnostic observations only;intervention not indicated Symptomatic; tubethoracostomy or medicalmanagement indicated; limitinginstrumental ADL Severe symptoms; limiting selfcare ADL; endoscopic oroperative intervention indicated(e.g., stent or primary closure) Life-threatening consequences;urgent operative interventionwith thoracoplasty, chronic opendrainage or multiplethoracotomies indicated Death Definition: A disorder characterized by an abnormal communication between the bronchus and another organ or anatomic site. Bronchial obstruction Asymptomatic; clinical ordiagnostic observations only;intervention not indicated Symptomatic (e.g., mildwheezing); endoscopicevaluation indicated;radiographic evidence ofatelectasis/lobar collapse;medical management indicated(e.g., steroids, bronchodilators) Shortness of breath with stridor;endoscopic interventionindicated (e.g., laser, stentplacement) Life-threatening respiratory orhemodynamic compromise;intubation or urgent interventionindicated Death Definition: A disorder characterized by blockage of a bronchus passage, most often by bronchial secretions and exudates. Bronchial stricture Asymptomatic; clinical ordiagnostic observations only;intervention not indicated Symptomatic (e.g., rhonchi orwheezing) but withoutrespiratory distress; medicalintervention indicated (e.g.,steroids, bronchodilators) Shortness of breath with stridor;endoscopic interventionindicated (e.g., laser, stentplacement) Life-threatening respiratory orhemodynamic compromise;intubation or urgent interventionindicated Death Definition: A disorder characterized by a narrowing of the bronchial tube. Bronchopleural fistula Asymptomatic; clinical ordiagnostic observations only;intervention not indicated Symptomatic; tubethoracostomy or medicalintervention indicated; limitinginstrumental ADL Severe symptoms; limiting selfcare ADL; endoscopic oroperative intervention indicated(e.g., stent or primary closure) Life-threatening consequences;urgent operative interventionwith thoracoplasty, chronic opendrainage or multiplethoracotomies indicated Death Definition: A disorder characterized by an abnormal communication between a bronchus and the pleural cavity. Bronchopulmonary hemorrhage Mild symptoms; intervention notindicated Moderate symptoms; medicalintervention indicated Transfusion, radiologic,endoscopic, or operativeintervention indicated (e.g.,hemostasis of bleeding site) Life-threatening respiratory orhemodynamic compromise;intubation or urgent interventionindicated Death Definition: A disorder characterized by bleeding from the bronchial wall and/or lung parenchyma.

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CTCAE 4.03 June 14, 2010 : Respiratory, thoracic and mediastinal disorders 66 Respiratory, thoracic and mediastinal disorders Grade Adverse Event 1 2 3 4 5 Bronchospasm Mild symptoms; intervention notindicated Symptomatic; medicalintervention indicated; limitinginstrumental ADL Limiting self care ADL; oxygensaturation decreased Life-threatening respiratory orhemodynamic compromise;intubation or urgent interventionindicated Death Definition: A disorder characterized by a sudden contraction of the smooth muscles of the bronchial wall. Chylothorax Asymptomatic; clinical ordiagnostic observations only;intervention not indicated Symptomatic; thoracentesis ortube drainage indicated Severe symptoms; electiveoperative intervention indicated Life-threatening respiratory orhemodynamic compromise;intubation or urgent interventionindicated Death Definition: A disorder characterized by milky pleural effusion (abnormal collection of fluid) resulting from accumulation of lymph fluid in the pleural cavity. Cough Mild symptoms; nonprescriptionintervention indicated Moderate symptoms, medicalintervention indicated; limitinginstrumental ADL Severe symptoms; limiting selfcare ADL Definition: A disorder characterized by sudden, often repetitive, spasmodic contraction of the thoracic cavity, resulting in violent release of air from the lungs and usually accompaniedby a distinctive sound. Dyspnea Shortness of breath withmoderate exertion Shortness of breath withminimal exertion; limitinginstrumental ADL Shortness of breath at rest;limiting self care ADL Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by an uncomfortable sensation of difficulty breathing. Epistaxis Mild symptoms; intervention notindicated Moderate symptoms; medicalintervention indicated (e.g.,nasal packing, cauterization;topical vasoconstrictors) Transfusion, radiologic,endoscopic, or operativeintervention indicated (e.g.,hemostasis of bleeding site) Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by bleeding from the nose. Hiccups Mild symptoms; intervention notindicated Moderate symptoms; medicalintervention indicated; limitinginstrumental ADL Severe symptoms; interferingwith sleep; limiting self careADL Definition: A disorder characterized by repeated gulp sounds that result from an involuntary opening and closing of the glottis. This is attributed to a spasm of the diaphragm. Hoarseness Mild or intermittent voicechange; fully understandable;self-resolves Moderate or persistent voicechanges; may requireoccasional repetition butunderstandable on telephone;medical evaluation indicated Severe voice changes includingpredominantly whisperedspeech Definition: A disorder characterized by harsh and raspy voice arising from or spreading to the larynx. Hypoxia Decreased oxygen saturationwith exercise (e.g., pulseoximeter <88%); intermittentsupplemental oxygen Decreased oxygen saturation atrest (e.g., pulse oximeter <88%or PaO2 <=55 mm Hg) Life-threatening airwaycompromise; urgent interventionindicated (e.g., tracheotomy orintubation) Death Definition: A disorder characterized by a decrease in the level of oxygen in the body. Laryngeal edema Asymptomatic; clinical ordiagnostic observations only;intervention not indicated Symptomatic; medicalintervention indicated (e.g.,dexamethasone, epinephrine,antihistamines) Stridor; respiratory distress;hospitalization indicated Life-threatening airwaycompromise; urgent interventionindicated (e.g., tracheotomy orintubation) Death Definition: A disorder characterized by swelling due to an excessive accumulation of fluid in the larynx. Laryngeal fistula Asymptomatic; clinical ordiagnostic observations only;intervention not indicated Symptomatic; tubethoracostomy or medicalmanagement indicated; limitinginstrumental ADL Severe symptoms; limiting selfcare ADL; endoscopic oroperative intervention indicated(e.g., stent or primary closure) Life-threatening consequences;urgent operative interventionindicated (e.g., thoracoplasty,chronic open drainage ormultiple thoracotomies) Death Definition: A disorder characterized by an abnormal communication between the larynx and another organ or anatomic site. Laryngeal hemorrhage Mild cough or trace hemoptysis;laryngoscopic findings Moderate symptoms; medicalintervention indicated Transfusion, radiologic,endoscopic, or operativeintervention indicated (e.g.,hemostasis of bleeding site) Life-threatening airwaycompromise; urgent interventionindicated (e.g., tracheotomy orintubation) Death Definition: A disorder characterized by bleeding from the larynx. Laryngeal inflammation Mild sore throat; raspy voice Moderate sore throat;analgesics indicated Severe throat pain; endoscopicintervention indicated Definition: A disorder characterized by an inflammation involving the larynx.

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CTCAE 4.03 June 14, 2010 : Respiratory, thoracic and mediastinal disorders 67 Respiratory, thoracic and mediastinal disorders Grade Adverse Event 1 2 3 4 5 Laryngeal mucositis Endoscopic findings only; milddiscomfort with normal intake Moderate discomfort; alteredoral intake Severe pain; severely alteredeating/swallowing; medicalintervention indicated Life-threatening airwaycompromise; urgent interventionindicated (e.g., tracheotomy orintubation) Death Definition: A disorder characterized by an inflammation involving the mucous membrane of the larynx. Laryngeal obstruction Asymptomatic; clinical ordiagnostic observations only;intervention not indicated Symptomatic (e.g., noisy airwaybreathing), but causing norespiratory distress; medicalmanagement indicated (e.g.,steroids); limiting instrumentalADL Limiting self care ADL; stridor;endoscopic interventionindicated (e.g., stent, laser) Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by blockage of the laryngeal airway. Laryngeal stenosis Asymptomatic; clinical ordiagnostic observations only;intervention not indicated Symptomatic (e.g., noisy airwaybreathing), but causing norespiratory distress; medicalmanagement indicated (e.g.,steroids) Limiting self care ADL; stridor;endoscopic interventionindicated (e.g., stent, laser) Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by a narrowing of the laryngeal airway. Laryngopharyngeal dysesthesia Mild symptoms; no anxiety;intervention not indicated Moderate symptoms; mildanxiety, but no dyspnea; shortduration of observation and oranxiolytic indicated; limitinginstrumental ADL Severe symptoms; dyspnea andswallowing difficulty; limiting selfcare ADL Life-threatening consequences Death Definition: A disorder characterized by an uncomfortable persistent sensation in the area of the laryngopharynx. Laryngospasm Transient episode; interventionnot indicated Recurrent episodes;noninvasive interventionindicated (e.g., breathingtechnique, pressure pointmassage) Persistent or severe episodesassociated with syncope; urgentintervention indicated (e.g.,fiberoptic laryngoscopy,intubation, botox injection) Death Definition: A disorder characterized by paroxysmal spasmodic muscular contraction of the vocal cords. Mediastinal hemorrhage Radiologic evidence only;minimal symptoms; interventionnot indicated Moderate symptoms; medicalintervention indicated Transfusion, radiologic,endoscopic, or electiveoperative intervention indicated(e.g., hemostasis of bleedingsite) Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by bleeding from the mediastinum. Nasal congestion Mild symptoms; intervention notindicated Moderate symptoms; medicalintervention indicated Associated with bloody nasaldischarge or epistaxis Definition: A disorder characterized by obstruction of the nasal passage due to mucosal edema. Pharyngeal fistula Asymptomatic; clinical ordiagnostic observations only;intervention not indicated Symptomatic; tubethoracostomy or medicalintervention indicated; limitinginstrumental ADL Severe symptoms; limiting selfcare ADL; endoscopic oroperative intervention indicated(e.g., stent or primary closure) Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by an abnormal communication between the pharynx and another organ or anatomic site. Pharyngeal hemorrhage Mild symptoms; intervention notindicated Moderate symptoms; medicalintervention indicated Transfusion, radiologic,endoscopic, or operativeintervention indicated (e.g.,hemostasis of bleeding site) Life-threatening respiratory orhemodynamic compromise;intubation or urgent interventionindicated Death Definition: A disorder characterized by bleeding from the pharynx. Pharyngeal mucositis Endoscopic findings only;minimal symptoms with normaloral intake; mild pain butanalgesics not indicated Moderate pain and analgesicsindicated; altered oral intake;limiting instrumental ADL Severe pain; unable toadequately aliment or hydrateorally; limiting self care ADL Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by an inflammation involving the mucous membrane of the pharynx. Pharyngeal necrosis Inability to aliment adequatelyby GI tract; tube feeding or TPNindicated; radiologic,endoscopic, or operativeintervention indicated Life-threatening consequences;urgent operative interventionindicated Death

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CTCAE 4.03 June 14, 2010 : Respiratory, thoracic and mediastinal disorders 68 Respiratory, thoracic and mediastinal disorders Grade Adverse Event 1 2 3 4 5 Definition: A disorder characterized by a necrotic process occurring in the pharynx. Pharyngeal stenosis Asymptomatic; clinical ordiagnostic observations only;intervention not indicated Symptomatic (e.g., noisy airwaybreathing), but causing norespiratory distress; medicalmanagement indicated (e.g.,steroids); limiting instrumentalADL Limiting self care ADL; stridor;endoscopic interventionindicated (e.g., stent, laser) Life-threatening airwaycompromise; urgent interventionindicated (e.g., tracheotomy orintubation) Death Definition: A disorder characterized by a narrowing of the pharyngeal airway. Pharyngolaryngeal pain Mild pain Moderate pain; limitinginstrumental ADL Severe pain; limiting self careADL Definition: A disorder characterized by marked discomfort sensation in the pharyngolaryngeal region. Pleural effusion Asymptomatic; clinical ordiagnostic observations only;intervention not indicated Symptomatic; interventionindicated (e.g., diuretics orlimited therapeuticthoracentesis) Symptomatic with respiratorydistress and hypoxia; surgicalintervention including chest tubeor pleurodesis indicated Life-threatening respiratory orhemodynamic compromise;intubation or urgent interventionindicated Death Definition: A disorder characterized by an increase in amounts of fluid within the pleural cavity. Symptoms include shortness of breath, cough and marked chest discomfort. Pleural hemorrhage Asymptomatic; mild hemorrhageconfirmed by thoracentesis Symptomatic or associated withpneumothorax; chest tubedrainage indicated >1000 ml of blood evacuated;persistent bleeding (150-200ml/hr for 2 4 hr); persistenttransfusion indicated; electiveoperative intervention indicated Life-threatening respiratory orhemodynamic compromise;intubation or urgent interventionindicated Death Definition: A disorder characterized by bleeding from the pleural cavity. Pleuritic pain Mild pain Moderate pain; limitinginstrumental ADL Severe pain; limiting self careADL Definition: A disorder characterized by marked discomfort sensation in the pleura. Pneumonitis Asymptomatic; clinical ordiagnostic observations only;intervention not indicated Symptomatic; medicalintervention indicated; limitinginstrumental ADL Severe symptoms; limiting selfcare ADL; oxygen indicated Life-threatening respiratorycompromise; urgent interventionindicated (e.g., tracheotomy orintubation) Death Definition: A disorder characterized by inflammation focally or diffusely affecting the lung parenchyma. Pneumothorax Asymptomatic; clinical ordiagnostic observations only;intervention not indicated Symptomatic; interventionindicated (e.g., tube placementwithout sclerosis) Sclerosis and/or operativeintervention indicated;hospitalization indicated Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by abnormal presence of air in the pleural cavity resulting in the collapse of the lung. Postnasal drip Mild symptoms; intervention notindicated Moderate symptoms; medicalintervention indicated Definition: A disorder characterized by excessive mucous secretion in the back of the nasal cavity or throat, causing sore throat and/or coughing. Productive cough Occasional/minimal productionof sputum with cough Moderate sputum production;limiting instrumental ADL Persistent or copious productionof sputum; limiting self care ADL Definition: A disorder characterized by expectorated secretions upon coughing. Pulmonary edema Radiologic findings only;minimal dyspnea on exertion Moderate dyspnea on exertion;medical intervention indicated;limiting instrumental ADL Severe dyspnea or dyspnea atrest; oxygen indicated; limitingself care ADL Life-threatening respiratorycompromise; urgent interventionor intubation with ventilatorysupport indicated Death Definition: A disorder characterized by accumulation of fluid in the lung tissues that causes a disturbance of the gas exchange that may lead to respiratory failure. Pulmonary fibrosis Mild hypoxemia; radiologicpulmonary fibrosis <25% of lungvolume Moderate hypoxemia; evidenceof pulmonary hypertension;radiographic pulmonary fibrosis25 50% Severe hypoxemia; evidence ofright-sided heart failure;radiographic pulmonary fibrosis>50 75% Life-threatening consequences(e.g., hemodynamic/pulmonarycomplications); intubation withventilatory support indicated;radiographic pulmonary fibrosis>75% with severehoneycombing Death Definition: A disorder characterized by the replacement of the lung tissue by connective tissue, leading to progressive dyspnea, respiratory failure or right heart failure. Pulmonary fistula Asymptomatic; clinical ordiagnostic observations only;intervention not indicated Symptomatic; tubethoracostomy or medicalmanagement indicated; limitinginstrumental ADL Limiting self care ADL;endoscopic stenting oroperative intervention indicated Life-threatening consequences;urgent operative interventionindicated Death

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CTCAE 4.03 June 14, 2010 : Respiratory, thoracic and mediastinal disorders 69 Respiratory, thoracic and mediastinal disorders Grade Adverse Event 1 2 3 4 5 Definition: A disorder characterized by an abnormal communication between the lung and another organ or anatomic site. Pulmonary hypertension Minimal dyspnea; findings onphysical exam or otherevaluation Moderate dyspnea, cough;requiring evaluation by cardiaccatheterization and medicalintervention Severe symptoms, associatedwith hypoxemia, right heartfailure; oxygen indicated Life-threatening airwayconsequences; urgentintervention indicated (e.g.,tracheotomy or intubation) Death Definition: A disorder characterized by an increase in pressure within the pulmonary circulation due to lung or heart disorder. Respiratory failure Life-threatening consequences;urgent intervention, intubation,or ventilatory support indicated Death Definition: A disorder characterized by impaired gas exchange by the respiratory system resulting in hypoxemia and a decrease in oxygenation of the tissues that may be associatedwith an increase in arterial levels of carbon dioxide. Retinoic acid syndrome Fluid retention; <3 kg of weightgain; intervention with fluidrestriction and/or diureticsindicated Moderate signs or symptoms;steroids indicated Severe symptoms;hospitalization indicated Life-threatening consequences;ventilatory support indicated Death Definition: A disorder characterized by weight gain, dyspnea, pleural and pericardial effusions, leukocytosis and/or renal failure originally described in patients treated with all-transretinoic acid. Sinus disorder Asymptomatic mucosal crusting;blood-tinged secretions Symptomatic stenosis oredema/narrowing interferingwith airflow; limiting instrumentalADL Stenosis with significant nasalobstruction; limiting self careADL Necrosis of soft tissue or bone;urgent operative interventionindicated Death Definition: A disorder characterized by involvement of the paranasal sinuses. Sleep apnea Snoring and nocturnal sleeparousal without apneic periods Moderate apnea and oxygendesaturation; excessive daytimesleepiness; medical evaluationindicated; limiting instrumentalADL Oxygen desaturation;associated with hypertension;medical intervention indicated;limiting self care ADL Cardiovascular orneuropsychiatric symptoms;urgent operative interventionindicated Death Definition: A disorder characterized by cessation of breathing for short periods during sleep. Sneezing Mild symptoms; intervention notindicated Moderate symptoms; medicalintervention indicated Definition: A disorder characterized by the involuntary expulsion of air from the nose. Sore throat Mild pain Moderate pain; limitinginstrumental ADL Severe pain; limiting self careADL; limiting ability to swallow Definition: A disorder characterized by of marked discomfort in the throat Stridor Respiratory distress limiting selfcare ADL; medical interventionindicated Life-threatening airwaycompromise; urgent interventionindicated (e.g., tracheotomy orintubation) Death Definition: A disorder characterized by a high pitched breathing sound due to laryngeal or upper airway obstruction. Tracheal fistula Asymptomatic; clinical ordiagnostic observations only;intervention not indicated Symptomatic; tubethoracostomy or medicalintervention indicated; limitinginstrumental ADL Severe symptoms; limiting selfcare ADL; endoscopic oroperative intervention indicated(e.g., stent or primary closure) Life-threatening consequences;urgent operative interventionindicated (e.g., thoracoplasty,chronic open drainage ormultiple thoracotomies) Death Definition: A disorder characterized by an abnormal communication between the trachea and another organ or anatomic site. Tracheal mucositis Endoscopic findings only;minimal hemoptysis, pain, orrespiratory symptoms Moderate symptoms; medicalintervention indicated; limitinginstrumental ADL Severe pain; hemorrhage orrespiratory symptoms; limitingself care ADL Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by an inflammation involving the mucous membrane of the trachea. Tracheal stenosis Asymptomatic; clinical ordiagnostic observations only;intervention not indicated Symptomatic (e.g., noisy airwaybreathing), but causing norespiratory distress; medicalmanagement indicated (e.g.,steroids) Stridor or respiratory distresslimiting self care ADL;endoscopic interventionindicated (e.g., stent, laser) Life-threatening airwaycompromise; urgent interventionindicated (e.g., tracheotomy orintubation) Death Definition: A disorder characterized by a narrowing of the trachea.

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CTCAE 4.03 June 14, 2010 : Respiratory, thoracic and mediastinal disorders 70 Respiratory, thoracic and mediastinal disorders Grade Adverse Event 1 2 3 4 5 Voice alteration Mild or intermittent change fromnormal voice Moderate or persistent changefrom normal voice; stillunderstandable Severe voice changes includingpredominantly whisperedspeech; may require frequentrepetition or face-to-face contactfor understandability; mayrequire assistive technology Definition: A disorder characterized by a change in the sound and/or speed of the voice. Wheezing Detectable airway noise withminimal symptoms Moderate symptoms; medicalintervention indicated; limitinginstrumental ADL Severe respiratory symptomslimiting self care ADL; oxygentherapy or hospitalizationindicated Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by a high-pitched, whistling sound during breathing. It results from the narrowing or obstruction of the respiratory airways. Respiratory, thoracic andmediastinal disorders Other,specify Asymptomatic or mildsymptoms; clinical or diagnosticobservations only; interventionnot indicated Moderate; minimal, local ornoninvasive interventionindicated; limiting age-appropriate instrumental ADL Severe or medically significantbut not immediately life-threatening; hospitalization orprolongation of existinghospitalization indicated;disabling; limiting self care ADL Life-threatening consequences;urgent intervention indicated Death

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CTCAE 4.03 June 14, 2010 : Skin and subcutaneous tissue disorders 71 24. Skin and subcutaneous tissue disorders Skin and subcutaneous tissue disorders Grade Adverse Event 1 2 3 4 5 Alopecia Hair loss of <50% of normal forthat individual that is notobvious from a distance but onlyon close inspection; a differenthair style may be required tocover the hair loss but it doesnot require a wig or hair piece tocamouflage Hair loss of >=50% normal forthat individual that is readilyapparent to others; a wig or hairpiece is necessary if the patientdesires to completelycamouflage the hair loss;associated with psychosocialimpact Definition: A disorder characterized by a decrease in density of hair compared to normal for a given individual at a given age and body location. Body odor Mild odor; physician interventionnot indicated; self careinterventions Pronounced odor; psychosocialimpact; patient seeks medicalintervention Definition: A disorder characterized by an abnormal body smell resulting from the growth of bacteria on the body. Bullous dermatitis Asymptomatic; blisters covering<10% BSA Blisters covering 10 30% BSA;painful blisters; limitinginstrumental ADL Blisters covering >30% BSA;limiting self care ADL Blisters covering >30% BSA;associated with fluid orelectrolyte abnormalities; ICUcare or burn unit indicated Death Definition: A disorder characterized by inflammation of the skin characterized by the presence of bullae which are filled with fluid. Dry skin Covering <10% BSA and noassociated erythema or pruritus Covering 10 30% BSA andassociated with erythema orpruritus; limiting instrumentalADL Covering >30% BSA andassociated with pruritus; limitingself care ADL Definition: A disorder characterized by flaky and dull skin; the pores are generally fine, the texture is a papery thin texture. Erythema multiforme Target lesions covering <10%BSA and not associated withskin tenderness Target lesions covering 10 -30% BSA and associated withskin tenderness Target lesions covering >30%BSA and associated with oral orgenital erosions Target lesions covering >30%BSA; associated with fluid orelectrolyte abnormalities; ICUcare or burn unit indicated Death Definition: A disorder characterized by target lesions (a pink-red ring around a pale center). Erythroderma Erythema covering >90% BSAwithout associated symptoms;limiting instrumental ADL Erythema covering >90% BSAwith associated symptoms (e.g.,pruritus or tenderness); limitingself care ADL Erythema covering >90% BSAwith associated fluid orelectrolyte abnormalities; ICUcare or burn unit indicated Death Definition: A disorder characterized by generalized inflammatory erythema and exfoliation. The inflammatory process involves > 90% of the body surface area. Fat atrophy Covering <10% BSA andasymptomatic Covering 10 30% BSA andassociated with erythema ortenderness; limiting instrumentalADL Covering >30% BSA;associated with erythema ortenderness; limiting self-careADL Definition: A disorder characterized by shrinking of adipose tissue. Hirsutism In women, increase in length,thickness or density of hair in amale distribution that the patientis able to camouflage byperiodic shaving, bleaching, orremoval of hair In women, increase in length,thickness or density of hair in amale distribution that requiresdaily shaving or consistentdestructive means of hairremoval to camouflage;associated with psychosocialimpact Definition: A disorder characterized by the presence of excess hair growth in women in anatomic sites where growth is considered to be a secondary male characteristic and underandrogen control (beard, moustache, chest, abdomen) Hyperhidrosis Limited to one site (palms,soles, or axillae); self careinterventions Involving >1 site; patient seeksmedical intervention; associatedwith psychosocial impact Generalized involving sitesother than palms, soles, oraxillae; associated withelectrolyte/hemodynamicimbalance Definition: A disorder characterized by excessive perspiration.

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CTCAE 4.03 June 14, 2010 : Skin and subcutaneous tissue disorders 72 Skin and subcutaneous tissue disorders Grade Adverse Event 1 2 3 4 5 Hypertrichosis Increase in length, thickness ordensity of hair that the patient iseither able to camouflage byperiodic shaving or removal ofhairs or is not concernedenough about the overgrowth touse any form of hair removal Increase in length, thickness ordensity of hair at least on theusual exposed areas of thebody [face (not limited tobeard/moustache area)plus/minus arms] that requiresfrequent shaving or use ofdestructive means of hairremoval to camouflage;associated with psychosocialimpact Definition: A disorder characterized by hair density or length beyond the accepted limits of normal in a particular body region, for a particular age or race. Hypohidrosis Symptomatic; limitinginstrumental ADL Increase in body temperature;limiting self care ADL Heat stroke Death Definition: A disorder characterized by reduced sweating. Lipohypertrophy Asymptomatic and covering<10% BSA Covering 10 30% BSA andassociated tenderness; limitinginstrumental ADL Covering >30% BSA andassociated tenderness andnarcotics or NSAIDs indicated;lipohypertrophy; limiting selfcare ADL Definition: A disorder characterized by hypertrophy of the subcutaneous adipose tissue at the site of multiple subcutaneous injections of insulin. Nail discoloration Asymptomatic; clinical ordiagnostic observations only;intervention not indicated Definition: A disorder characterized by a change in the color of the nail plate. Nail loss Asymptomatic separation of thenail bed from the nail plate ornail loss Symptomatic separation of thenail bed from the nail plate ornail loss; limiting instrumentalADL Definition: A disorder characterized by loss of all or a portion of the nail. Nail ridging Asymptomatic; clinical ordiagnostic observations only;intervention not indicated Definition: A disorder characterized by vertical or horizontal ridges on the nails. Pain of skin Mild pain Moderate pain; limitinginstrumental ADL Severe pain; limiting self careADL Definition: A disorder characterized by marked discomfort sensation in the skin. Palmar-plantarerythrodysesthesia syndrome Minimal skin changes ordermatitis (e.g., erythema,edema, or hyperkeratosis)without pain Skin changes (e.g., peeling,blisters, bleeding, edema, orhyperkeratosis) with pain;limiting instrumental ADL Severe skin changes (e.g.,peeling, blisters, bleeding,edema, or hyperkeratosis) withpain; limiting self care ADL Definition: A disorder characterized by redness, marked discomfort, swelling, and tingling in the palms of the hands or the soles of the feet. Periorbital edema Soft or non-pitting Indurated or pitting edema;topical intervention indicated Edema associated with visualdisturbance; increasedintraocular pressure, glaucomaor retinal hemorrhage; opticneuritis; diuretics indicated;operative intervention indicated Definition: A disorder characterized by swelling due to an excessive accumulation of fluid around the orbits of the face. Photosensitivity Painless erythema anderythema covering <10% BSA Tender erythema covering 10 -30% BSA Erythema covering >30% BSAand erythema with blistering;photosensitivity; oralcorticosteroid therapy indicated;pain control indicated (e.g.,narcotics or NSAIDs) Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by an increase in sensitivity of the skin to light.

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CTCAE 4.03 June 14, 2010 : Skin and subcutaneous tissue disorders 73 Skin and subcutaneous tissue disorders Grade Adverse Event 1 2 3 4 5 Pruritus Mild or localized; topicalintervention indicated Intense or widespread;intermittent; skin changes fromscratching (e.g., edema,papulation, excoriations,lichenification, oozing/crusts);oral intervention indicated;limiting instrumental ADL Intense or widespread;constant; limiting self care ADLor sleep; oral corticosteroid orimmunosuppressive therapyindicated Definition: A disorder characterized by an intense itching sensation. Purpura Combined area of lesionscovering <10% BSA Combined area of lesionscovering 10 30% BSA;bleeding with trauma Combined area of lesionscovering >30% BSA;spontaneous bleeding Definition: A disorder characterized by hemorrhagic areas of the skin and mucous membrane. Newer lesions appear reddish in color. Older lesions are usually a darker purple colorand eventually become a brownish-yellow color. Rash acneiform Papules and/or pustulescovering <10% BSA, which mayor may not be associated withsymptoms of pruritus ortenderness Papules and/or pustulescovering 10 30% BSA, whichmay or may not be associatedwith symptoms of pruritus ortenderness; associated withpsychosocial impact; limitinginstrumental ADL Papules and/or pustulescovering >30% BSA, which mayor may not be associated withsymptoms of pruritus ortenderness; limiting self careADL; associated with localsuperinfection with oralantibiotics indicated Papules and/or pustulescovering any % BSA, whichmay or may not be associatedwith symptoms of pruritus ortenderness and are associatedwith extensive superinfectionwith IV antibiotics indicated; life-threatening consequences Death Definition: A disorder characterized by an eruption of papules and pustules, typically appearing in face, scalp, upper chest and back. Rash maculo-papular Macules/papules covering<10% BSA with or withoutsymptoms (e.g., pruritus,burning, tightness) Macules/papules covering 10 -30% BSA with or withoutsymptoms (e.g., pruritus,burning, tightness); limitinginstrumental ADL Macules/papules covering>30% BSA with or withoutassociated symptoms; limitingself care ADL Definition: A disorder characterized by the presence of macules (flat) and papules (elevated). Also known as morbillform rash, it is one of the most common cutaneous adverseevents, frequently affecting the upper trunk, spreading centripetally and associated with pruritus. Scalp pain Mild pain Moderate pain; limitinginstrumental ADL Severe pain; limiting self careADL Definition: A disorder characterized by marked discomfort sensation in the skin covering the top and the back of the head. Skin atrophy Covering <10% BSA;associated with telangiectasiasor changes in skin color Covering 10 30% BSA;associated with striae oradnexal structure loss Covering >30% BSA;associated with ulceration Definition: A disorder characterized by the degeneration and thinning of the epidermis and dermis. Skin hyperpigmentation Hyperpigmentation covering<10% BSA; no psychosocialimpact Hyperpigmentation covering>10% BSA; associatedpsychosocial impact Definition: A disorder characterized by darkening of the skin due to excessive melanin deposition. Skin hypopigmentation Hypopigmentation ordepigmentation covering <10%BSA; no psychosocial impact Hypopigmentation ordepigmentation covering >10%BSA; associated psychosocialimpact Definition: A disorder characterized by loss of skin pigment. Skin induration Mild induration, able to moveskin parallel to plane (sliding)and perpendicular to skin(pinching up) Moderate induration, able toslide skin, unable to pinch skin;limiting instrumental ADL Severe induration, unable toslide or pinch skin; limiting jointmovement or orifice (e.g.,mouth, anus); limiting self careADL Generalized; associated withsigns or symptoms of impairedbreathing or feeding Death Definition: A disorder characterized by an area of hardness in the skin. Skin ulceration Combined area of ulcers <1 cm;nonblanchable erythema ofintact skin with associatedwarmth or edema Combined area of ulcers 1 2cm; partial thickness skin lossinvolving skin or subcutaneousfat Combined area of ulcers >2 cm;full-thickness skin loss involvingdamage to or necrosis ofsubcutaneous tissue that mayextend down to fascia Any size ulcer with extensivedestruction, tissue necrosis, ordamage to muscle, bone, orsupporting structures with orwithout full thickness skin loss Death Definition: A disorder characterized by circumscribed, inflammatory and necrotic erosive lesion on the skin.

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CTCAE 4.03 June 14, 2010 : Skin and subcutaneous tissue disorders 74 Skin and subcutaneous tissue disorders Grade Adverse Event 1 2 3 4 5 Stevens-Johnson syndrome Skin sloughing covering <10%BSA with associated signs (e.g.,erythema, purpura, epidermaldetachment and mucousmembrane detachment) Skin sloughing covering 10 -30% BSA with associated signs(e.g., erythema, purpura,epidermal detachment andmucous membranedetachment) Death Definition: A disorder characterized by less than 10% total body skin area separation of dermis. The syndrome is thought to be a hypersensitivity complex affecting the skin and themucous membranes. Telangiectasia Telangiectasias covering <10%BSA Telangiectasias covering >10%BSA; associated withpsychosocial impact Definition: A disorder characterized by local dilatation of small vessels resulting in red discoloration of the skin or mucous membranes. Toxic epidermal necrolysis Skin sloughing covering >=30%BSA with associated symptoms(e.g., erythema, purpura, orepidermal detachment) Death Definition: A disorder characterized by greater than 30% total body skin area separation of dermis. The syndrome is thought to be a hypersensitivity complex affecting the skin and themucous membranes. Urticaria Urticarial lesions covering <10%BSA; topical interventionindicated Urticarial lesions covering 10 -30% BSA; oral interventionindicated Urticarial lesions covering >30%BSA; IV intervention indicated Definition: A disorder characterized by an itchy skin eruption characterized by wheals with pale interiors and well-defined red margins. Skin and subcutaneous tissuedisorders Other, specify Asymptomatic or mildsymptoms; clinical or diagnosticobservations only; interventionnot indicated Moderate; minimal, local ornoninvasive interventionindicated; limiting age-appropriate instrumental ADL Severe or medically significantbut not immediately life-threatening; hospitalization orprolongation of existinghospitalization indicated;disabling; limiting self care ADL Life-threatening consequences;urgent intervention indicated Death

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CTCAE 4.03 June 14, 2010 : Social circumstances 75 25. Social circumstances Social circumstances Grade Adverse Event 1 2 3 4 5 Menopause Menopause occurring at age 4653 years of age Menopause occurring at age 4045 years of age Menopause occurring beforeage 40 years of age Definition: A disorder characterized by the permanent cessation of menses, usually defined by 12 consecutive months of amenorrhea in a woman over 45 years of age. Social circumstances Other,specify Asymptomatic or mildsymptoms; clinical or diagnosticobservations only; interventionnot indicated Moderate; minimal, local ornoninvasive interventionindicated; limiting age-appropriate instrumental ADL Severe or medically significantbut not immediately life-threatening; hospitalization orprolongation of existinghospitalization indicated;disabling; limiting self care ADL Life-threatening consequences;urgent intervention indicated Death

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CTCAE 4.03 June 14, 2010 : Surgical and medical procedures 76 26. Surgical and medical procedures Surgical and medical procedures Grade Adverse Event 1 2 3 4 5 Surgical and medicalprocedures Other, specify Asymptomatic or mildsymptoms; clinical or diagnosticobservations only; interventionnot indicated Moderate; minimal, local ornoninvasive interventionindicated; limiting age-appropriate instrumental ADL Severe or medically significantbut not immediately life-threatening; hospitalization orprolongation of existinghospitalization indicated;disabling; limiting self care ADL Life-threatening consequences;urgent intervention indicated Death

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CTCAE 4.03 June 14, 2010 : Vascular disorders 77 27. Vascular disorders Vascular disorders Grade Adverse Event 1 2 3 4 5 Capillary leak syndrome Symptomatic; medicalintervention indicated Severe symptoms; interventionindicated Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by leakage of intravascular fluids into the extravascular space. This syndrome is observed in patients who demonstrate a state of generalizedleaky capillaries following shock syndromes, low-flow states, ischemia-reperfusion injuries, toxemias, medications, or poisoning. It can lead to generalized edema and multiple organfailure. Flushing Asymptomatic; clinical ordiagnostic observations only;intervention not indicated Moderate symptoms; medicalintervention indicated; limitinginstrumental ADL Symptomatic, associated withhypotension and/or tachycardia;limiting self care ADL Definition: A disorder characterized by episodic reddening of the face. Hematoma Mild symptoms; intervention notindicated Minimally invasive evacuation oraspiration indicated Transfusion, radiologic,endoscopic, or electiveoperative intervention indicated Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by a localized collection of blood, usually clotted, in an organ, space, or tissue, due to a break in the wall of a blood vessel. Hot flashes Mild symptoms; intervention notindicated Moderate symptoms; limitinginstrumental ADL Severe symptoms; limiting selfcare ADL Definition: A disorder characterized by an uncomfortable and temporary sensation of intense body warmth, flushing, sometimes accompanied by sweating upon cooling. Hypertension Prehypertension (systolic BP120 139 mm Hg or diastolicBP 80 89 mm Hg) Stage 1 hypertension (systolicBP 140 159 mm Hg ordiastolic BP 90 99 mm Hg);medical intervention indicated;recurrent or persistent (>=24hrs); symptomatic increase by>20 mm Hg (diastolic) or to>140/90 mm Hg if previouslyWNL; monotherapy indicatedPediatric: recurrent or persistent(>=24 hrs) BP >ULN;monotherapy indicated Stage 2 hypertension (systolicBP >=160 mm Hg or diastolicBP >=100 mm Hg); medicalintervention indicated; morethan one drug or more intensivetherapy than previously usedindicatedPediatric: Same as adult Life-threatening consequences(e.g., malignant hypertension,transient or permanentneurologic deficit, hypertensivecrisis); urgent interventionindicatedPediatric: Same as adult Death Definition: A disorder characterized by a pathological increase in blood pressure; a repeatedly elevation in the blood pressure exceeding 140 over 90 mm Hg. Hypotension Asymptomatic, intervention notindicated Non-urgent medical interventionindicated Medical intervention orhospitalization indicated Life-threatening and urgentintervention indicated Death Definition: A disorder characterized by a blood pressure that is below the normal expected for an individual in a given environment. Lymph leakage Symptomatic; medicalintervention indicated Severe symptoms; radiologic,endoscopic or elective operativeintervention indicated Life-threatening consequences;urgent intervention indicated Death Definition: A disorder characterized by the loss of lymph fluid into the surrounding tissue or body cavity. Lymphedema Trace thickening or faintdiscoloration Marked discoloration; leatheryskin texture; papillary formation;limiting instrumental ADL Severe symptoms; limiting selfcare ADL Definition: A disorder characterized by excessive fluid collection in tissues that causes swelling. Lymphocele Asymptomatic; clinical ordiagnostic observations only;intervention not indicated Symptomatic; medicalintervention indicated Severe symptoms; radiologic,endoscopic or elective operativeintervention indicated Definition: A disorder characterized by a cystic lesion containing lymph. Peripheral ischemia Brief (<24 hrs) episode ofischemia managed non-surgically and withoutpermanent deficit Recurring or prolonged (>=24hrs) and/or invasive interventionindicated Life-threatening consequences;evidence of end organ damage;urgent operative interventionindicated Death Definition: A disorder characterized by impaired circulation to an extremity. Phlebitis Present Definition: A disorder characterized by inflammation of the wall of a vein. Superficial thrombophlebitis Present Definition: A disorder characterized by a blood clot and inflammation involving a superficial vein of the extremities.

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CTCAE 4.03 June 14, 2010 : Vascular disorders 78 Vascular disorders Grade Adverse Event 1 2 3 4 5 Superior vena cava syndrome Asymptomatic; incidental findingof SVC thrombosis Symptomatic; medicalintervention indicated (e.g.,anticoagulation, radiation orchemotherapy) Severe symptoms; multi-modality intervention indicated(e.g., anticoagulation,chemotherapy, radiation,stenting) Life-threatening consequences;urgent multi-modalityintervention indicated (e.g.,lysis, thrombectomy, surgery) Death Definition: A disorder characterized by obstruction of the blood flow in the superior vena cava. Signs and symptoms include swelling and cyanosis of the face, neck, and upper arms,cough, orthopnea and headache. Thromboembolic event Venous thrombosis (e.g.,superficial thrombosis) Venous thrombosis (e.g.,uncomplicated deep veinthrombosis), medicalintervention indicated Thrombosis (e.g.,uncomplicated pulmonaryembolism [venous], non-emboliccardiac mural [arterial]thrombus), medical interventionindicated Life-threatening (e.g.,pulmonary embolism,cerebrovascular event, arterialinsufficiency); hemodynamic orneurologic instability; urgentintervention indicated Death Definition: A disorder characterized by occlusion of a vessel by a thrombus that has migrated from a distal site via the blood stream. Vasculitis Asymptomatic, intervention notindicated Moderate symptoms, medicalintervention indicated Severe symptoms, medicalintervention indicated (e.g.,steroids) Life-threatening; evidence ofperipheral or visceral ischemia;urgent intervention indicated Death Definition: A disorder characterized by inflammation involving the wall of a vessel. Visceral arterial ischemia Brief (<24 hrs) episode ofischemia managed medicallyand without permanent deficit Prolonged (>=24 hrs) orrecurring symptoms and/orinvasive intervention indicated Life-threatening consequences;evidence of end organ damage;urgent operative interventionindicated Death Definition: A disorder characterized by a decrease in blood supply due to narrowing or blockage of a visceral (mesenteric) artery. Vascular disorders Other,specify Asymptomatic or mildsymptoms; clinical or diagnosticobservations only; interventionnot indicated Moderate; minimal, local ornoninvasive interventionindicated; limiting age-appropriate instrumental ADL Severe or medically significantbut not immediately life-threatening; hospitalization orprolongation of existinghospitalization indicated;disabling; limiting self care ADL Life-threatening consequences;urgent intervention indicated Death

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28. Publication Information NIH Publication No. 09-5410Revised June 2010Reprinted June 2010