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Mortality and morbidity following bone marrow transplantation

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Title:
Mortality and morbidity following bone marrow transplantation predictive utility of psychological variables
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Pearman, Timothy P., 1969-
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English
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vi, 78 leaves : ill. ; 29 cm.

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Subjects / Keywords:
Anxiety ( jstor )
Bone marrow ( jstor )
Bone marrow transplantation ( jstor )
Mortality ( jstor )
Psychology ( jstor )
Psychometrics ( jstor )
Psychosociology ( jstor )
Quality of life ( jstor )
Symptomatology ( jstor )
Transplantation ( jstor )
Anxiety ( mesh )
Bone Marrow Transplantation -- psychology ( mesh )
Department of Clinical and Health Psychology thesis Ph.D ( mesh )
Depressive Disorder ( mesh )
Dissertations, Academic -- College of Health Professions -- Department of Clinical and Health Psychology -- UF ( mesh )
Patient Compliance ( mesh )
Personality Assessment ( mesh )
Social Support ( mesh )
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bibliography ( marcgt )
theses ( marcgt )
non-fiction ( marcgt )

Notes

Thesis:
Thesis (Ph. D.)--University of Florida, 1997.
Bibliography:
Includes bibliographical references (leaves 68-77).
Additional Physical Form:
Also available online.
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Typescript.
General Note:
Vita.
Statement of Responsibility:
by Timothy Patrick Pearman.

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University of Florida
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Copyright Timothy P. Pearman. Permission granted to the University of Florida to digitize, archive and distribute this item for non-profit research and educational purposes. Any reuse of this item in excess of fair use or other copyright exemptions requires permission of the copyright holder.
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MORTALITY AND MORBIDITY FOLLOWING BONE MARROW
TRANSPLANTATION: PREDICTIVE UTILITY OF PSYCHOLOGICAL
VARIABLES













By

TIMOTHY PATRICK PEARMAN














A DISSERTATION PRESENTED TO THE GRADUATE SCHOOL OF THE
UNIVERSITY OF FLORIDA IN PARTIAL FULFILLMENT OF THE
REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY

UNIVERSITY OF FLORIDA

1997













ACKNOWLEDGMENTS

I wish to thank my dissertation chairperson, Jim Rodrigue, Ph.D., for his support

and guidance throughout all phases of this project. The supportive, collegial and

knowledgeable presence which he brought to this project was invaluable to me. I owe

thanks to Stephen Boggs, Ph.D., Duane Dede, Ph.D., and Karolyn Godbey, Ph.D. for

their theoretical and practical contributions to the scientific rigor of my study. I would

also like to acknowledge the gracious assistance of Jan Moreb, M.D. and John Graham-

Pole, M.D., who allowed me to use their patients as research subjects and were also very

helpful in research design related to medical variables. In addition, I am very grateful to

the men and women who participated in my study. Their courage in dealing with the

rigors of bone marrow transplantation continues to amaze and inspire me. Finally, I wish

to thank my parents, grandparents and friends, in particular Dave Moser, for their

continued support and encouragement.














11ii














TABLE OF CONTENTS

page

ACKNOWLEDGMENTS .................................................................ii

AB STRA CT ................................................................ ..... ...........v

CHAPTERS

1 INTRODUCTION......................... ...............1

2 REVIEW OF THE LITERATURE.............. ..............4

H istory ..................................................................... .. 4
Description of Current BMT Procedures................. .............6
Psychological Factors Involved in BMT.................... .......8
Psychological Factors Involved in Development of Medical Illness.. 13
Influence of Psychological Factors on Immunologic Functioning.....14
Quality of Life in a BMT Population ..............................................17
Quality of Life: Generic vs. Disease-Specific Measurement..............23

3 SPECIFIC AIMS AND HYPOTHESES................................30

4 M ETH OD S .............. ......... ................. ....... 33

Demographics................ ............................ .................33
Subjects............ ...... ........... .................. .............. 35
Procedure ..................................................... ............. 35
Measures ....................... .............................37
Independent Variables ...........................................37
Dependent Variables................ ..........................41
Statistical A nalysis ............................................................43

5 RESULTS ......... ............ ................................. 48

Interrater R eliability.............. ............. ......................... 48
Variables Included/Excluded from Multiple Regressions and
Survival Analyses ............... .............. ................. 48
iii















page

Survival Analyses and Multiple Regressions..............................50
T-tests........................... ................ 52

6 DISCUSSION ........................... ..... ......... ... ............. 56

REFEREN CES ............................................. ............... ..............68

BIOGRAPHICAL SKETCH.............................. ................... .. ................. 78



































iv














Abstract of Dissertation Presented to the Graduate School of the University of Florida in
Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy

MORTALITY AND MORBIDITY FOLLOWING BONE MARROW
TRANSPLANTATION: PREDICTIVE UTILITY OF PSYCHOLOGICAL
VARIABLES

By

Timothy Patrick Pearman

August 1997

Chairperson: James R. Rodrigue
Cochairperson: Duane E. Dede
Major Department: Clinical and Health Psychology

Bone marrow transplantation (BMT) is a treatment for a wide range of hematolgic,

immunologic, metabolic and neoplastic diseases. Until recently, studies investigating

BMT outcome focused primarily on medical variables, such as graft-versus-host disease

and the effect of T cell depleted marrow on relapse. Recently, however, several studies

have investigated the impact of psychological variables on BMT outcome. These studies

have investigated the impact of depression, anxiety, family support, quality of life and

personality on survival after BMT. Overall, these studies have reported mixed results

suggesting that depression, anxiety, perceived family support, and personality may have

some impact on survival time after BMT.

The purpose of the current study was to empirically investigate the predictive

v













utility of psychological variables (affect, family support, past compliance history) on BMT

outcome (survival time, physical functioning and quality of life post-BMT). Patients were

assessed retrospectively by two independent examiners to rate their levels of pre-BMT

social support, affect and compliance history. Subjects were then assessed post-BMT to

measure their quality of life, symptom report and survival time. Results of the study

suggested that pre-BMT psychosocial variables were linked to outcome in terms of both

mortality and psychological morbidity. People with higher levels of anxiety and

depression pre-transplant were more likely to report poorer perceptions of physical health,

increased frequency of symptoms and increased distress about these symptoms post-

transplant. People with lower levels of social support appear to be at increased risk for

mortality compared with those with adequate social support. However, social support

may cause individuals to focus on their symptoms more than they otherwise would and to

decrease their activity level accordingly. Individuals with higher levels of social support

reported more frequent symptoms and more distress about these symptoms than did

individuals with lower levels of social support. The results of the study will be useful in

helping transplant teams to identify patients at risk for negative outcome to BMT and to

develop interventions to aid patients at high risk. The implications and limitations of the

study, as well as future research directions, are discussed.



vi













CHAPTER 1
INTRODUCTION

Bone marrow transplantation (BMT) is a treatment for a wide range of

hematologic, immunologic, metabolic and neoplastic diseases. While the concept of bone

marrow transplantation dates back to the 1890s, not until the 1970s did rapid clinical

progress occur. By the 1980s, BMT had emerged as a treatment with some degree of

success in curing immune deficiency diseases, severe aplastic anemia and leukemia

(Treleaven & Barrett, 1992). Bone marrow transplantation refers to five specific

procedures: (1) syngeneic transplantation, in which the bone marrow of a genetically

identical twin is transplanted; (2) allogeneic transplantation, in which marrow from a

related or unrelated donor is used; (3) autologous, in which the patient's own bone

marrow is cryogenically preserved and reintroduced into the patient's system, (4) stem cell

transplantation, in which stem cells are extracted from bone marrow or peripheral blood

and cultured before re-infusion and (5) cord blood transplantation, in which stem cells are

taken from umbilical cord blood supply, cultured and re-infused. However, for simplicity,

these procedures will be grouped together under the general term bone marrow

transplantation. BMT typically occurs as part of a regimen of total body irradiation and

chemotherapy.

Until recently, studies investigating BMT outcome focused primarily on medical

variables, such as graft-versus-host disease (GVHD) (Sullivan et al., 1989; cited in

1










2


Treleaven & Barrett, 1992), the effect of T cell depleted marrow on relapse (Mitsuyasu et

al., 1986; cited in Champlin, 1990; Storb et al., 1989; cited in Champlin, 1990), and the

impact ofimmunosuppression on survival in BMT patients (Meyers, Flournoy, & Thomas,

1982; cited in Champlin, 1990). However, several recent studies have investigated the

impact ofpsychosocial variables on BMT outcome. These studies have investigated the

impact of depression, anxiety, family support, quality of life, and personality on survival

after BMT (Andrykowski, Brady & Henslee-Downey, 1994; Colon, Callies, Popkin &

McGlave, 1991; Neuser, 1988). Overall, these studies have reported mixed results

suggesting that depression, anxiety, perceived family support, and personality may have

some impact on survival time after BMT.

The current study is an attempt to empirically investigate the predictive utility of

psychosocial variables on BMT outcome (survival time, physical functioning and quality of

life post-BMT). At the University of Florida Health Science Center, BMT patients are

routinely assessed using clinical interviews and standardized psychological measures as

part of the pre-transplant screening. Psychosocial factors are considered for the same

reasons other medical criteria are used: (1) to ensure that potential benefits outweigh the

risks to the patient, and (2) to wisely allocate a scarce resource (Olbrisch & Levenson,

1995). These psychological variables can be combined into composite scores reflecting

patients' adaptation along several psychological dimensions. The utility of these pre-

transplant psychological dimensions in predicting mortality and morbidity post-BMT was










3


investigated. For BMT patients still living, this composite was used to predict physical

functioning and quality of life. Quality of life and physical functioning were assessed using

a standardized health-related quality of life (HRQOL) instrument, a BMT-specific QOL

measure, and a symptom checklist. The results of this study will hopefully be useful in

assisting transplant teams in developing interventions to aid patients at high risk for

negative outcome of BMT. In the literature review section below, several areas will be

briefly covered: a description of the history and procedural aspects of BMT will be given,

the influence of psychological factors on immunologic/medical variables will be reviewed,

the impact of psychological factors on BMT outcome will be investigated, and quality of

life in mixed medical and BMT populations will be covered.














CHAPTER 2
REVIEW OF THE LITERATURE

History

Bone marrow transplantation is a procedure which gained widespread acceptance

in the 1980s as a highly regarded treatment for a variety of disorders. The first BMT was

attempted in 1891 when bone marrow was administered orally in cases of defective blood

formation. Treleaven and Barrett (1992) noted that there was no positive effect from this

intervention because there was no possibility of transferring living cells through oral

administration. In 1937, Schretzenmayr (cited in Treleaven & Barrett, 1992) administered

intramuscular injections of bone marrow to anemic patients, and had some positive results

due to the transfer of living cells. In 1952, Lorenz (cited in Treleaven & Barrett, 1992)

established that marrow transplantation could correct bone marrow failure syndromes, and

could protect patients against the effects of radiation and chemotherapy. Thus began

modem research on allogeneic and autologous BMT.

During the 1950s and 1960s much research was done on a variety of important

variables in BMT. For instance, graft versus host disease (GVHD) was first described

during this time (Mathe et al., 1963; cited in Treleaven & Barrett, 1992). GVHD is a

fairly common syndrome in allogeneic transplantation in which the newly infused marrow

recognizes the host's tissues as foreign, and begins to attack the patient's immune system.

Another important medical advance was Dausset et al.'s (1965; cited in Treleaven &

4













Barrett, 1992) description of the human leukocyte antigen (HLA) system. This discovery

set the groundwork for bone marrow matching, thereby increasing the success rate of

allogeneic grafts.

The 1980s saw a tremendous expansion in the use of BMT worldwide. Also,

worldwide reporting of BMT results to the International Bone Marrow Transplant

Registry in Milwaukee has made statistical analysis of large patient groups possible.

Recently, there has been increasing interest in studying donors for allogeneic BMT other

than HLA-identical siblings, including matched but unrelated donors (Powles et al., 1980;

cited in Treleaven & Barrett, 1992). There also has been research investigating techniques

to "purge" or rid the patient's marrow of existing leukemic cells before it is reinfused in

autologous transplants. This procedure shows promise in decreasing the rate of relapse

(Laporte et al., 1994) and has been used mainly in patients with acute leukemia or

lymphoma in clinical remission (Moreb, J., 1995, personal communication).

A relatively new area of investigation in BMT research is stem cell and cord blood

transplantation. The hematopoietic stem cells are responsible for marrow regeneration

after BMT. Sufficient numbers of stem cells for transplantation can be obtained from the

peripheral blood supply after treatment with chemotherapy or growth factors. Transplants

can also be achieved using stem cells obtained from cord blood at the time of delivery

(Thomas, 1997). This blood is tissue typed and cryopreserved for later use. Given the

general availability and ease of procuring cord blood, this type of transplantation is a good










6


alternative to bone marrow or peripheral blood cells as a source of transplantable tissue

(Piacibello et al., 1997). Two advantages of cord blood transplantation are the ease in

identifying a suitable donor and the seemingly improved rate of graft versus host disease

(GVHD) compared to bone marrow or peripheral blood stem cell transplantation (Weber-

Nordt et al., 1996).

Description of Current BMT Procedures

As noted above, there are several types of bone marrow transplants: syngeneic,

allogeneic, autologous, stem cell, and cord blood. Since the current study involves only

patients receiving autologous, allogeneic and syngeneic transplants, these procedures only

will be described further. The majority of allogeneic marrow transplants are for leukemia

or other malignancies, but they also are performed on patients with aplastic anemia and

other "bone marrow failure disorders" (Champlin, 1990). Autologous transplants usually

are performed on patients with hematologic malignancies and solid tumors.

Allogeneic BMT differs from solid organ transplants in that bone marrow is more

easily rejected than solid organs, and more intensive immunosuppressive treatment is

required to achieve durable engraftment (Champlin, 1990). If the patient is not sufficiently

immunosuppressed, graft rejection can occur. Conversely, graft versus host disease can

occur if immunocompetent cells in the donor's marrow react against the host tissues

(Andrykowski et al., 1994). Graft rejection and GVHD are more common with increasing











7


genetic disparity between the donor and host marrow. Typically, BMT is accompanied by

a conditioning regimen of high dose chemotherapy and total body irradiation (TBI).

Allogeneic BMT encompasses three types of grafts: histocompatible,

haploidentical, and matched unrelated donor (MUD) grafts. These grafts differ both in the

source of the marrow, and the extent of tissue match between the donor and host marrow.

The extent of tissue match is based on the human leukocyte antigen (HLA) system. Six

antigens are isolated and matched. Histocompatible BMT involves transplantation of

marrow that is completely HLA-matched (i.e., HLA identical). Haploidentical BMT uses

donor marrow that is only partially HLA-matched (i.e., less than a 6 antigen match).

BMT using an unrelated donor can be either haploidentical or histocompatible. Morbidity

risk rises with increased HLA mismatching, however, mortality risk is less adversely

affected by mismatch (Andrykowski, Brady, & Henslee-Downey, 1994).

Autologous BMT does not carry with it the problem of graft rejection and GVHD,

since the patient is infused with his or her own marrow. However, relapse is higher in

patients receiving autologous transplantation (Moreb, J., 1995, personal communication).

This is presumably due to the presence of cancer cells in the cryopreserved marrow. New

techniques have been developed for purging autologous bone marrow, but their clinical

utility is still being validated (Laporte et al., 1994).

Following transplantation, there are three stages through which patients progress

(Champlin, 1990). In Stage 1, patients are immune suppressed with a cytotoxic regimen











8


that leaves them susceptible to infections from bacteria, viruses, and fungi. In Stage 2,

which lasts up to four months post-BMT, patients are at the highest risk of graft failure,

acute GVHD, and infections from cytomegalovirus (CMV). In Stage 3, patients often are

confronted with chronic GVHD and the constant threat of secondary malignancies and

relapse. Champlin (1990) also notes that abnormalities in the immune systems of BMT

patients persist beyond one year post-BMT. However, most indicators of immune

function are restored by one year post-transplant.

Psychological Factors Involved in BMT

Not surprisingly, BMT places great demands on the emotional resources of

patients, family members, and hospital staff. Some BMT patients exhibit anxiety,

depression, withdrawal, anger, "survivor guilt," non-cooperation with staff or with self-

care requirements, sleep difficulty, anorexia, and paranoia (Andrykowski, 1994a). Some

have suggested that all BMT patients experience these symptoms to some degree at

predictable, consistent times during transplantation (Brown & Kelly, 1976). The

relationship between these psychological symptoms and health outcomes (i.e., quality of

life) has only recently been investigated.

Colon, Callies, Popkin, and McGlave (1991) investigated the impact of depression

and family support on survival post-BMT in 100 adult leukemia patients. In this study,

retrospective chart review yielded non-objective measures of pre-transplant depression

and family support. Depression, family support, and number of remissions from leukemia










9


were used to predict post-transplant survival. The results yielded three findings: 1)

patients who were depressed had poorer survival rates compared to non-depressed

patients; 2) patients with low ratings of family support had poorer survival rates than

patients with adequate family support; and 3) patients who were in their first remission

from leukemia had improved survival rates compared to those in second remission or

relapse. Although these findings provided some evidence for the predictive utility of

psychosocial variables pre-transplantation, this study has several important limitations,

including the lack of a prospective design, and the absence of standardized rating scales to

measure psychosocial variables such as depression and family support.

In another study, Andrykowski, Brady, and Henslee-Downey (1994) prospectively

assessed depression, quality of life, mental adjustment to cancer, demographic variables

and medical variables in a sample of 42 adults with leukemia who were undergoing

allogeneic transplantation. Results indicated that quality of graft match was the only

variable that showed a significant univariate relationship with survival. Patients receiving

a histocompatible graft survived longer than patients receiving a haploidentical or matched

unrelated donor (MUD) graft. However, trends were found for several psychosocial

variables. Specifically, higher "anxious preoccupation" and poorer functional quality of

life pre-BMT were associated with shorter post-BMT survival. No other psychosocial

variables (e.g. depression) showed a trend toward significance. The authors suggested










10


that the small sample size was likely responsible for their failure to show significant utility

ofpsychosocial variables in predicting survival.

Gregurek et al. (1996) administered the State-Trait Anxiety Inventory (Spielberger

et al., 1970) to 35 patients during the first week of allogeneic BMT and again at the end of

isolation from laminar air flow. They were interested in anxiety as a possible predictor of

acute GVHD (Stage II-IV). Patients were evaluated for acute GVHD on days +20, +40

and +100 post-transplant. The authors found that state and trait anxiety were both

significantly elevated during week one of BMT in patients who subsequently developed

acute GVHD. With respect to the outcome of BMT and level of anxiety, only state

anxiety during the last week of isolation was significantly higher in patients who

subsequently died than in survivors. The authors concluded that anxiety may influence

alloreactivity and the development of GVHD through the action of cytokines, which play a

role in connecting the neuroendocrine and immune systems.

Neuser (1988) examined the impact of personality on survival time post-BMT in

35 adult patients with a variety of diagnoses. Patients were given a German-language

version of the Personality Research Form (PRF) within the first two days after admission

to the hospital. They found that one factor, "striving for recognition and help," was

predictive of post-BMT survival. Neuser (1988) suggests that this scale might be highly

correlated with patient compliance (i.e. patients scoring highly on this scale are more

compliant). In another study, Syrjala et al. (1993) investigated the physical and













psychosocial functioning of 67 allogeneic BMT survivors for 6 years post-BMT. They

found that a high level of family conflict pre-BMT was predictive of difficulty in physical

and psychological functioning after transplantation.

Jenkins, Lester, Alexander, and Whittaker (1994) examined the influence of

psychosocial variables such as depression and anxiety on length of stay, survival post-

BMT, and psychosocial adjustment post-BMT. Twenty eight patients undergoing BMT

(both allogeneic and autologous) completed self-report forms measuring anxiety and

depression. They were followed up to 6 months post-discharge. The authors failed to

find a significant link between depression or anxiety and survival. Also, pre-BMT

depression and anxiety were not associated with increased length of stay. However,

psychosocial morbidity post-BMT was correlated with depression and anxiety pre-

transplant. Specifically, depressed patients reported greater degrees of impairment

vocationally and psychologically post-BMT.

In a follow-up study, Murphy, Jenkins & Whittaker (1996) gathered data on fifty-

six patients using both structured, diagnostic interviews as well as unstructured interviews.

They then compared the mean survival of patients with and without depression. The

authors found that the presence of depressive illness did not correlate with length of

survival. In addition, the presence of"fighting spirit" as a predominant coping style did

not correlate with survival. The authors suggest that survival may be more closely related

to physical rather than psychosocial factors.










12


Leigh, Wilson, Burns & Clark (1995; cited in Gregurek et al., 1996) prospectively

assessed 31 BMT patients pre-transplant using measures of anxiety, depression and social

adjustment. Patients were then assessed using the same instruments at 4 and 8 months

after BMT. Overall, 54% of their sample showed "psychosocial morbidity" defined as

anxiety or depression in excess of normal populations on the measures used. Subjects

who scored abnormally following BMT also tended to score abnormally pre-transplant,

suggesting a predictive value ofpre-BMT psychosocial assessment. In addition,

psychological morbidity was unrelated to type of transplant. Patients who had undergone

intensive therapy prior to BMT fared better in terms of psychological morbidity than did

patients who had not undergone major medical treatment prior to BMT. Finally, subjects

who received psychotherapy following their diagnosis were less likely to have depression

or anxiety at 4 or 8 month follow up.

In summary, the question of whether psychosocial variables impact on morbidity

and mortality in BMT patients has yet to be fully answered. While there have been mixed

results in this area of inquiry, preliminary results suggest that psychological variables such

as depression and anxiety may play a role in post-BMT mortality and morbidity.

Theoretically, why should this be the case? Two lines of research, one investigating the

role of psychological factors in the development of medical illness, and the other

investigating the field ofpsychoneuroimmunology, provide theoretical support for the

current investigation.











13


Psychological Factors Involved in Development of Medical Illness

A related area of study is the impact of psychological factors such as depression

and personality on the development of medical illnesses. While many studies have found

links of varying significance between psychosocial factors and the development of cancer

(Blumberg, West & Ellis, 1954; Funch, & Marshall, 1983; Fox, 1983) only two of the

more well designed studies will be reviewed here.

Shekelle et al. (1981) administered the Minnesota Multiphasic Personality

Inventory (MMPI) to a group of 2,107 male employees at Western Electric. The authors

hypothesized that depression as measured by the MMPI would be associated with

increased risk of death from cancer over a 17 year follow up period. Approximately 19%

of these men were judged to be depressed, and these men experienced a twofold increase

in odds of death from cancer over the next 17 years. The authors controlled for age,

cigarette smoking, ETOH consumption, family cancer history and occupation. Both

depressed and non-depressed groups were similar on all of these factors. While unable to

establish causation in this study, the authors nonetheless point out that the magnitude of

the correlations are similar to those observed between coronary heart disease and its major

risk factors of high cholesterol, hypertension and cigarette smoking. Death from cancer

was not associated with any of the other standard scales of the MMPI.

Linkins and Comstock (1990) published a study which closely replicated that of

Shekelle et al. (1981). The authors administered the Center for Epidemiologic Studies










14


Depression Scale (CES-D) to a group of 2,264 subjects. These subjects were followed for

12 years post-test administration. The authors found no significant correlation between

depressed mood and development of cancer, although there was a trend for depressed

subjects to develop cancer more frequently than non-depressed subjects. However,

factoring in cigarette smoking, the authors found huge increases in cancer risk in

depressed smokers, compared to their non-depressed, non-smoking peers.

In summary, these studies indicate that there is a correlation between negative

affect and the development of cancer. However, a causative relationship has not been

established, and the strength of the relationship is not entirely clear at the present time.

Influence of Psychological Factors on Immunologic Functioning

Why have studies found correlations between psychological factors, development

of medical illness, and survival? The relatively new field of psychoneuroimmunology may

provide some answers. Psychoneuroimmunologists decry the body-mind dichotomy as

artificial and frankly false. They posit that behavioral/psychological processes are capable

of altering immune function and that conversely, events that occur as part of immune

responses should modulate behavior (Maier, Watkins, & Fleshner, 1994). There is an

intricate link between the central nervous system (CNS) and the immune system (see

Maier, Watkins & Fleshner, 1994, for a detailed review). The sympathetic nervous system

innervates immune organs such as the thymus, bone marrow, spleen and lymph nodes.

Also, the brain releases factors that cause endocrine glands to secrete hormones into the










15


circulation. This enables hormones to reach the various immune-related organs and bind

to hormone receptors on these organs. The hypothalamus is also integral to immune

function, and can increase or decrease immune response.

Conditioned immunity refers to the capability of psychological events to alter

immune function. There are two lines of research investigating conditioned immunity:

classical conditioning of immunity (Smith & McDaniels, 1983), and the impact of stress on

immunity. Classically conditioned immunity (e.g., pairing a taste with an

immunosuppressive drug in a Pavlovian manner) has been demonstrated in animals and

humans, although it is unclear if this conditioned immunity is clinically significant in

humans in the form of disease progression or onset. Bovjberg et al. (1990) found that

women who had undergone chemotherapy displayed immunosuppression after simply

being brought to the hospital prior to chemotherapy. Grochowitz et al. (1991) suggested

that conditioned immunosuppression could delay tissue rejection in rats receiving heart

transplantation.

The impact of stress on immune functioning has also been a topic of study. Stress

has been found to activate the sympathetic nervous system and the hypothalamic-pituitary-

adrenal (HPA) axis, which impacts immune functioning (Maier, Watkins, & Fleshner,

1994). In particular, anger, anxiety, and depression have all been found to decrease

measures of immune functioning. Initial studies supported the observation that while










16


acute exposure to a stressor can suppress immune response, repeated exposure results in

adaptation and in some cases, enhanced response (Stein, Keller, & Schleifer, 1985).

Recently, two comprehensive review studies have investigated the impact of

depression on immunity. Stein et al. (1991) noted that "no consistent or reproducible

alterations of functional measures of lymphocytes" were reported in depressed patients.

However, Weisse (1992) noted that "indexes of immunocompetence are lower among the

clinically depressed." A large scale, meta-analytic study was conducted by Herbert and

Cohen (1993) to attempt to clarify the research in this area. The authors included

evaluations of all published studies as well as separate analyses restricted to studies

meeting methodological criteria. Thirty-five studies were included overall, and included

both enumerative and functional measures of immune functioning. Enumerative measures

consist of counting the number of immune cells, or the number of antigens in a blood

sample. Functional measures study how effectively immune cells are functioning.

Herbert and Cohen (1993) suggest that, overall, substantial evidence exists

positing a relationship between depression and both enumerative and functional measures

of immunity. Effect sizes in methodologically controlled studies ranged from moderate

(-.24) to large (-.45). Two possible explanations for this correlation are suggested. First,

depression is associated with activation of the HPA axis and the sympathetic nervous

system. Activation of these pathways results in elevated serum levels of cortisol and

catecholamines. Immune cells have receptors for these hormones, suggesting that these










17


hormones play a role in immune modulation. An alternative explanation is that depressed

people typically sleep less, have poorer nutritional intake, and have fewer health-

promoting behaviors than non-depressed counterparts (Herbert & Cohen, 1993).

Overall, psychoneuroimmunology posits that a bi-directional set of processes

occur. Classical conditioning and stress can alter immune function, and, conversely,

immune reactions and products can feed back and modulate behavior and psychological

state. This serves as a theoretical basis for the impact ofpsychosocial variables on

mortality and morbidity in a BMT population.

Quality of Life in a BMT Population

In addition to survival, health-related quality of life is an important outcome

variable in transplantation research. Quality of life is a concept which has many facets,

and incorporates aspects of physical health, personal and occupational functioning,

sociability, and feelings of personal distress and well-being (Andrykowski, 1994a).

Health-related quality of life (HRQOL) covers five categories of concepts, including

duration of life, impairments, functional status, perception of health and social

opportunities (Patrick & Deyo, 1989). Until recently, QOL has not been widely

researched in BMT patients. Research has been devoted to investigating mortality and

medical morbidity (e.g. GVHD), while the impact of BMT on the long-term quality of life

of its recipients has been ignored. However, as MacKeigan and Pathak (1992) point out,

even when life is prolonged, it is important to measure QOL because patients may











18


experience treatment-induced adverse effects. As BMT continues to improve survival, it

is important to be cognizant of QOL issues in order to establish the relative costs and

benefits of this procedure.

There is considerable diversity in the outcome variables examined in this area,

however, there are several broad subject areas. Cognitive and sexual functioning have

been measured, as have employment status, perceptions of physical health, performance of

daily activities and psychological and social adjustment. Research has focused on

examining the long-term QOL of BMT recipients, and also identifying pre-BMT variables

that account for variance in post-BMT QOL (Andrykowski, 1994a).

Cognitive functioning has been assessed in several studies. Andrykowski et al.

(1990) found that cognitive impairments such as slowed reaction time and difficulties in

reasoning were common in post-BMT patients. Also, the extent of this cognitive

dysfunction was correlated with dose of total body irradiation (TBI) received. Several

studies have also identified cognitive dysfunction in pediatric BMT patients (Kramer et al.,

1992; Smedler et al., 1990).

Sexual dysfunction is also an area within the QOL literature which has been

investigated. Sexual dysfunction is a common occurrence, with men experiencing erectile

difficulties, women experiencing vaginal dryness, and both sexes frequently experiencing

sterility (Cust et al., 1989) due to the TBI and chemotherapy. Studies, while small in

number, suggest that greater than 25% of adult BMT recipients report decreased sexual










19


interest, enjoyment or activity following BMT (Baruch et al., 1991; Mumma et al., 1992;

Vose et al., 1992; Wingard et al., 1992).

Baker et al. (1994) examined a range of quality of life variables in a population of

135 BMT survivors 6-149 months post-BMT and found that survivors showed a high

degree of overall satisfaction with life. However, these survivors were least satisfied with

their bodies, level of physical strength and ability to attain sexual satisfaction. Lack of

social support was predictive of anger and negative affect. Patients transplanted at a later

age experienced decreased quality of life overall.

Other studies that have investigated a broad range of QOL variables in a BMT

population have been small in scope (i.e. < 26 patients) and have lacked standardized,

reliable outcome measures. Andrykowski, Henslee-Downey, and Farrell (1989)

investigated psychosocial and physical functioning in 23 adults 3-52 months post-BMT.

Compared to a normative cancer population, BMT patients experienced more mood

disturbance, and poorer QOL. Also, older patients (greater than age 30) reported poorer

QOL and more mood disturbance than younger patients.

Wolcott et al. (1986) investigated adaptation in patients greater than one year post

BMT. They reported that approximately 75% of their sample was "doing well" with the

other 25% reporting emotional distress, chronic physical symptoms, low self esteem and

low QOL. Hengeveld, Houtman and Zwaan (1988) studied 17 adults 1-5 years post-

BMT. Approximately 50% of the sample reported physical complications, sexual










20


problems, infertility and failure to return to employment. Despite this, the authors indicate

that the majority of patients report positive changes in personality and social relationships.

Altmaier, Gingrich, and Fyfe (1991) reported on the QOL in 12 patients two years

post-BMT. They compared perceptions of physical health as well as psychological and

role functioning to a matched sample of leukemia patients receiving chemotherapy only.

BMT patients reported more problems with sexual and vocational functioning; however,

they did not differ from chemotherapy patients in their perception of physical health and

their levels of psychological distress. However, Lesko et al. (1992) found no differences

between BMT and conventional chemotherapy groups with regard to social and

psychological functioning. However, both groups report greater levels of distress relative

to normative, healthy samples.

Litwins, Rodrigue and Weiner (1994) compared QOL in 32 BMT recipients and

22 conventional chemotherapy patients. No differences were found between groups on

any QOL measure. In addition, both groups reported generally good QOL compared to a

normative healthy group.

Prieto, et al. (1996) measured physical and psychological functioning on a sample

of 117 BMT survivors. Median survival time was 55 months (range 6-154). Current

functioning varied considerably across patients. However, the authors found that 31% of

patients reported disturbances in their sex life. Psychiatric disturbance (anxiety and

depression) was present in 22% of patients. They found that quality of life, psychosocial










21


distress and occupational status improved with the passage of time, particularly within the

first 3 years post-BMT. Lower SES, older age at BMT, shorter time post-BMT, female

gender and impotence were significant predictors of impaired QOL.

Finally, Belec (1992) studied 24 BMT patients 1-3 years post-transplant and

assessed QOL. The vast majority of patients perceived their QOL to be acceptable, but

when present, problems centered around physical health and employment. Recently,

several studies have improved upon the above studies by increasing sample size, and

including standardized, reliable measures of outcome and QOL. Andrykowski et al.

(1990) assessed a variety of QOL domains in BMT and renal transplant patients. Fifty-

eight patients total were sampled. Overall, the groups were comparable, with neither

group reporting a "normal" QOL. Both groups experienced difficulty in vocational

functioning, mood disturbances, and poor perceptions of physical health. Dose of TBI

received during pre-BMT conditioning, and age at BMT were negatively correlated with

current QOL.

Chao, Tierney, and Bloom (1992) studied fifty-eight adult autologous BMT

recipients at 90 days and 12 months post-BMT. They found that patients' ratings of QOL

significantly improved between 90 days and 12 months. Eighty-eight percent of patients

at 12 months reported above average to excellent QOL. In addition, 77% were employed

and 64% considered their sexual functioning to be as satisfying as pre-BMT functioning.










22


In keeping with the above results, Schmidt et al. (1993) found that approximately

75% of patients in a sample of allogeneic BMT patients returned to work after 1 year

post-BMT, while a minority reported sleep difficulties or sexual dysfunction. Wingard et

al. (1991) reported that perceived health, physical function, and social functioning were

reported to be good or excellent for most patients in their sample of 135 BMT patients at

least 6 months post-BMT. Approximately 75% of subjects were employed or enrolled in

school. However, despite the average reports of good functioning, some patients were

still significantly impaired. Role retention was generally associated with greater life

satisfaction. This finding regarding role retention was replicated in another study (Baker,

Curbow & Wingard, 1991).

Summarizing the literature on QOL in a BMT population, it is apparent that post-

BMT QOL varies considerably. A majority of patients report average to above average

QOL compared to normative healthy populations. There is little understanding regarding

what factors predict this variability in QOL post-BMT. Demographically, younger

patients seem to fare better after BMT. Retention of roles (e.g. head of household,

employed, homemaker, etc.) has also been associated with greater life satisfaction.

Among treatment variables, dose of TBI has been linked to poorer sexual, cognitive, and

physical functioning (Andrykowski, 1994). Very little is known regarding the impact of

premorbid psychosocial variables (i.e. affect, coping skills, social support) on post-BMT

QOL or physical functioning.










23


Quality of Life: Generic vs. Disease-Specific Measurement

The current study is an attempt to determine the impact of psychological variables

on several domains of QOL, and also survival post-BMT. There is currently a debate in

the literature regarding the measurement of QOL (Andrykowski, 1994). Controversy

centers around whether to measure QOL in a disease-specific format, or a "generic" QOL

format. Generic health status measures are those that measure variables which are

applicable across a wide range of illnesses. Disease-specific measures are those designed

to assess specific patient populations, with the goal of measuring clinical change (Patrick

& Deyo, 1989). The popularity of disease-specific measures is due to the clinical

sensitivity of these scales. These scales are good for measuring changes that occur over

time, and quantifying minimally important changes.

Four different models are relevant in examining the use of generic and disease-

specific measures (Patrick & Deyo, 1989). The first approach is to include both generic

and disease-specific measures in the same study, even though the measures may overlap

substantially. The second approach is to compare a generic instrument and a generic

instrument modified for the population of interest. However, there are no BMT-modified

instruments in the literature. The third approach is to use a generic health status

instrument with a condition-specific instrument. This is similar to the first approach

except that the illness-specific measure should have a different conceptual basis and










24


minimal overlap with the generic measure. The fourth approach is to have a battery of

specific measures which are scored independently and reported as individual scores.

The relative advantages and disadvantages of generic and disease-specific

measures depend primarily on the specific objective of the study. HRQOL measures may

be used to discriminate among respondents at a point in time, to predict future outcomes,

or to measure change over time (Patrick & Deyo, 1989). Generic measures typically have

low content validity because they contain items of little or no relevance to particular

patient groups. By contrast, disease-specific measures have high content validity for

studies of particular patient populations. However, generic measures have greater

construct validity than illness-specific measures. Reliability is a related issue in which

generic measures fare better than disease-specific instruments. There are few comparative

studies of the test-retest reliability of disease-specific measures versus that of generic

measures (Patrick & Deyo, 1989). In summary, generic measures are well standardized,

but disease-specific measures have the advantage of ease of administration, and good

applicability to a specific population. Also, disease-specific measures are useful in

identifying important concerns of patients with particular conditions, and for measuring

small, clinically important changes in specific groups.

Andrykowski (1994) suggests that it is important to measure both generic and

population specific aspects of QOL in a BMT population. He notes several instruments,

including the SF-36 Health Survey (Ware & Sherbourne, 1992), the Sickness Impact










25

Profile (Bergner, Bobbitt, Carter & Gilson, 1981), the FACT-G (Cella, Tulsky & Gray,

1993), and the Functional Living Index-Cancer (Schipper, Clinch, McMurray & Levitt,

1984), which are appropriate for measuring QOL in a BMT population. The first two

instruments are appropriate for all adult BMT recipients while the latter two are

appropriate for all BMT recipients with malignant disease.

Generic measures listed above include the Sickness Impact Profile (SIP) and the

SF-36 Health Survey. The SIP is a measure which provides a profile of scores for

different components of HRQOL. The SIP assesses sickness-related dysfunction in 12

different categories, producing a score for each category (Bergner et al., 1981). The SF-

36 Health Survey (Stewart, Hays, & Ware, 1988) covers a wide spectrum of health

concepts for use in general medical populations. Both the SIP and the SF-36 have been

tested extensively in a wide variety of patient populations and are well standardized (for a

review of patient populations, see Patrick & Deyo, 1989). MacKeigan and Pathak (1992)

suggest that while there is no obvious answer regarding what the "best" QOL instrument

for use in a certain population, the SF-36 questionnaire is practical, reliable, and valid for a

wide range of medical populations.

Disease-specific HRQOL measures (in a cancer population) include the Karnofsky

Performance Status Scale for cancer (Karnofsky & Burchenal, 1949), the Quality of Life

Index (QLI) (Mor, Laliberte, & Morris, 1984), and the Functional Living Index: Cancer

(Spitzer, Dobson & Hall, 1981), the European Organization for Research and Treatment










26


of Cancer QLQ-C30 (Aaronson, et. al, 1993) the Cancer Rehabilitation Evaluation

System-Short Form (CARES-SF) (Schag, Ganz & Heinrich, 1991) and the Functional

Assessment of Cancer Therapy scale (FACT) (Cella, et. al, 1993).

Ferrell et al. (1992) assessed QOL in a BMT population using an instrument

termed the BMT-Quality of Life Survey (BMT-QOLS). The qualitative instrument

consisted of a one-time interview of 119 BMT survivors using six open-ended questions.

Content validity was established by a panel of BMT experts. Content analysis was

performed on verbatim written responses to the six questions. The instrument yielded four

domains of QOL in a BMT population: physical, psychological, social and spiritual well-

being.

In a more methodologically rigorous study, Chao et. al (1992) developed a

questionnaire for autologous BMT patients which addresses physical, psychological and

functional well-being and treatment related side effects. The analysis included 59 subjects.

The 14 item measure combined disease specific symptoms, specific measures of quality of

life, and a global measure of QOL. They also included measures of sexual activity, work

status, and perception of physical appearance. They found good reliability (r=.80) in a

randomly selected group of 20 patients administered the test twice.

Overall, the BMT-specific QOL instruments currently available are unsatisfactory

for inclusion in the present study. None of the above measures include a strategy for

summing the information they gather into an overall QOL rating. This limits their ability










27


to be analyzed meaningfully. As an alternative to inclusion of a BMT-specific QOL

instrument, the current study will include a cancer-specific QOL measure. These measures

have been well-validated in the literature and will be reviewed next.

Cancer-specific QOL measures have been in existence since the early 1980s

(Moinpour, 1994). Several of the more well-validated measures will be reviewed below.

The Functional Living Index-Cancer (FLIC) was one of the first measures to be validated

in a cancer population (Schipper, Clinch, McMurray, & Levitt, 1984). The measure is

cancer specific, functionally oriented, designed for patient administration, and is reliable

and valid. Four principal areas of functional importance were defined: 1)

vocational/activity 2) affect/psychological state 3) social interaction, and 4) somatic

sensation.

Several measures have been developed since that time which provide a total score,

such as the Cancer Rehabilitation Evaluation System Short Form (CARES-SF) (Schag,

Ganz & Heinrich, 1991), and the Functional Assessment of Cancer Therapy (FACT)

(Cella et. al, 1993). These measures are both well-validated and reliable for use in a

cancer population.

The CARES-SF provides a total score and scores on five main domains: 1)

physical functioning; 2) psychosocial functioning; 3) sexual functioning; 4) marital

interaction; 5) medical interaction. Psychometric properties of the CARES-SF have been










28


documented (Schag, Ganz, & Heinrich, 1991). The CARES-SF contains a total of 59

questions, making it one of the more time-consuming measures to complete.

The FACT scale is one of the most rigorously validated measures available for use

in a cancer population. In addition, the FACT scale contains only 28 questions, and can

be completed by patients in approximately 5 minutes. Data was collected over a five year

time period on 545 patients in a variety of health centers, with a variety of cancer types.

Factor analysis created five subscales: 1) physical well-being; 2) social well-being; 3)

emotional well being; 4) functional well-being; and 5) relationship with doctor.

Convergent validity was high between this measure and other cancer-specific QOL

measures (Cella, et. al, 1993). In addition, the FACT was sufficiently sensitive to detect

differences in QOL based on stage of disease. Test-retest correlation coefficients for a

sample of 60 patients were high, ranging from .82 to .92 for the five domain scales.

Another cancer-specific QOL measure which has been well received is the

European Organization for Research and Treatment of Cancer (EORTC) 30 item quality

of life scale. The EORTC QLQ-C30 incorporates five functional scales (physical, role,

cognitive, emotional, and social), three symptom scales (fatigue, pain, and nausea and

vomiting), and a global health and quality of life scale. The questionnaire takes

approximately 12 minutes to complete, and is designed to be filled out by patients. All

scales demonstrated adequate reliability and validity, with the exception of the role

functioning scale, which is also one of the briefest scales.










29


In sum, all of the cancer-specific QOL measures described above are strong from a

psychometric standpoint. They are all applicable to a wide range of cancer types, and

have adequate validity and reliability. For the purposes of the current study, it was

necessary to choose one of these established measures. The EORTC was eliminated from

consideration due to the fact that its role functioning scale is not well validated. This was

a concern, since it has been suggested that role functioning is crucial for regaining

adequate QOL following BMT (Wingard et. al, 1991). The CARES-SF was eliminated

from consideration due to its length. It has been posited that brevity is an important

consideration to improve compliance when choosing a QOL measure (Aaronson et al.,

1993). The FACT was used in the current study due to its strong psychometric

properties, and its brevity and applicability to a BMT population. This measure has been

endorsed for use in a BMT population (Andrykowski, 1994).













CHAPTER 3
SPECIFIC AIMS AND HYPOTHESES

The current study focused on patients at least 2 months post-BMT. The purpose

of the study was to determine the utility ofpre-transplant variables (psychosocial,

demographic and medical) in predicting survival, physical functioning and quality of life

(QOL) post-transplantation. The independent variables chosen for study have been

previously associated with survival or quality of life in either a BMT population or a

cancer population.

In terms of survival time, it was hypothesized that: (1) significant affective

symptoms (depression and anxiety), (2) lower levels of family/social support, (3) a history

of inadequate compliance with medical regimens pre-BMT, (4) increased age at BMT, (5)

increased time from initial diagnosis to BMT, (6) poor marrow-graft match (in allogeneic

patients), (7) later disease state (not in first remission) and (8) allogeneic transplantation

(as opposed to autologous BMT) would be associated with decreased survival time. As

noted above, these variables were chosen for study due to their association with survival

or quality of life in either a BMT or cancer population. The predictive utility of affective

symptoms on survival and quality of life has been reviewed above. Higher levels of

family/social support have been associated with increased survival time and increased

quality of life in a cancer population (Ell, et. al, 1992; Ganz, et. al, 1991). Noncompliance

can have life-threatening implications (Andrykowski, 1994); however, it is unknown how

30










31


past compliance behavior predicts mortality or morbidity in BMT. The demographic,

disease, and treatment-related variables were chosen for study because they have been

associated with post-BMT mortality or morbidity in previous studies (Parr, Messino &

McIntyre, 1991; Kamani & August, 1984).

In terms of quality of life, it was hypothesized that the above mentioned

psychosocial, demographic and medical variables would be associated with poorer quality

of life post-BMT. In terms of symptom self-report, it was hypothesized that the above

mentioned psychosocial, demographic and medical variables would be associated with

poorer quality of life post-BMT.

In addition, several "secondary hypotheses" were investigated. In terms of

psychosocial variables, it was hypothesized that (1) undergoing psychological or

psychiatric treatment either during BMT or post-BMT and (2) experiencing significant life

stress/events post-BMT (e.g. death of a friend, divorce, etc.) would be associated with

increased mortality and morbidity post-BMT.

Several medical variables were examined. Within the allogeneic BMT group,

consistent with clinical findings (Moreb, J., personal communication), it was suggested

that diagnosis would be associated with differential outcome, with acute leukemia patients

and patients with myelodysplastic syndromes having increased mortality and morbidity

compared to chronic myelogenous leukemia and aplastic anemia patients. Within an

autologous BMT group, it was hypothesized that patients not in complete remission at the










32


time of BMT would have increased mortality and morbidity compared to patients with no

evidence of disease.

It was hypothesized that deceased subjects would have more symptoms of anxiety

and depression pre-BMT, lower levels of social support and poorer compliance. Finally,

it was hypothesized that patients undergoing psychological treatment would experience

improved quality of life and physical functioning post-BMT.

The results of this study add to the sparse existing literature investigating the

impact of psychosocial variables on outcome in bone marrow transplantation.

Investigation of the hypotheses above can assist in providing relevant information to the

medical staff regarding who is likely to survive and adapt well to BMT. This information

should be used to determine which patients are appropriate for BMT and to develop

interventions to aid patients at high risk for mortality or morbidity post-BMT. These

interventions should be aimed at enabling high risk patients to become better recipients for

BMT.













CHAPTER 4
METHODS

All protocols were reviewed and approved by the University of Florida Health

Science Center's Institutional Review Board (IRB). No financial incentives were offered

to the subjects for their participation in the study.

Demographics

One hundred and eight patients were contacted about participating in the study.

Sixty-six subjects (61% of those contacted) were included in the analyses. Of these

patients, 42% were male and 58% were female. The mean age of the patients at the time

of BMT was 35 years. Patients had an average of 14 years of education. Mean length of

time from diagnosis to time of transplant was 15 months (standard deviation =14 months).

Forty-seven percent of the patients were in their first remission at the time ofBMT, 39%

were in a subsequent remission or relapse and no data were obtained for 14% of patients.

Thirty-four percent of patients underwent allogeneic transplantation, with 66%

undergoing autologous transplantation. At the time ofpost-BMT data collection, 70% of

the study sample (n=46) were alive and 30% (n=20) were deceased. Patients completed

post-BMT measures 3 months to six years after receiving their transplant. Mean survival

time post-BMT was 18.5 months (sd=17.09 months). Forty-two patients refused to

participate. Of these patients, two refused telephone interviews, five were not able to be

33











34


reached by telephone and did not return telephone messages, and the rest of the patients

did not return mailed questionnaires. (See Table 1)

Table 1: Demographic. Disease, and Medical Data

Variable Percentage or value SD and Range (if applicable)


Male 42%
Female 58%

Diagnosis
ALL or myelodysplasia 16%
CML or aplastic anemia 24%
other diagnoses 60%

Disease status
First remission 47%
Second remission or relapse 40%
Missing data 13%

Transplant Type
Allogeneic 34%
Autologous 66%

Mortality
Alive at follow-up 70%
Deceased at follow-up 30%

Mean age at BMT 35.4 years (sd=12.74, range=17-60)

Mean years of education 13.7 years (sd=2.3, range=9-20)

Mean months from diagnosis to BMT 15.0 months (sd=13.95, range=4-75)











35


Subjects

Eligibility criteria for participation in the study were as follows: (1) Subjects had

completed a pre-BMT assessment in the Psychology Clinic at Shands Hospital, University

of Florida, during the period from 1990-1995, (2) Subjects had subsequently undergone

allogeneic or autologous bone marrow transplantation, (3) Subjects were at least 16 years

old at time of transplantation and (4) Subjects were currently at least 2 months post-BMT.

During the time period from 1990-1995, approximately 165 bone marrow

transplantations were performed on adult patients at Shands Hospital. Subjects were

recruited from this patient population.

Procedures

As per the eligibility criteria, all patients were seen for a pre-transplant

psychological assessment in the Psychology Clinic at Shands Hospital. The pre-transplant

assessment typically lasts 2-3 hours and consists of a clinical interview and psychological

testing.

All psychological testing data were combined with interview data to form a

composite: the Transplant Candidate Evaluation Rating Form (TCERF), which

summarized assessment data relevant to transplantation. Similar instruments have been

described in the literature as a way of assessing transplant candidates in terms of pre-

transplant psychosocial variables (Olbrisch & Levenson, 1989; Twillman et al., 1993).

The format of the TCERF is quite similar to these instruments.










36


In the current study, the TCERF was rated by two advanced graduate students

who received training to ensure their understanding of the rating scale. One student

served as the primary reviewer and the other served as a reliability check. Prior to

beginning the ratings of study subjects, raters practiced completing the TCERF on ten

"mock" subjects independently. Interrater reliability was then measured to assure the

training was adequate. As recommended by Hartmann (1982), lower limits of acceptable

percentage agreement ranged from .60-.75. During the study, every fifth subject was

evaluated by both raters as a check of interrater reliability.

Initially, data collection was planned to occur by telephone interviews. All

potential subjects were notified by mail that they would be contacted by phone regarding a

research study. A brief description of the study was given in this letter and elaborated on

in a follow-up phone call. This phone call served to inform the patients about the purpose

of the study, answer any questions they had, inform them of any possible risks and benefits

of participating, and obtain their consent to be involved in the study. Patients giving their

consent were asked to fill out a number of measures over the phone (see Measures section

below). These measures consisted of a symptom checklist, a generic QOL instrument, and

a cancer-specific QOL instrument. The assessment lasted approximately one half hour.

Due to difficulties contacting patients by telephone, the entire packet of the above

questionnaires was sent to most subjects (n=54) and they were provided with stamped

envelopes in which to return the completed questionnaires. This inconsistency in data










37


collection methods is a potential confounding variable. However, two of the measures

used, the FACT and the SF-36 were designed to be administered either in a structured

interview or by patient self-report and have demonstrated reliability in both settings

(MacKeigan & Pathak, 1992; Ware & Sherbourne, 1992).

Measures

Independent Variables

As indicated previously, all prospective BMT candidates are interviewed clinically

at the time of pre-BMT assessment. However, the battery of psychological tests

administered varies considerably across patients because until recently, there has been no

specific assessment battery guidelines in the literature. Specific tests administered

typically (but not always) include subtests of the Wechsler Adult Intelligence Scale-

Revised (WAIS-R) (Wechsler, 1981), the Minnesota Multiphasic Personality Inventory

(MMPI) (Hathaway & McKinley, 1970), the State-Trait Anxiety Inventory (STAI)

(Spielberger et al., 1970), and the Beck Depression Inventory (BDI) (Beck et al., 1988).

The MMPI is often used to assess personality functioning in bone marrow

transplantation candidates. The MMPI is an empirically derived measure and contains 10

clinical scales, four validity scales, and four supplementary scales. The MMPI has been

extensively used in many populations and has adequate reliability and validity. For a

detailed description of the MMPI, see Dahlstrom, Welsh and Dahlstrom (1972).











38


Negative affect is typically measured by the STAI and the BDI. The STAI is a 40-

item questionnaire which measures two components of anxiety: state anxiety and trait

anxiety (Spielberger, Gorsuch & Lushene, 1970). State anxiety is anxiety which is caused

by a person's response to certain, specific conditions. Trait anxiety is defined as anxiety

which is characterologic in nature and is not situation specific. Reliability and validity have

been established (Turner et al., 1986; Spielberger & Vagg, 1984) and the STAI has been

used extensively in a wide variety of populations (Novy, Nelson, Goodwin, & Rowzee,

1993; Sutker, Bugg, & Allain, 1991; Donham, Ludenia, Sands, & Holzer, 1984).

The BDI is a 21-item questionnaire that measures depressive symptomatology

such as insomnia, weight loss, feelings of sadness, pessimism, guilt, suicidal ideation, etc.

The measure yields a summary score, which can then be compared to normative samples

to derive an index of depression. Reliability and validity of the measure have been

extensively reviewed and are adequate (Beck, Steer, & Garbin, 1988).

While these tests are typically administered as part of the pre-BMT screening,

there is nonetheless a fair amount of variability and these tests are sometimes not used.

The variability in psychological testing may be seen as a problem; however, this was

compensated for by combining psychological test results and interview data into a

composite of psychosocial functioning using the Transplant Candidate Evaluation Rating

Form (TCERF). The TCERF rates psychosocial functioning in a variety of domains

including affect, compliance and social support. Each domain is rated on a five point,











39


Likert-type scale. Raters were aided by a guide sheet which provided detailed descriptions

of criteria for each numeric rating. The descriptions are described below. As noted

earlier, interrater reliability data was gathered to ensure the scientific rigor of this measure.

Also, in clinical practice there is no standard battery of tests used to assess pre-BMT

patients. Similar rating scales to the TCERF are just beginning to be described in the

literature (Olbrisch & Levenson, 1993; Twillman, et al., 1993). Therefore, this study is in

line with current clinical practice, and hopefully will serve to demonstrate a useful way in

which clinical interview data can be combined with variable psychological testing data.

Three variables from the TCERF were analyzed as potential independent variables:

affect, social support and compliance history. Also measured as secondary variables were:

psychological or psychiatric treatment and life events/stress. Patients were asked about

past history of psychological treatment, as well as several questions regarding the

occurrence of significant life events since BMT.

As noted above, TCERF variables were rated on a five point scale. Raters were

trained to use the scale using an expanded description form. On the affect domain, a score

of one on the affect scale is described as follows: "At least two of the following criteria

met: a) concerns about anxiety or depression or other emotion mentioned in psychological

evaluation which is severe enough to merit concern about the recipient's suitability for

transplant, b) history of one or more psychiatric hospital admissions or c) suicidal ideation

or attempt mentioned in psychological evaluation." A score of five is described as











40


follows: "Psychological evaluation mentions appropriate fears, anxiety, anger and sadness.

Anxiety and depression are within normal limits." Similarly detailed descriptions of the

ratings are listed for all numbered ratings on all three scales. For the social support

variable, a score of one represents the following: "Both of the following criteria met: a.

patient reports that s/he does not know who will be the primary caretaker following BMT

and b. patient reports no strong relationships or very unstable relationships." A score of

five represents the following: "Stable, committed relationships, good mental health in

social supporters, caretaker in town with patient throughout BMT process." For the

compliance variable, a score of one is described as follows: "Concerns with all of the

following are mentioned in the psychological evaluation: a. difficulty being compliant with

medications, b. frequent missed appointments with medical, psychological services or

tardiness to appointments and c. problems with dietary, exercise and smoking domains. A

score of five represents that the patient "Has an excellent compliance history." No

concerns are noted in the psychological evaluation." For all variables, a score of zero

indicates that the rater is "unable to rate" for that domain.

Also measured were disease, treatment, and demographic variables that have been

shown to have either an empirical or theoretical association with BMT mortality and

morbidity. These variables included: age at BMT, months from diagnosis to BMT, extent

of marrow graft match (histocompatible vs. haploidentical or matched unrelated donor

(MUD)), type of transplant (autologous vs. allogeneic) and disease state (first remission or











41


first chronic phase vs. all other later stages). Secondary demographic and medical

variables measured were: socioeconomic status (SES), sex, diagnosis (within the

allogeneic BMT group) and remission status (in the autologous BMT group).

Dependent Variables

Three variables were measured post-transplant: survival, quality of life (QOL), and

physical functioning/somatic symptoms. Two methods were used to determine survival

data for subjects. First, survival data is kept on record at Shands Hospital, and if the

patient was deceased, the death date was noted. If the patient's survival status is

unknown, this was obtained via telephone interview with the patient, or the spouse or

significant other if the patient was deceased. If the patient was deceased, the date of death

was obtained from the spouse or significant other.

Two Health Related Quality of life (HRQOL) measures were used. First, the

Medical Outcomes Study 36-item Short Form (SF-36), a generic HRQOL measure, was

administered. This measure was both rationally and empirically developed by Ware and

colleagues (Ware & Sherbourne, 1992; McHorney, Ware, Rogers, Raczek, & Lu, 1992;

McHorney, Ware, Lu, & Sherbourne, 1994). The SF-36 assesses eight health concepts

including: limitations in physical activities because of health problems, limitations in social

activities because of physical or emotional problems, limitations in role activities because

of health problems, limitations in role activities due to emotional problems, pain, general

mental health (psychological distress and well-being), vitality (energy and fatigue), and










42


patient perception of general health status. The survey is designed to be a self-report

measure, or to be administered over the telephone by an interviewer. In a sample of 3,053

adults, the internal reliabilities of the subscales ranged from .77 to .92 (Stewart et al.,

1992).

Also, a cancer-specific HRQOL measure was given. The literature is practically

non-existent on QOL measures specifically assessing QOL in a bone marrow

transplantation population. Therefore, a cancer-specific QOL instrument will be

substituted. The FACT-G is a cancer-specific instrument which includes a total QOL

score, as well as four subscale scores for physical, functional, social, and emotional well-

being, and a satisfaction with treatment relationship score. The measure has demonstrated

adequate internal consistency and reliability (Cella, et. al, 1993).

A symptom checklist was added to the post-transplantation battery in order to

attain information about post-transplant physical/medical condition. The Transplant

Symptom Frequency Questionnaire, which has been modeled after the work ofLough et

al. (1987), was used for assessment. This questionnaire assesses the frequency of 35

symptoms using a 0-4 rating (0=never have symptom and 4=always have symptom). In

addition, for each symptom, the questionnaire inquires, "Is this a problem for you?" The

symptom frequency checklist yields two scores. The first is a "total frequency score" (sum

of 0-4 ratings on all questions). The second is a "total problem score" (number of "yes"











43


responses on the questionnaire). These 2 scores were analyzed as relevant physical

functioning outcome variables.

Finally, the Transplant Recipient Information Questionnaire provided a structured

format for inquiring about socioeconomic status (SES), prior psychiatric or psychological

treatment, and significant life events/life stress in the past 6 months. Socioeconomic status

was measured on a 4 point Likert-type scale, while prior psychiatric treatment and

significant life events were analyzed as dichotomous variables (yes/no). Means and

standard deviations for dependent and independent measures are presented in Table 2.

Statistical Analysis

Interrater reliability data were gathered on the TCERF by computing percentage

agreement (Cohen, 1969).

First, it was hypothesized that negative psychosocial indicators (higher pre-BMT

levels of anxiety and depression, lower levels of family/social support, a history of

inadequate compliance with medical regimens pre-BMT), negative demographic indicators

(increased age at BMT, increased time from initial diagnosis to BMT) and negative

medical indicators (poor marrow-graft match, later disease state and allogeneic

transplantation) would be associated with decreased survival time. Correlation

coefficients were computed to examine the association of various psychosocial,

demographic and medical variables to survival time. Those variables showing at least a

slight trend toward association (p<.20) were included in a stepwise Cox proportional











44


Table 2: Means and standard deviations of measures


Measure Mean SD

Transplant Candidate Evaluation Rating Form (TCERF)
Social Support 4.18 .89
Affect 4.18 .91
Compliance 4.26 .90

Life Stress 1.77 1.54

Functional Assessment of Cancer (FACT)
Physical Well-Being 5.20 5.07
Emotional Well-Being 5.39 2.10
Satisfaction with Doctor 7.07 1.36
Family Well-Being 14.74 3.87
Total Score 53.61 5.43

SF-36
General Health Scale 68.37 23.54
General Mental Health 79.83 14.36

Symptom Checklist
Problem Score 6.17 7.04
Frequency Score 27.54 16.26





hazards linear regression model. The stepwise Cox model is a multivariate measure to

determine the relative contribution of each psychosocial, demographic and medical

variable to prediction of survival time post-BMT.










45


Second, it was hypothesized that these negative psychosocial indicators,

demographic indicators and medical indicators would be associated with poorer quality of

life post-BMT. Again, correlation coefficients were computed to asses the relationship

between psychosocial, demographic and medical variables with quality of life. Variables

showing at least a trend (p<.20) toward an association with QOL and symptom self-report

were included in a number of multiple linear regression models analyzing the utility of

psychosocial variables in predicting post-BMT quality of life.

Specifically, multiple regression equations were analyzed for two domains of the

SF-36: 1) general mental health and 2) patient perception of general health status. These

domains were chosen because of their adequate internal reliability and because they

address the most general and relevant variables of interest to this study. This yielded a

total of 2 multiple regression equations measuring the contribution of relevant

demographic, psychosocial, and medical variables to the prediction of general mental

health and patient perception of general health status.

For the FACT-G analysis, one multiple regression equation was used to measure

the association of various demographic, medical, and psychosocial variables with the total

score on the FACT-G. Also, five multiple regression equations were used to examine the

association of the independent variables with each of the domain scores: 1) physical well-

being; 2) functional well-being; 3) social well-being; 4) emotional well-being and; 5)

satisfaction with treatment relationship.











46


Third, it was hypothesized that negative psychosocial, demographic and medical

variables would be associated with increased symptom self-report. Again, correlation

coefficients were computed measuring the association of psychosocial, demographic and

medical variables with symptom self-report. Variables demonstrating at least a slight trend

toward a significant association (p<.20) were included in multiple regression equations. A

total of two multiple regressions were performed to examine the Symptom Checklist

variables. These multiple regressions measured the association of relevant demographic,

psychosocial, and medical variables to: 1) the total frequency score, and 2) the total

problem score.

Several secondary hypotheses were also investigated. First, it was hypothesized

that patients undergoing psychological or psychiatric treatment either during BMT or

post-BMT would experience increased mortality and morbidity post-BMT. A t-test was

run to examine this hypothesis. Second, it was hypothesized that patients experiencing

significant life stress post-BMT would experience increased mortality and morbidity post-

BMT. This was examined by computing correlation coefficients measuring the association

of life stress with survival time, quality of life and symptom self-report. If life stress were

found to be at least slightly correlated to mortality or morbidity (p<.20) it would be

included in Cox regression analysis or multiple regression analysis as described above.

Several hypotheses regarding the effect of medical variables on outcome (see Chapter 3)

had to be dropped from the analyses due to lack of data.











47


T-tests were performed to investigate whether deceased and still-living subjects

differed in terms of their pre-BMT affect, social support and compliance. T-tests were

also run comparing subjects having psychological treatment in terms of their outcome

(quality of life, survival time, physical functioning).













CHAPTER 5
RESULTS

Interrater Reliability

Interrater reliability was calculated as described above. Every fifth subject (20% of

the entire sample) was evaluated by both raters to cross-check validity. This yielded a

sample of 13 subjects for whom percentage agreement was computed. Percentage

agreement was .60 for Social Support, .73 for Affect and .80 for Compliance. These

values are within the guidelines suggested by Hartmann (1982) for acceptable interrater

reliability in the social sciences.

Variables Included/Excluded from Multiple Regressions and Survival Analyses

As noted in the Statistical Analysis Plan, correlation coefficients were computed to

investigate the association between pre-BMT demographic, physical/medical and

psychosocial variables (independent variables) and post-BMT survival time, quality of life

and physical functioning (dependent variables). Independent variables showing at least a

slight trend toward an association with outcome variables were included in either Cox

regression analysis or multiple regression analysis.

Survival Time: The following variables showed a trend toward an association with

survival time and were therefore included in the Cox regression analysis: education (r=. 18,

p=.15) and SES (r=.22, p=.08) (demographic variables); treatment type (r=-.21, p=.04),

remission status (r=-.23, p=.04), diagnosis (in allogeneic transplant) (r=-.15, p=.17) and

48











49


number of remissions (r=. 15, p=. 17) (medical variables). Affect, social support, and

compliance history were also included in the Cox regression analysis since they were the

primary psychosocial variables of interest. Variables demonstrating no relationship

(p>.20) to survival time and therefore not included in the Cox analysis are as follows:

lifestress, age at BMT, gender and time from diagnosis to BMT. Quality of marrow-graft

match was dropped from the analysis due to the low number of subjects for whom this

information could be procured from medical records.

QOL and Symptom Self-Report: The following variables showed a trend toward an

association with quality of life variables or symptom report variables and were therefore

included in a number of multiple regression equations: age at BMT (r=-.2152, p=.08),

education (r=.20, p=.11), SES (r=.29, p=.02) (demographic variables), and pre-BMT

affect (r=.50, p<.001), social support (r-.27, p=.07), compliance (r=.28, p=.06) and life

stress (r=-.32, p=.009)(psychosocial variables). The following variables did not show an

association to quality of life or symptom report (p>.20) and therefore were eliminated

from multiple regression analyses: gender, psychological or psychiatric treatment history,

diagnosis, treatment type, remission status (again, likely an artifact), disease state and time

from diagnosis to BMT. Quality of graft-match was eliminated as a variable due to

insufficient sample size for which this information could be procured.











50


Survival Analysis and Multiple Regressions

In terms of survival time analysis, none of the medical, demographic, or

psychosocial variables significantly predicted post-BMT survival time. Given the

robustness of the literature, it is likely that extent of graft-match does have significant

predictive value (Andrykowski, et al., 1994), however, this variable was dropped from the

analysis due to difficulty procuring this information from medical records.

In terms of the multiple regression analyses performed, none of the demographic,

medical or psychosocial variables was predictive of responses on the SF-36 General

Mental Health Scale, although pre-BMT affect showed a trend toward significance

(F=2.0, p=.09). Patients experiencing higher levels of affective distress pre-BMT were

more likely to rate their mental health as poor following treatment.

None of the medical variables was predictive of patient responses on the SF-36

General Health Scale. However, patients experiencing fewer life stresses were more likely

to rate their post-BMT health in a positive manner (F=2.8, p<.05). Also, patients

experiencing lower levels of negative affect pre-BMT affect were more likely to rate their

post-BMT health highly (F=3.22, p<.01). Interestingly, patients who reported lower

levels of social support pre-BMT were more likely to rate their health in a positive manner

post-BMT (F=2.7, p<.05). Also, patients who ranked poorly in terms of pre-BMT

compliance were more likely to view their general health as good post-BMT (F=2.4,

p<.05).











51


None of the medical, demographic, or psychosocial variables was significantly

correlated to subjects' Functional Assessment of Cancer (FACT-G) Total score, the

FACT-G Family Well-Being Scale or the Emotional Well-Being Scale. However, pre-

BMT affect was predictive of post-BMT scores on the FACT-G Physical Well-Being

Scale (F=3.05, p<.05). Pre-BMT social support (F=2.6, p<.05) and compliance (F=2.4,

p<.05) also significantly predicted physical well-being. In sum, subjects judged to have

lower levels of negative affect pre-BMT affect, higher levels of social support and better

compliance history were more likely to report feeling physically healthy on the FACT-G

Physical Well-Being Scale.

Several medical, demographic and psychosocial variables were associated with

increased scores on the FACT-G Satisfaction with Doctor scale. The following variables

were significantly associated with increased satisfaction with the treating physician: male

gender (r=.39, p<.05), lower SES (r=-.43, p<.05), allogeneic transplant (F=3.5, p<.05),

decreased life stress (F=3.8, p<.01), decreased negative affect pre-BMT (F=3.5, p<.01),

lower levels of pre-BMT social support (F=3.2, p<.01) and poorer pre-BMT compliance

(F=3.1, p<. 01).

No medical or demographic variables were significantly correlated with Frequency

of Symptoms (on Symptom Checklist). However, patients experiencing more life stress

experienced greater frequency of symptoms (F=3.1, p<.05), as did patients with more

symptoms of anxiety and depression pre-BMT (F=3.0, p<.05) and poorer compliance











52


(F=2.7, p<.05). Patients judged to have higher levels of social support pre-BMT

surprisingly reported greater frequency of symptoms post-BMT (F=2.6, p<.05).

In terms of how distressing subjects reported their physical symptoms to be

(Symptom Checklist Total Problem Score), subjects with higher levels of negative affect

pre-BMT (F=2.9, p<.05) and poorer compliance (F=3.4, p<.01) judged their symptoms to

be more problematic than did subjects with higher ratings of pre-BMT affect and

compliance. Also, subjects with higher levels of pre-BMT social support rated their

symptoms as more disturbing than did individuals with lower levels of social support

(F=2.6, p<.05).

T-Tests

T-tests were run comparing deceased individuals with individuals still living in

terms of their pre-BMT affect, compliance and social support. Individuals with lower

levels of social support pre-BMT were more likely to be deceased at the time of follow-up

(one tailed t=1.72, p<.05). Individuals with higher levels of negative affect pre-BMT

showed a trend toward being more likely to expire during the follow-up period compared

with individuals with lower levels of negative affect pre-BMT (one tailed t=1.58, p=.06).

T-tests were also performed comparing individuals who had received

psychological or psychiatric treatment with those who had not in terms of their survival

time, likelihood of being alive at time of follow-up, quality of life and symptom report.

The only significant result was that individuals who had received psychological treatment











53


reported greater frequency of symptoms (2-tailed t=3.07, p<.01) and greater distress

about these symptoms (2-tailed t=2.58, p<.05) than individuals who had not received

psychological treatment (See Tables 3 and 4).











54


Table 3: Results of regression analyses on predictors of quality of life and symptom report



Outcome variable Significant predictors Beta Adjusted R2 F

SF-36 General Health .22 2.38
Lifestress -.37
Affect .29
Social Support -.03
Compliance -.04

FACT Physical Well-Being .23 2.41
Affect -.39
Social Support -.01
Compliance -.16

FACT Satisfaction with M.D. .30 3.09
Gender .39
SES -.43
Transplant Type .16
Lifestress -.27
Affect .18
Social Support -.16
Compliance -.19

Symptom Checklist-Frequency .27 2.74
Lifestress .44
Affect -.21
Social Support .03
Compliance -.27

Symptom Checklist-Problem .33 3.39
Affect -.41
Social Support .13
Compliance -.39











55


Table 4: Psychosocial Variables significantly associated with mortality, QOL and symptom
report

Variable Association

Social support 1. Subjects with poor pre-BMT social
support more likely to be deceased at follow-
up

2. Adequate pre-BMT social support
predicts decreased self-reported activity
level, increased symptom frequency and
symptom distress at follow-up

Affect 1. Subjects with fewer symptoms of
depression and anxiety pre-BMT have more
positive perceptions of their health,
decreased symptom frequency and symptom
distress at follow-up

Compliance 1. Increased pre-BMT compliance predicts
decreased symptom frequency and symptom
distress

Lifestress 1. Increased life stress predicts poorer
perception of general health, increased
symptom frequency and symptom distress













CHAPTER 6
DISCUSSION

No psychological, demographic or medical variables were predictive of survival

time. This is likely an artifact, because in other studies (e.g. Andrykowski et al., 1994)

quality of marrow-graft match was significantly predictive of survival time. In the current

study, however, difficulty obtaining medical record data forced the removal of this variable

from analysis. Based on the literature (Murphy, Jenkins & Whittaker, 1996; Andrykowski

et al., 1994; Jenkins et al., 1994), it does appear that survival time is mediated

predominantly by medical variables rather than psychosocial or demographic variables.

Jenkins et al. (1994) notes that psychosocial variables appear to have a more prominent

effect on quality of life and post-BMT emotional state than mortality. Murphy, Jenkins &

Whittaker (1996) failed to find a significant link between depression and survival.

Gregurek et al. (1996) found that an elevated level of anxiety during the first week of

BMT was significantly predictive of developing acute GVHD (Stage II-IV) but was not

predictive of eventual mortality. This suggests that psychological factors may play a role

in medical morbidity, but may have too subtle an effect to actually influence mortality.

These studies are in contrast to the only study to date which has linked psychosocial

factors (depression and low family support) to mortality (Colon, et al., 1991). It should

be noted that there are methodologic problems with the Colon et al. study and the results

have not been replicated.

56











57


In the current study, subjects who were judged to have lower levels of social

support were more likely to be deceased at time of follow up compared to subjects with

adequate social support. Although there is a great deal of literature linking social support

to emotional adjustment to cancer (see Rowland, 1989 for a review), few studies have

investigated the relationship between naturally occurring social support (i.e. families,

friends in the community) and mortality. To date, only Colon et al. (1991) has examined

naturally occurring social support networks and their outcome on survival time or

mortality. Colon et al. (1991) found that individuals undergoing BMT who reported

adequate family support were more likely to be alive at the time of follow up compared to

individuals who rated their family support as poor. Gregurek et al. (1996) has suggested

that psychosocial factors (such as emotional state and social support) may influence

alloreactivity through the action of cytokines, which play a role in connecting the

neuroendocrine and immune systems.

Research has also investigated the effect of social support interventions on

mortality. According to Holland (1991) over 20 intervention studies have been conducted

that involved social interactions, the majority of which demonstrated an improvement in

psychological adjustment. However, the data on mortality are more equivocal. Most of

the social support intervention studies lacked theoretical frameworks and had serious

methodological flaws. These studies focused on either peer discussion or education (see

Helgeson & Cohen, 1996 for a review of these studies). Helgeson & Cohen conclude that











58


although their review includes several studies that found effects of social support

interventions on mortality (Fawzy et al., 1993; Morgenstern et al., 1984; Spiegel et al.,

1989), the number of studies focusing on mortality or symptom report are not sufficient to

assess the effectiveness of these interventions or to speculate on responsible mechanisms

for the protective effect of social support. In sum, it appears that social support may

protect people to some extent from mortality. However, the most helpful type of social

support (i.e. family support vs. peer discussion group vs. peer education group) has not

yet been determined. The "protective" components of a peer discussion group may be

very different from the "protective" components in a naturally occurring social support

group (like a family). Further research needs to clarify exactly what components of

naturally occurring social support and social support interventions protect people from

mortality and morbidity. This would enable identification of individuals at increased risk

of mortality due to decreased social support and would allow interventions designed to

address the specific component of social support which protects individuals from

mortality.

People who reported elevated levels of life stress (e.g. divorce, death of a friend or

relative, loss ofjob) at the time of follow-up reported poorer perceptions of their general

health and more frequent symptoms of illness than did individuals who reported little or no

life stress. This again points to a connection between an individual's psychological state

and his or her perceptions of physical health. Stress has been found to activate the











59


sympathetic nervous system and HPA axis, thereby decreasing immune functioning

(Maier, Watkins & Fleshner, 1994; Stein, Keeler & Schleifer, 1985). Consistent with this,

it was also found that subjects who had lower levels of negative affect pre-BMT had more

positive perceptions of their general health at the time of follow-up. Further, individuals

with lower levels of negative affect pre-BMT reported decreased symptom frequency and

were less distressed by the symptoms which they did experience. This is consistent with

Gregurek et al. (1996) who found that subjects undergoing BMT who had elevated

anxiety levels were more likely to develop acute GVHD.

Some have suggested (Baker et al., 1994; Hobfoll & Walfisch, 1984; cited in

Baker et al., 1994) that self-esteem may play a large role in determining adaptive

functioning and perception of physical health following BMT. Individuals with improved

self-esteem seem to fare better post-BMT than individuals with low self-esteem. While

self-esteem was not measured in the current study, it would be expected that self-esteem

would play a large role in determining pre-BMT affective state. Since having adequate

self-esteem may enable people to experience improved affect, both pre- and post-BMT,

this is an area meriting further research. Learning how certain people maintain their self-

esteem and improve post-BMT quality of life in the face of many physical, mental status

and emotional changes could foster the development of interventions designed to aid those

with poor self-esteem both pre-BMT and during BMT.











60


Conflicting data was found with regard to the impact of social support and

compliance on perceptions of physical health. On the SF-36, patients who had lower

levels of social support and compliance rated their physical health as better than

individuals with higher levels of social support and compliance. However, on the FACT-

G, patients were more likely to report good physical health who had higher levels of social

support and compliance pre-BMT. This may be due to the fact that the SF-36 and the

FACT-G measure subtly different things. The SF-36 is a general health survey, while the

FACT-G is a cancer-specific quality of life instrument. As a result, the SF-36 focuses on

general activity level as a way of measuring physical health, while the FACT-G focuses on

cancer-specific physical symptoms as a measure of physical health. Looked at in this light,

individuals with lower levels of social support may be forced to be more active and

independent than those subjects with social support networks to help them complete

activities. Therefore, based on reports of physical activity, individuals with less social

support would appear to view themselves as healthier than individuals with more social

support. At any rate, the relationship between social support, compliance and perception

of physical health remains unresolved at this time.

With regard to symptom frequency and distress related to symptoms, individuals

with higher levels of pre-BMT social support and poorer compliance reported higher

levels of symptoms and more emotional distress over these symptoms. It would be

expected that individuals with poorer compliance histories would experience more











61


symptoms. However, the relationship between social support and symptom report is not

entirely clear. It is possible that caretakers tend to focus on symptoms in an attempt to

take care of patients, leading the patient to "notice" symptoms more than he or she would

if forced to function independently of family and friends.

However, it is also possible that individuals' level of social support changed from

pre- to post-BMT. Little research has focused on what changes take place in terms of

family relationships during and following BMT. One study (Syrjala, et al., 1993) found

that there was little change in social support over time; however, another study (Zabora, et

al., 1992) found that there were great changes in social support over time with some

patients reporting increased social support and others reporting decreased support. This

means that level of social support prior to BMT may not even predict level of social

support post-BMT. This in turn would make it difficult to predict quality of life post-

BMT based on pre-BMT social support. Zabora and colleagues found that families tended

to set goals and time periods in which they expected the BMT patient to resume family

and career roles, and when these goals were not fulfilled, family conflict was typical. They

also found that, in general, BMT patients' significant others experienced a significant

worsening in their emotional state up to six months after BMT as well as reporting

increased physical fatigue. In sum, the fact that little is known about changes in social

support over time for BMT patients makes it difficult to make inferences about the











62


relationship of pre-BMT social support to post-BMT report of physical symptoms in BMT

patients.

Social support was not found to correlate with post-BMT affective state.

Individuals with lower levels of social support were no more likely to report emotional

distress at follow up. This is in contrast to Baker et al. (1994) who found that patients

with less social support were more likely to experience high levels of anger and negative

affect post-transplant. However, in the Baker et al. study, patients were reporting social

support post-BMT. Therefore, these patients may be expected to experience anger and

negative affect in response to the current stress of low family support. As noted above, it

is unclear at the present time how or if social support changes during the time between

pre-transplant and one year post-transplant (Wingard, 1994). Patients in our study were

rated on social support pre-BMT and those with low levels of support pre-BMT may have

improved their level of social support during and after transplantation. Indeed, at least

one study has found that social adjustment post-BMT is comparable with a healthy

community sample overall in various domains of work, family, marital and leisure activities

(Wolcott, Wellisch & Fawzy, 1986), suggesting that BMT patients acclimate well into

their communities following BMT.

Individuals in the current study who had undergone psychological or psychiatric

treatment in the past were more likely to rate their frequency of physical symptoms as

high. This is likely due to the fact that individuals with more severe physical symptoms










63


may be more emotionally distressed than individuals with few symptoms and therefore,

more likely to receive psychiatric treatment. Individuals on the Bone Marrow Treatment

Unit at the University of Florida are monitored closely by the staff, who notify the

Psychology Dept. if psychological distress appears to be in excess of normal levels. At

that time, psychotherapy is typically initiated.

A relatively new area of investigation is the FACT-G Satisfaction with Doctor

scale. In the current study, males, people with lower socioeconomic status, lifestress,

social support and compliance, people with fewer symptoms of anxiety and/or depression

pre-BMT, and people undergoing allogeneic treatment were more likely to have higher

ratings of satisfaction with their doctor. This suggests that patients who have lower levels

of social support may look for this support in their treating physician. Also, patients with

lower SES and fewer affective symptoms pre-BMT may be more likely to trust their

physician and therefore, report increased satisfaction. Individuals receiving allogeneic

treatment may report higher patient satisfaction due to having increased contact with their

doctors compared to autologous BMT patients. This would likely be due to the fact that

allogeneic BMT survivors are more likely to experience GVHD, necessitating closer

follow-up after BMT and increased contact with medical staff. It is unclear why males or

individuals with poor pre-BMT compliance would have higher physician satisfaction.

In summary, pre-BMT psychosocial variables appear linked to outcome in terms of

both mortality and psychological morbidity. People with higher levels of anxiety and/or











64


depression pre-transplant were more likely to report poorer perceptions of physical health,

greater frequency of symptoms and greater distress about these symptoms. People with

lower levels of social support appear to be at increased risk for mortality compared to

those with higher levels of social support. However, higher levels of social support may

cause individuals to focus on their symptoms more than they otherwise would and to

decrease their activity level accordingly. Individuals with higher levels of social support

reported more frequent symptoms and more distress about these symptoms than did

individuals with lower levels of social support.

The current findings are very encouraging, as they suggest that psychosocial

factors do have a strong influence on outcome in terms of quality of life and possibly

mortality. This is important because interventions designed to modify patients' affective

state, level of social support and compliance behavior are existent in the literature, but

only now are beginning to receive strong empirical support (e.g. Andrykowski et al.,

1994; Gregurek et al., 1996). The clinical implications for the current study are important.

First, the role of psychologists in screening patients for risk factors in BMT is

strengthened given the current data. Also, treating physicians should know that outcome

may be improved if a patient's affective state is closely monitored and interventions put in

place at the first sign of affective distress in excess of normal.

There are several limitations of the current study. The first is the retrospective

nature of the design. The second is the use of a subjective rating scale to measure











65


subjects' pre-transplant psychological functioning. However, the subjective rating scale is

modeled after several other rating scales found to have adequate reliability and validity in a

BMT population (Presberg, et al., 1995). Third, the sample size was somewhat small,

limiting statistical power. Difficulty in obtaining medical information was another limiting

factor, necessitating the elimination of several important medical predictor variables from

the analysis. Future studies should use a prospective design and standardized

psychological measures (as in the Gregurek et al., 1996 and Andrykowski et al., 1994

studies).

Related to the limitations above is the response rate of the current study. Since

only 61% of those contacted to participate in the study actually participated, it is

interesting to question whether a self-selected sample such as this one is significantly

different from a true cross-section of BMT survivors. While there is no research

examining this issue in a BMT population, it is not expected that there would be many

differences between study participants and non-participants. Anecdotally, participants in

the study had a wide range of experiences in terms of quality of life. Some were quite

pleased with the results, reporting few side effects and few lingering symptoms, while

other BMT patients reported chronic GVHD, difficulty returning to work, and problems in

physical and emotional functioning. It is therefore suspected that the sample in our study

is fairly representative of BMT survivors as a whole.











66


Future research should also address the complex relationship between social

support and mortality. It seems plausible that higher levels of social support protect

patients from mortality (Helgeson & Cohen, 1996). It is not yet clear which types of

social support (i.e. family support vs. peer discussion or educational support groups) are

the most helpful in decreasing mortality. However, it may be true that particular types of

social support (for example, cancer support groups) which motivate patients to increase

their independence and take an active role in maintaining social support networks may be

the most effective in decreasing psychosocial morbidity (i.e. quality of life, symptom

report) as well as mortality. Based on the current study, interventions such as group or

individual psychotherapy which (hopefully) increase patient independence, provide social

support and decrease depression and anxiety could "inoculate" people against mortality

and morbidity post-BMT.

The complex role between social support, role retention, and quality of life should

also be further examined. It appears that role retention is a critical component in

determining not only BMT patients' quality of life, but also family functioning post-BMT

(Baker, et al., 1994). The sooner a BMT patient is able to resume roles such as family

caretaker, parent, employee, etc., the faster the family unit is able to resume normal

functioning. While medical variables certainly play the largest role in an individual's ability

to resume typical role functioning, psychological variables also play a part. Since it is

unclear what changes occur in social support over time following BMT, it is critical to










67


examine ways to allow BMT patients to exert control over their treatment and life style

following BMT, thereby increasing their ability to resume role functioning, increase social

support and hopefully protect themselves from increased risk of mortality and morbidity.

Finally, continued research into the development and refinement of rating scales

similar to the one used in this study (see Presberg, 1995) would be helpful. Since the

current state of clinical practice in this area involves the use of a multitude of psychosocial

assessment techniques and instruments, finding a means of summarizing testing and

interview data in a valid and reliable way is essential to identifying patients at high risk for

negative outcome in BMT. Particular issues to focus on include the measurement of

reliability between samples of BMT patients and between raters.














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BIOGRAPHICAL SKETCH

Timothy Pearman was born in Allentown, Pennsylvania, on October 5, 1969. He

received a Bachelor of Arts degree from the Pennsylvania State University in May, 1991,

and entered the University of Florida in August, 1991. He received a Master of Science

degree from University of Florida in May, 1994. He completed his clinical internship at

Tulane University Medical Center and is currently living in New Orleans, Louisiana.





























78














I certify that I have read this study and that in my opinion it conforms to
acceptable standards of scholarly presentation and is fully adequate, in scope and quality,
as a dissertation for the degree of Doctor pf Philsoph


Far /es Rodrigue, Cir
oAsociate Professor of Clinical and Health
/Psychology

I certify that I have read this study and that in my opinion it conforms to
acceptable standards of scholarly presentation and is fully adequate, in scope and quality,
as a dissertation for the degree of Do of Philosophy.


Duane Dede, Cochair
Assistant Professor of Clinical and Health
Psychology

I certify that I have read this study and that in my opinion it conforms to
acceptable standards of scholarly presentation and is fully adequate, in scope and quality,
as a dissertation for the degree of Doctor of Philosophy.


Stephen Boggs
Associate Professor of Clinical and Health
Psychology

I certify that I have read this study and that in my opinion it conforms to
acceptable standards of scholarly presentation and is fully adequate, in scope and quality,
as a dissertation for the degree of Doctor of Philosophy.


Karolyn Godby
Associate Professor of Nursing














I certify that I have read this study and that in my opinion it conforms to
acceptable standards of scholarly presentation and is fully adequate, in scope and quality,
as a dissertation for the degree of Doctor of Philosophy.


Jan Moreb
Associate Professor of Hematology and Oncology

This dissertation was submitted to the Graduate Faculty of the College of Health
Professions and to the Graduate School and was accepted as partial fulfillment of the
requirements for the degree of Doctor of Philosophy.

August 1997
Dean, College of Health Profesions


Dean, Graduate School




Full Text

PAGE 1

MORTALITY AND MORBIDITY FOLLOWING BONE MARROW TRANSPLANTATION: PREDICTIVE UTILITY OF PSYCHOLOGICAL VARIABLES By TIMOTHY PATRICK PEARMAN A DISSERTATION PRESENTED TO THE GRADUATE SCHOOL OF THE UNIVERSITY OF FLORIDA IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY UNIVERSITY OF FLORIDA 1997

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ACKNOWLEDGMENTS I wish to thank my dissertation chairperson, Jim Rodrigue, Ph.D., for his support and guidance throughout all phases of this project. The supportive, collegial and knowledgeable presence which he brought to this project was invaluable to me. I owe thanks to Stephen Boggs, Ph.D., Duane Dede, Ph.D., and Karolyn Godbey, Ph.D. for their theoretical and practical contributions to the scientific rigor of my study. I would also like to acknowledge the gracious assistance of Jan Moreb, M.D. and John GrahamPole, M.D., who allowed me to use their patients as research subjects and were also very helpful in research design related to medical variables. In addition, I am very grateful to the men and women who participated in my study. Their courage in dealing with the rigors of bone marrow transplantation continues to amaze and inspire me. Finally, I wish to thank my parents, grandparents and friends, in particular Dave Moser, for their continued support and encouragement.

PAGE 3

TABLE OF CONTENTS page ACKNOWLEDGMENTS ii ABSTRACT v CHAPTERS 1 INTRODUCTION 1 2 REVIEW OF THE LITERATURE 4 History 4 Description of Current BMT Procedures 6 Psychological Factors Involved in BMT 8 Psychological Factors Involved in Development of Medical Illness.. 13 Influence of Psychological Factors on Immunologic Functioning 14 Quality ofLife in a BMT Population 17 Quality ofLife: Generic vs. Disease-Specific Measurement 23 3 SPECIFIC AIMS AND HYPOTHESES 30 4 METHODS 33 Demographics 33 Subjects 35 Procedure 35 Measures 37 Independent Variables 37 Dependent Variables 41 Statistical Analysis 43 5 RESULTS 48 Interrater Reliability 48 Variables Included/Excluded from Multiple Regressions and Survival Analyses 48 iii

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page Survival Analyses and Multiple Regressions 50 T-tests 52 6 DISCUSSION 56 REFERENCES 68 BIOGRAPHICAL SKETCH 78 IV

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Abstract of Dissertation Presented to the Graduate School of the University of Florida in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy MORTALITY AND MORBIDITY FOLLOWING BONE MARROW TRANSPLANTATION; PREDICTIVE UTILITY OF PSYCHOLOGICAL VARIABLES By Timothy Patrick Pearman August 1997 Chairperson: James R. Rodrigue Cochairperson: Duane E. Dede Major Department: Clinical and Health Psychology Bone marrow transplantation (BMT) is a treatment for a wide range of hematolgic, immunologic, metabolic and neoplastic diseases. Until recently, studies investigating BMT outcome focused primarily on medical variables, such as graft-versus-host disease and the effect of T cell depleted marrow on relapse. Recently, however, several studies have investigated the impact of psychological variables on BMT outcome. These studies have investigated the impact of depression, anxiety, family support, quality of life and personality on survival after BMT. Overall, these studies have reported mixed results suggesting that depression, anxiety, perceived family support, and personality may have some impact on survival time after BMT. The purpose of the current study was to empirically investigate the predictive

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utility of psychological variables (affect, family support, past compliance history) on BMT outcome (survival time, physical functioning and quality of life post-BMT). Patients were assessed retrospectively by two independent examiners to rate their levels of pre-BMT social support, affect and compliance history. Subjects were then assessed post-BMT to measure their quality of life, symptom report and survival time. Results of the study suggested that pre-BMT psychosocial variables were linked to outcome in terms of both mortality and psychological morbidity. People with higher levels of anxiety and depression pre-transplant were more likely to report poorer perceptions of physical health, increased frequency of symptoms and increased distress about these symptoms posttransplant. People with lower levels of social support appear to be at increased risk for mortality compared with those with adequate social support. However, social support may cause individuals to focus on their symptoms more than they otherwise would and to decrease their activity level accordingly. Individuals with higher levels of social support reported more frequent symptoms and more distress about these symptoms than did individuals with lower levels of social support. The results of the study will be useful in helping transplant teams to identify patients at risk for negative outcome to BMT and to develop interventions to aid patients at high risk. The implications and limitations of the study, as well as future research directions, are discussed. VI

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CHAPTER 1 INTRODUCTION Bone marrow transplantation (BMT) is a treatment for a wide range of hematologic, immunologic, metabolic and neoplastic diseases. While the concept of bone marrow transplantation dates back to the 1890s, not until the 1970s did rapid clinical progress occur. By the 1980s, BMT had emerged as a treatment with some degree of success in curing immune deficiency diseases, severe aplastic anemia and leukemia (Treleaven & Barrett, 1992). Bone marrow transplantation refers to five specific procedures: (1) syngeneic transplantation, in which the bone marrow of a genetically identical twin is transplanted; (2) allogeneic transplantation, in which marrow from a related or unrelated donor is used; (3) autologous, in which the patient's own bone marrow is cryogenically preserved and reintroduced into the patient's system, (4) stem cell transplantation, in which stem cells are extracted from bone marrow or peripheral blood and cultured before re-infusion and (5) cord blood transplantation, in which stem cells are taken from umbilical cord blood supply, cultured and re-inflised. However, for simplicity, these procedures will be grouped together under the general term bone marrow transplantation, BMT typically occurs as part of a regimen of total body irradiation and chemotherapy. Until recently, studies investigating BMT outcome focused primarily on medical variables, such as graft-versus-host disease (GVHD) (Sullivan et al., 1989; cited in 1

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Treleaven & Barrett, 1992), the effect of T cell depleted marrow on relapse (Mitsuyasu et al., 1986; cited in Champlin, 1990; Storb et al., 1989; cited in Champlin, 1990), and the impact of immunosuppression on survival in BMT patients (Meyers, Flournoy, & Thomas, 1982; cited in Champlin, 1990). However, several recent studies have investigated the impact of psychosocial variables on BMT outcome. These studies have investigated the impact of depression, anxiety, family support, quality of life, and personality on survival after BMT (Andrykowski, Brady & Henslee-Downey, 1994; Colon, Callies, Popkin & McGlave, 1991; Neuser, 1988). Overall, these studies have reported mixed results suggesting that depression, anxiety, perceived family support, and personality may have some impact on survival time after BMT. The current study is an attempt to empirically investigate the predictive utility of psychosocial variables on BMT outcome (survival time, physical fiinctioning and quality of life post-BMT). At the University of Florida Health Science Center, BMT patients are routinely assessed using clinical interviews and standardized psychological measures as part of the pre-transplant screening. Psychosocial factors are considered for the same reasons other medical criteria are used; (1) to ensure that potential benefits outweigh the risks to the patient, and (2) to wisely allocate a scarce resource (Olbrisch & Levenson, 1995). These psychological variables can be combined into composite scores reflecting patients' adaptation along several psychological dimensions. The utility of these pretransplant psychological dimensions in predicting mortality and morbidity post-BMT was

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investigated. For BMT patients still living, this composite was used to predict physical functioning and quality of life. Quality of life and physical functioning were assessed using a standardized health-related quality of life (HRQOL) instrument, a BMT-specific QOL measure, and a symptom checklist. The results of this study will hopefully be useful in assisting transplant teams in developing interventions to aid patients at high risk for negative outcome of BMT. In the literature review section below, several areas will be briefly covered; a description of the history and procedural aspects of BMT will be given, the influence of psychological factors on immunologic/medical variables will be reviewed, the impact of psychological factors on BMT outcome will be investigated, and quality of life in mixed medical and BMT populations will be covered.

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CHAPTER 2 REVIEW OF THE LITERATURE History Bone marrow transplantation is a procedure which gained widespread acceptance in the 1980s as a highly regarded treatment for a variety of disorders. The first BMT was attempted in 1891 when bone marrow was administered orally in cases of defective blood formation. Treleaven and Barrett (1992) noted that there was no positive effect from this intervention because there was no possibility of transferring living cells through oral administration. In 1937, Schretzenmayr (cited in Treleaven & Barrett, 1992) administered intramuscular injections of bone marrow to anemic patients, and had some positive results due to the transfer of living cells. In 1952, Lorenz (cited in Treleaven & Barrett, 1992) established that marrow transplantation could correct bone marrow failure syndromes, and could protect patients against the effects of radiation and chemotherapy. Thus began modern research on allogeneic and autologous BMT. During the 1950s and 1960s much research was done on a variety of important variables in BMT. For instance, graft versus host disease (GVHD) was first described during this time (Mathe et al, 1963; cited in Treleaven & Barrett, 1992). GVHD is a fairly common syndrome in allogeneic transplantation in which the newly inftised marrow recognizes the host's tissues as foreign, and begins to attack the patient's immune system. Another important medical advance was Dausset et al.'s (1965; cited in Treleaven & 4 -'-****j,t'>&

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Barrett, 1992) description of the human leukocyte antigen (HLA) system. This discovery set the groundwork for bone marrow matching, thereby increasing the success rate of allogeneic grafts. The 1980s saw a tremendous expansion in the use of BMT worldwide. Also, worldwide reporting of BMT results to the International Bone Marrow Transplant Registry in Milwaukee has made statistical analysis of large patient groups possible. Recently, there has been increasing interest in studying donors for allogeneic BMT other than HLA-identical siblings, including matched but unrelated donors (Powles et al., 1980; cited in Treleaven & Barrett, 1992). There also has been research investigating techniques to "purge" or rid the patient's marrow of existing leukemic cells before it is reinflised in autologous transplants. This procedure shows promise in decreasing the rate of relapse (Laporte et al., 1994) and has been used mainly in patients with acute leukemia or lymphoma in clinical remission (Moreb, J., 1995, personal communication). A relatively new area of investigation in BMT research is stem cell and cord blood transplantation. The hematopoietic stem cells are responsible for marrow regeneration after BMT. Sufficient numbers of stem cells for transplantation can be obtained from the peripheral blood supply after treatment with chemotherapy or growth factors. Transplants can also be achieved using stem cells obtained from cord blood at the time of delivery (Thomas, 1997). This blood is tissue typed and cryopreserved for later use. Given the general availability and ease of procuring cord blood, this type of transplantation is a good

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alternative to bone marrow or peripheral blood cells as a source of transplantable tissue (Piacibello et al., 1997). Two advantages of cord blood transplantation are the ease in identifying a suitable donor and the seemingly improved rate of graft versus host disease (GVHD) compared to bone marrow or peripheral blood stem cell transplantation (WeberNordtetal., 1996). Description of Current BMT Procedures As noted above, there are several types of bone marrow transplants: syngeneic, allogeneic, autologous, stem cell, and cord blood. Since the current study involves only patients receiving autologous, allogeneic and syngeneic transplants, these procedures only will be described further. The majority of allogeneic marrow transplants are for leukemia or other malignancies, but they also are performed on patients with aplastic anemia and other "bone marrow failure disorders" (Champlin, 1990). Autologous transplants usually are performed on patients with hematologic malignancies and solid tumors. Allogeneic BMT differs from solid organ transplants in that bone marrow is more easily rejected than solid organs, and more intensive immunosuppressive treatment is required to achieve durable engraftment (Champlin, 1990). If the patient is not sufficiently immunosuppressed, graft rejection can occur. Conversely, graft versus host disease can occur if immunocompetent cells in the donor's marrow react against the host tissues (Andrykowski et al., 1994). Graft rejection and GVHD are more common with increasing

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genetic disparity between the donor and host marrow. Typically, BMT is accompanied by a conditioning regimen of high dose chemotherapy and total body irradiation (TBI). Allogeneic BMT encompasses three types of grafts: histocompatible, haploidentical, and matched unrelated donor (MUD) grafts. These grafts differ both in the source of the marrow, and the extent of tissue match between the donor and host marrow. The extent of tissue match is based on the human leukocyte antigen (HLA) system. Six antigens are isolated and matched. Histocompatible BMT involves transplantation of marrow that is completely HLA-matched (i.e., KLA identical). Haploidentical BMT uses donor marrow that is only partially HLA-matched (i.e., less than a 6 antigen match). BMT using an unrelated donor can be either haploidentical or histocompatible. Morbidity risk rises with increased HLA mismatching, however, mortality risk is less adversely affected by mismatch (Andrykowski, Brady, & Henslee-Downey, 1994). Autologous BMT does not carry with it the problem of graft rejection and GVHD, since the patient is inftised with his or her own marrow. However, relapse is higher in patients receiving autologous transplantation (Moreb, J., 1995, personal communication). This is presumably due to the presence of cancer cells in the cryopreserved marrow. New techniques have been developed for purging autologous bone marrow, but their clinical utility is still being validated (Laporte et al., 1994). Following transplantation, there are three stages through which patients progress (Champlm, 1990). In Stage 1, patients are immune suppressed with a cytotoxic regimen

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8 that leaves them susceptible to infections from bacteria, viruses, and fungi. In Stage 2, which lasts up to four months post-BMT, patients are at the highest risk of graft failure, acute GVHD, and infections from cytomegalovirus (CMV). In Stage 3, patients often are confronted with chronic GVHD and the constant threat of secondary malignancies and relapse. Champlin (1990) also notes that abnormalities in the immune systems of BMT patients persist beyond one year post-BMT. However, most indicators of immune fiinction are restored by one year post-transplant. Psychological Factors Involved in BMT Not surprisingly, BMT places great demands on the emotional resources of patients, family members, and hospital staff". Some BMT patients exhibit anxiety, depression, withdrawal, anger, "survivor guilt," non-cooperation with staff or with selfcare requirements, sleep difficulty, anorexia, and paranoia (Andrykowski, 1994a). Some have suggested that all BMT patients experience these symptoms to some degree at predictable, consistent times during transplantation (Brown & Kelly, 1976). The relationship between these psychological symptoms and health outcomes (i.e., quality of life) has only recently been investigated. Colon, Callies, Popkin, and McGlave (1991) investigated the impact of depression and family support on survival post-BMT in 100 adult leukemia patients. In this study, retrospective chart review yielded non-objective measures of pre-transplant depression and family support. Depression, family support, and number of remissions from leukemia

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were used to predict post-transplant survival. The results yielded three findings: 1) patients who were depressed had poorer survival rates compared to non-depressed patients; 2) patients with low ratings of family support had poorer survival rates than patients with adequate family support; and 3) patients who were in their first remission from leukemia had improved survival rates compared to those in second remission or relapse. Although these findings provided some evidence for the predictive utility of psychosocial variables pre-transplantation, this study has several important limitations, including the lack of a prospective design, and the absence of standardized rating scales to measure psychosocial variables such as depression and family support. In another study, Andrykowski, Brady, and Henslee-Downey (1994) prospectively assessed depression, quality of life, mental adjustment to cancer, demographic variables and medical variables in a sample of 42 adults with leukemia who were undergoing allogeneic transplantation. Results indicated that quality of graft match was the only variable that showed a significant univariate relationship with survival. Patients receiving a histocompatible graft survived longer than patients receiving a haploidentical or matched unrelated donor (MUD) graft. However, trends were found for several psychosocial variables. Specifically, higher "anxious preoccupation" and poorer fimctional quality of Hfe pre-BMT were associated with shorter post-BMT survival. No other psychosocial variables (e.g. depression) showed a trend toward significance. The authors suggested

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10 that the small sample size was likely responsible for their failure to show significant utility of psychosocial variables in predicting survival. Gregurek et al. (1996) administered the State-Trait Anxiety Inventory (Spielberger et al, 1970) to 35 patients during the first week of allogeneic BMT and again at the end of isolation from laminar air flow. They were interested in anxiety as a possible predictor of acute GVHD (Stage II-IV). Patients were evaluated for acute GVHD on days +20, +40 and +100 post-transplant. The authors found that state and trait anxiety were both significantly elevated during week one of BMT in patients who subsequently developed acute GVHD. With respect to the outcome of BMT and level of anxiety, only state anxiety during the last week of isolation was significantly higher in patients who subsequently died than in survivors. The authors concluded that anxiety may influence alloreactivity and the development of GVHD through the action of cytokines, which play a role in connecting the neuroendocrine and immune systems. Neuser (1988) examined the impact of personality on survival time post-BMT in 35 adult patients with a variety of diagnoses. Patients were given a German-language version of the Personality Research Form (PRF) within the first two days after admission to the hospital. They found that one factor, "striving for recognition and help," was predictive of post-BMT survival. Neuser (1988) suggests that this scale might be highly correlated with patient compliance (i.e. patients scoring highly on this scale are more compliant). In another study, Syrjala et al. (1993) investigated the physical and

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11 psychosocial functioning of 67 allogeneic BMT survivors for 6 years post-BMT. They found that a high level of family conflict pre-BMT was predictive of difficulty in physical and psychological functioning after transplantation. Jenkins, Lester, Alexander, and Whittaker (1994) examined the influence of psychosocial variables such as depression and anxiety on length of stay, survival postBMT, and psychosocial adjustment post-BMT. Twenty eight patients undergoing BMT (both allogeneic and autologous) completed self-report forms measuring anxiety and depression. They were followed up to 6 months post-discharge. The authors failed to find a significant link between depression or anxiety and survival. Also, pre-BMT depression and anxiety were not associated with increased length of stay. However, psychosocial morbidity post-BMT was correlated with depression and anxiety pretransplant. Specifically, depressed patients reported greater degrees of impairment vocationally and psychologically post-BMT. In a follow-up study, Murphy, Jenkins & Whittaker (1996) gathered data on fiftysix patients using both structured, diagnostic interviews as well as unstructured interviews. They then compared the mean survival of patients with and without depression. The authors found that the presence of depressive illness did not correlate with length of survival. In addition, the presence of "fighting spirit" as a predominant coping style did not correlate with survival. The authors suggest that survival may be more closely related to physical rather than psychosocial factors.

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12 Leigh, Wilson, Burns & Clark (1995; cited in Gregurek et al., 1996) prospectively assessed 31 BMT patients pre-transplant using measures of anxiety, depression and social adjustment. Patients were then assessed using the same instruments at 4 and 8 months after BMT. Overall, 54% of their sample showed "psychosocial morbidity" defined as anxiety or depression in excess of normal populations on the measures used. Subjects who scored abnormally following BMT also tended to score abnormally pre-transplant, suggesting a predictive value of pre-BMT psychosocial assessment. In addition, psychological morbidity was unrelated to type of transplant. Patients who had undergone intensive therapy prior to BMT fared better in terms of psychological morbidity than did patients who had not undergone major medical treatment prior to BMT. Finally, subjects who received psychotherapy following their diagnosis were less likely to have depression or anxiety at 4 or 8 month follow up. In summary, the question of whether psychosocial variables impact on morbidity and mortality in BMT patients has yet to be fully answered. While there have been mixed results in this area of inquiry, preliminary results suggest that psychological variables such as depression and anxiety may play a role in post-BMT mortality and morbidity. Theoretically, why should this be the case? Two lines of research, one investigating the role of psychological factors in the development of medical illness, and the other mvestigating the field of psychoneuroimmunology, provide theoretical support for the current investigation.

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13 Psychological Factors Involved in Develop ment of Medical Illness A related area of study is the impact of psychological factors such as depression and personality on the development of medical illnesses. While many studies have found links of varying significance between psychosocial factors and the development of cancer (Blumberg, West & Ellis, 1954; Punch, & Marshall, 1983; Fox, 1983) only two of the more well designed studies will be reviewed here. Shekelle et al. (1981) administered the Minnesota Multiphasic Personality Inventory (MMPI) to a group of 2, 107 male employees at Western Electric. The authors hypothesized that depression as measured by the MMPI would be associated with increased risk of death from cancer over a 17 year follow up period. Approximately 19% of these men were judged to be depressed, and these men experienced a twofold increase in odds of death from cancer over the next 17 years. The authors controlled for age, cigarette smoking, ETOH consumption, family cancer history and occupation. Both depressed and non-depressed groups were similar on all of these factors. While unable to establish causation in this study, the authors nonetheless point out that the magnitude of the correlations are similar to those observed between coronary heart disease and its major risk factors of high cholesterol, hypertension and cigarette smoking. Death from cancer was not associated with any of the other standard scales of the MMPI. Linkins and Comstock (1990) published a study which closely replicated that of Shekelle et al. (1981). The authors administered the Center for Epidemiologic Studies

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14 Depression Scale (CES-D) to a group of 2,264 subjects. These subjects were followed for 12 years post-test administration. The authors found no significant correlation between depressed mood and development of cancer, although there was a trend for depressed subjects to develop cancer more frequently than non-depressed subjects. However, factoring in cigarette smoking, the authors found huge increases in cancer risk in depressed smokers, compared to their non-depressed, non-smoking peers. In summary, these studies indicate that there is a correlation between negative affect and the development of cancer. However, a causative relationship has not been established, and the strength of the relationship is not entirely clear at the present time. Influence of Psycholo gical Factors on Immunologic Functioning Why have studies found correlations between psychological factors, development of medical illness, and survival? The relatively new field of psychoneuroimmunology may provide some answers. Psychoneuroimmunologists decry the body-mind dichotomy as artificial and frankly false. They posit that behavioral/psychological processes are capable of altering immune function and that conversely, events that occur as part of immune responses should modulate behavior (Maier, Watkins, & Fleshner, 1994). There is an intricate link between the central nervous system (CNS) and the immune system (see Maier, Watkins & Fleshner, 1994, for a detailed review). The sympathetic nei^ous system innervates immune organs such as the thymus, bone marrow, spleen and lymph nodes. Also, the brain releases factors that cause endocrine glands to secrete hormones into the

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15 circulation. This enables hormones to reach the various immune-related organs and bind to hormone receptors on these organs. The hypothalamus is also integral to immune function, and can increase or decrease immune response. Conditioned immunity refers to the capability of psychological events to alter immune ilinction. There are two lines of research investigating conditioned immunity: classical conditioning of immunity (Smith & McDaniels, 1983), and the impact of stress on immunity. Classically conditioned immunity (e.g., pairing a taste with an immunosuppressive drug in a Pavlovian manner) has been demonstrated in animals and humans, although it is unclear if this conditioned immunity is clinically significant in humans in the form of disease progression or onset. Bovjberg et al. (1990) found that women who had undergone chemotherapy displayed immunosuppression after simply being brought to the hospital prior to chemotherapy. Grochowitz et al. (1991) suggested that conditioned immunosuppression could delay tissue rejection in rats receiving heart transplantation. The impact of stress on immune functioning has also been a topic of study. Stress has been found to activate the sympathetic nervous system and the hypothalamic-pituitaryadrenal (HP A) axis, which impacts immune functioning (Maier, Watkins, & Fleshner, 1994). In particular, anger, anxiety, and depression have all been found to decrease measures of immune functioning. Initial studies supported the obsen/ation that while

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16 acute exposure to a stressor can suppress immune response, repeated exposure results in adaptation and in some cases, enhanced response (Stein, Keller, fe Schleifer, 1985). Recently, two comprehensive review studies have investigated the impact of depression on immunity. Stein et al. (1991) noted that "no consistent or reproducible alterations of functional measures of lymphocytes" were reported in depressed patients. However, Weisse (1992) noted that "indexes of immunocompetence are lower among the clinically depressed." A large scale, meta-analytic study was conducted by Herbert and Cohen (1993) to attempt to clarify the research in this area. The authors included evaluations of all published studies as well as separate analyses restricted to studies meeting methodological criteria. Thirty-five studies were included overall, and included both enumerative and functional measures of immune functioning. Enumerative measures consist of counting the number of immune cells, or the number of antigens in a blood sample. Functional measures study how effectively immune cells are functioning. Herbert and Cohen (1993) suggest that, overall, substantial evidence exists positing a relationship between depression and both enumerative and fonctional measures of immunity. Effect sizes in methodologically controlled studies ranged from moderate (-.24) to large (-.45). Two possible explanations for this correlation are suggested. First, depression is associated with activation of the HPA axis and the sympathetic nervous system. Activation of these pathways results in elevated serum levels of Cortisol and catecholamines. Immune cells have receptors for these hormones, suggesting that these

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17 hormones play a role in immune modulation. An alternative explanation is that depressed people typically sleep less, have poorer nutritional intake, and have fewer healthpromoting behaviors than non-depressed counterparts (Herbert & Cohen, 1993). Overall, psychoneuroimmunology posits that a bi-directional set of processes occur. Classical conditioning and stress can alter immune function, and, conversely, immune reactions and products can feed back and modulate behavior and psychological state. This serves as a theoretical basis for the impact of psychosocial variables on mortality and morbidity in a BMT population. Qualitv of Life in 3 RMT Pop ulation In addition to survival, health-related quality of life is an important outcome variable in transplantation research. Quality of life is a concept which has many facets, and incorporates aspects of physical health, personal and occupational functioning, sociability, and feelings of personal distress and well-being (Andiykowski, 1994a). Health-related quality of life (HRQOL) covers five categories of concepts, including duration of life, impairments, functional status, perception of health and social opportunities (Patrick & Deyo, 1989). Until recently, QOL has not been widely researched in BMT patients. Research has been devoted to investigating mortality and medical morbidity (e.g. GVHD), while the impact of BMT on the long-term quality of life of its recipients has been ignored. However, as MacKeigan and Pathak (1992) point out, even when hfe is prolonged, it is important to measure QOL because patients may

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experience treatment-induced adverse effects. As BMT continues to improve survival, it is important to be cognizant of QOL issues in order to establish the relative costs and benefits of this procedure. There is considerable diversity in the outcome variables examined in this area, however, there are several broad subject areas. Cognitive and sexual functioning have been measured, as have employment status, perceptions of physical health, performance of daily activities and psychological and social adjustment. Research has focused on examining the long-term QOL of BMT recipients, and also identifying pre-BMT variables that account for variance in post-BMT QOL (Andrykowski, 1994a). Cognitive functioning has been assessed in several studies. Andiykowski et al. (1990) found that cognitive impairments such as slowed reaction time and difficulties in reasoning were common in post-BMT patients. Also, the extent of this cognitive dysfunction was correlated with dose of total body irradiation (TBI) received. Several studies have also identified cognitive dysfunction in pediatric BMT patients (Kramer et al., 1992;Smedleretal., 1990). Sexual dysfunction is also an area within the QOL literature which has been investigated. Sexual dysfunction is a common occurrence, with men experiencing erectile difficulties, women experiencing vaginal dryness, and both sexes frequently experiencing sterility (Cust et al., 1989) due to the TBI and chemotherapy. Studies, while small in number, suggest that greater than 25% of adult BMT recipients report decreased sexual

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19 interest, enjoyment or activity following BMT (Baruch et al, 1991; Mumma et al., 1992; Vose et al., 1992; Wingard et al., 1992). Baker et al. (1994) examined a range of quality of life variables in a population of 135 BMT survivors 6-149 months post-BMT and found that survivors showed a high degree of overall satisfaction with life. However, these survivors were least satisfied with their bodies, level of physical strength and ability to attain sexual satisfaction. Lack of social support was predictive of anger and negative affect. Patients transplanted at a later age experienced decreased quality of life overall. Other studies that have investigated a broad range of QOL variables in a BMT population have been small in scope (i.e. < 26 patients) and have lacked standardized, reliable outcome measures. Andiykowski, Henslee-Downey, and Farrell (1989) investigated psychosocial and physical functioning in 23 adults 3-52 months post-BMT. Compared to a normative cancer population, BMT patients experienced more mood disturbance, and poorer QOL. Also, older patients (greater than age 30) reported poorer QOL and more mood disturbance than younger patients. Wolcott et al. (1986) investigated adaptation in patients greater than one year post BMT. They reported that approximately 75% of their sample was "doing well" with the other 25% reporting emotional distress, chronic physical symptoms, low self esteem and low QOL. Hengeveld, Houtman and Zwaan (1988) studied 17 adults 1-5 years postBMT. Approximately 50% of the sample reported physical complications, sexual

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20 problems, infertility and failure to return to employment. Despite this, the authors indicate that the majority of patients report positive changes in personality and social relationships. Altmaier, Gingrich, and Fyfe (1991) reported on the QOL in 12 patients two years post-BMT. They compared perceptions of physical health as well as psychological and role functioning to a matched sample of leukemia patients receiving chemotherapy only. BMT patients reported more problems with sexual and vocational fimctioning; however, they did not differ from chemotherapy patients in their perception of physical health and their levels of psychological distress. However, Lesko et al. (1992) found no differences between BMT and conventional chemotherapy groups with regard to social and psychological functioning. However, both groups report greater levels of distress relative to normative, healthy samples. Litwins, Rodrigue and Weiner (1994) compared QOL in 32 BMT recipients and 22 conventional chemotherapy patients. No differences were found between groups on any QOL measure. In addition, both groups reported generally good QOL compared to a normative healthy group. Prieto, et al. (1996) measured physical and psychological functioning on a sample of 1 17 BMT survivors. Median survival time was 55 months (range 6-154). Current functioning varied considerably across patients. However, the authors found that 3 1% of patients reported disturbances in their sex life. Psychiatric disturbance (anxiety and depression) was present in 22% of patients. They found that quality of life, psychosocial

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21 distress and occupational status improved with the passage of time, particularly within the first 3 years post-BMT. Lower SES, older age at BMT, shorter time post-BMT, female gender and impotence were significant predictors of impaired QOL. Finally, Belec (1992) studied 24 BMT patients 1-3 years post-transplant and assessed QOL. The vast majority of patients perceived their QOL to be acceptable, but when present, problems centered around physical health and employment. Recently, several studies have improved upon the above studies by increasing sample size, and including standardized, reliable measures of outcome and QOL. Andrykowski et al. (1990) assessed a variety of QOL domains in BMT and renal transplant patients. Fiftyeight patients total were sampled. Overall, the groups were comparable, with neither group reporting a "normal" QOL. Both groups experienced difficulty in vocational functioning, mood disturbances, and poor perceptions of physical health. Dose of TBI received during pre-BMT conditioning, and age at BMT were negatively correlated with current QOL. Chao, Tierney, and Bloom (1992) studied fifty-eight adult autologous BMT recipients at 90 days and 12 months post-BMT. They found that patients' ratings of QOL significantly improved between 90 days and 12 months. Eighty-eight percent of patients at 12 months reported above average to excellent QOL. In addition, 77% were employed and 64% considered their sexual fiinctioning to be as satisfying as pre-BMT fiinctioning.

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22 In keeping with the above results, Schmidt et al. (1993) found that approximately 75% of patients in a sample of allogeneic BMT patients returned to work after 1 year post-BMT, while a minority reported sleep difficulties or sexual dysfunction. Wingard et al. (1991) reported that perceived health, physical function, and social functioning were reported to be good or excellent for most patients in their sample of 135 BMT patients at least 6 months post-BMT. Approximately 75% of subjects were employed or enrolled in school. However, despite the average reports of good functioning, some patients were still significantly impaired. Role retention was generally associated with greater life satisfaction. This finding regarding role retention was replicated in another study (Baker, Curbow & Wingard, 1991). Summarizing the literature on QOL in a BMT population, it is apparent that postBMT QOL varies considerably. A majority of patients report average to above average QOL compared to normative healthy populations. There is little understanding regarding what factors predict this variability in QOL post-BMT. Demographically, younger patients seem to fare better after BMT. Retention of roles (e.g. head of household, employed, homemaker, etc.) has also been associated with greater life satisfaction. Among treatment variables, dose of TBI has been linked to poorer sexual, cognitive, and physical functioning (Andiykowski, 1994). Veiy little is known regarding the impact of premorbid psychosocial variables (i.e. affect, coping skills, social support) on post-BMT QOL or physical functioning.

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23 Quality of Life: Generic vs. Disease-Sp ecific Measurement The current study is an attempt to determine the impact of psychological variables on several domains of QOL, and also survival post-BMT. There is currently a debate in the literature regarding the measurement of QOL (Andiykowski, 1994). Controversy centers around whether to measure QOL in a disease-specific format, or a "generic" QOL format. Generic heahh status measures are those that measure variables which are applicable across a wide range of illnesses. Disease-specific measures are those designed to assess specific patient populations, with the goal of measuring clinical change (Patrick & Deyo, 1989). The popularity of disease-specific measures is due to the clinical sensitivity of these scales. These scales are good for measuring changes that occur over time, and quantifying minimally important changes. Four different models are relevant in examining the use of generic and diseasespecific measures (Patrick & Deyo, 1989), The first approach is to include both generic and disease-specific measures in the same study, even though the measures may overlap substantially. The second approach is to compare a generic instrument and a generic instrument modified for the population of interest. However, there are no BMT-modified instruments in the literature. The third approach is to use a generic health status instrument with a condition-specific instrument. This is similar to the first approach except that the illness-specific measure should have a different conceptual basis and

PAGE 30

24 minimal overlap with the generic measure. The fourth approach is to have a battery of specific measures which are scored independently and reported as individual scores. The relative advantages and disadvantages of generic and disease-specific measures depend primarily on the specific objective of the study. HRQOL measures may be used to discriminate among respondents at a point in time, to predict future outcomes, or to measure change over time (Patrick & Deyo, 1989). Generic measures typically have low content validity because they contain items of little or no relevance to particular patient groups. By contrast, disease-specific measures have high content validity for studies of particular patient populations. However, generic measures have greater construct validity than illness-specific measures. Reliability is a related issue in which generic measures fare better than disease-specific instruments. There are few comparative studies of the test-retest reliability of disease-specific measures versus that of generic measures (Patrick & Deyo, 1989). In summary, generic measures are well standardized, but disease-specific measures have the advantage of ease of administration, and good applicability to a specific population. Also, disease-specific measures are useful in identifying important concerns of patients with particular conditions, and for measuring small, clinically important changes in specific groups. Andrykowski (1994) suggests that it is important to measure both generic and population specific aspects of QOL in a BMT population. He notes several instruments, including the SF-36 Health Suivey (Ware & Sherbourne, 1992), the Sickness Impact

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25 Profile (Bergner, Bobbitt, Carter & Gilson, 1981), the FACT-G (Cella, Tulsky & Gray, 1993), and the Functional Living Index-Cancer (Schipper, Clinch, McMurray & Levitt, 1984), which are appropriate for measuring QOL in a BMT population. The first two instruments are appropriate for all adult BMT recipients while the latter two are appropriate for all BMT recipients with malignant disease. Generic measures listed above include the Sickness Impact Profile (SIP) and the SF-36 Health Survey. The SIP is a measure which provides a profile of scores for different components of HRQOL. The SIP assesses sickness-related dysfijnction in 12 different categories, producing a score for each category (Bergner et al., 1981). The SF36 Health Survey (Stewart, Hays, & Ware, 1988) covers a wide spectrum of health concepts for use in general medical populations. Both the SIP and the SF-36 have been tested extensively in a wide variety of patient populations and are well standardized (for a review of patient populations, see Patrick & Deyo, 1989). MacKeigan and Pathak (1992) suggest that while there is no obvious answer regarding what the "best" QOL instrument for use in a certain population, the SF-36 questionnaire is practical, reliable, and valid for a wide range of medical populations. Disease-specific HRQOL measures (in a cancer population) include the Karnofsky Performance Status Scale for cancer (Karnofsky & Burchenal, 1949), the Quality of Life Index (QLI) (Mor, Laliberte, & Morris, 1984), and the Functional Living Index: Cancer (Spitzer, Dobson & Hall, 1981), the European Organization for Research and Treatment

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26 of Cancer QLQ-C30 (Aaronson, et. al, 1993) the Cancer Rehabilitation Evaluation System-Short Form (CARES-SF) (Schag, Ganz & Heinrich, 1991) and the Functional Assessment of Cancer Therapy scale (FACT) (Cella, et. al, 1993). Ferrell et al. (1992) assessed QOL in a BMT population using an instrument termed the BMT-Quality of Life Survey (BMT-QOLS). The qualitative instrument consisted of a one-time interview of 119 BMT survivors using six open-ended questions. Content validity was established by a panel of BMT experts. Content analysis was performed on verbatim written responses to the six questions. The instrument yielded four domains of QOL in a BMT population; physical, psychological, social and spiritual wellbeing. In a more methodologically rigorous study, Chao et. al (1992) developed a questionnaire for autologous BMT patients which addresses physical, psychological and functional well-being and treatment related side effects. The analysis included 59 subjects. The 14 item measure combined disease specific symptoms, specific measures of quality of life, and a global measure of QOL. They also included measures of sexual activity, work status, and perception of physical appearance. They found good reliability (r=.80) in a randomly selected group of 20 patients administered the test twice. Overall, the BMT-specific QOL instruments currently available are unsatisfactory for inclusion in the present study. None of the above measures include a strategy for summing the information they gather into an overall QOL rating. This limits their ability

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27 to be analyzed meaningfully. As an alternative to inclusion of a BMT-specific QOL instrument, the current study will include a cancer-specific QOL measure. These measures have been well-validated in the literature and will be reviewed next. Cancer-specific QOL measures have been in existence since the early 1980s (Moinpour, 1994). Several of the more well-validated measures will be reviewed below. The Functional Living Index-Cancer (FLIC) was one of the first measures to be validated in a cancer population (Schipper, Clinch, McMurray, & Levitt, 1984). The measure is cancer specific, fiinctionally oriented, designed for patient administration, and is reliable and valid. Four principal areas of functional importance were defined: 1) vocational/activity 2) affect/psychological state 3) social interaction, and 4) somatic sensation. Several measures have been developed since that time which provide a total score, such as the Cancer Rehabilitation Evaluation System Short Form (CARES-SF) (Schag, Ganz & Heinrich, 1991), and the Functional Assessment of Cancer Therapy (FACT) (Cella et. al, 1993). These measures are both well-validated and reliable for use in a cancer population. The CARES-SF provides a total score and scores on five main domains: 1) physical functioning; 2) psychosocial functioning; 3) sexual fiinctioning; 4) marital interaction; 5) medical interaction. Psychometric properties of the CARES-SF have been

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28 documented (Schag, Ganz, & Heinrich, 1991). The CARES-SF contains a total of 59 questions, making it one of the more time-consuming measures to complete. The FACT scale is one of the most rigorously validated measures available for use in a cancer population. In addition, the FACT scale contains only 28 questions, and can be completed by patients in approximately 5 minutes. Data was collected over a five year time period on 545 patients in a variety of health centers, with a variety of cancer types. Factor analysis created five subscales: 1) physical well-being; 2) social well-being; 3) emotional well being; 4) flinctional well-being; and 5) relationship with doctor. Convergent validity was high between this measure and other cancer-specific QOL measures (Cella, et. al, 1993). In addition, the FACT was sufficiently sensitive to detect differences in QOL based on stage of disease. Test-retest correlation coefficients for a sample of 60 patients were high, ranging from .82 to .92 for the five domain scales. Another cancer-specific QOL measure which has been well received is the European Organization for Research and Treatment of Cancer (EORTC) 30 item quality of life scale. The EORTC QLQ-C30 incorporates five functional scales (physical, role, cognitive, emotional, and social), three symptom scales (fatigue, pain, and nausea and vomiting), and a global health and quality of life scale. The questionnaire takes approximately 12 minutes to complete, and is designed to be filled out by patients. All scales demonstrated adequate reliability and validity, with the exception of the role fijnctioning scale, which is also one of the briefest scales.

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29 In sum, all of the cancer-specific QOL measures described above are strong from a psychometric standpoint. They are all applicable to a wide range of cancer types, and have adequate validity and reliability. For the purposes of the current study, it was necessary to choose one of these established measures. The EORTC was eliminated from consideration due to the fact that its role functioning scale is not well validated. This was a concern, since it has been suggested that role functioning is crucial for regaining adequate QOL following BMT (Wingard et. al, 1991). The CARES-SF was eliminated from consideration due to its length. It has been posited that brevity is an important consideration to improve compliance when choosing a QOL measure (Aaronson et al., 1993). The FACT was used in the current study due to its strong psychometric properties, and its brevity and applicability to a BMT population. This measure has been endorsed for use in a BMT population (Andrykowski, 1994).

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CHAPTER 3 SPECIFIC AIMS AND HYPOTHESES The current study focused on patients at least 2 months post-BMT. The purpose of the study was to determine the utility of pre-transplant variables (psychosocial, demographic and medical) in predicting survival, physical functioning and quality of life (QOL) post-transplantation. The independent variables chosen for study have been previously associated with survival or quality of life in either a BMT population or a cancer population. In terms of survival time, it was hypothesized that: (1) significant affective symptoms (depression and anxiety), (2) lower levels of family/social support, (3) a history of inadequate compliance with medical regimens pre-BMT, (4) increased age at BMT, (5) increased time from initial diagnosis to BMT, (6) poor marrow-grafl match (in allogeneic patients), (7) later disease state (not in first remission) and (8) allogeneic transplantation (as opposed to autologous BMT) would be associated with decreased survival time. As noted above, these variables were chosen for study due to their association with survival or quality of life in either a BMT or cancer population. The predictive utility of affective symptoms on survival and quality of life has been reviewed above. Higher levels of family/social support have been associated with increased survival time and increased quality of life in a cancer population (Ell, et. al, 1992; Ganz, et. al, 1991). Noncompliance can have life-threatening implications (Andrykowski, 1994); however, it is unknown how 30

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31 past compliance behavior predicts mortality or morbidity in BMT. The demographic, disease, and treatment-related variables were chosen for study because they have been associated with post-BMT mortality or morbidity in previous studies (Parr, Messino & Mclntyre, 1991; Kamani & August, 1984). In terms of quality of life, it was hypothesized that the above mentioned psychosocial, demographic and medical variables would be associated with poorer quality of life post-BMT. In terms of symptom self-report, it was hypothesized that the above mentioned psychosocial, demographic and medical variables would be associated with poorer quality of life post-BMT. In addition, several "secondary hypotheses" were investigated. In terms of psychosocial variables, it was hypothesized that (1) undergoing psychological or psychiatric treatment either during BMT or post-BMT and (2) experiencing significant life stress/events post-BMT (e.g. death of a friend, divorce, etc.) would be associated with increased mortality and morbidity post-BMT. Several medical variables were examined. Within the allogeneic BMT group, consistent with clinical findings (Moreb, J., personal communication), it was suggested that diagnosis would be associated with differential outcome, with acute leukemia patients and patients with myelodysplastic syndromes having increased mortality and morbidity compared to chronic myelogenous leukemia and aplastic anemia patients. Within an autologous BMT group, it was hypothesized that patients not in complete remission at the

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32 time of BMT would have increased mortality and morbidity compared to patients with no evidence of disease. It was hypothesized that deceased subjects would have more symptoms of anxiety and depression pre-BMT, lower levels of social support and poorer compliance. Finally, it was hypothesized that patients undergoing psychological treatment would experience improved quality of life and physical functioning post-BMT. The results of this study add to the sparse existing literature investigating the impact of psychosocial variables on outcome in bone marrow transplantation. Investigation of the hypotheses above can assist in providing relevant information to the medical staff regarding who is likely to survive and adapt well to BMT. This information should be used to determine which patients are appropriate for BMT and to develop interventions to aid patients at high risk for mortality or morbidity post-BMT. These interventions should be aimed at enabling high risk patients to become better recipients for BMT.

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CHAPTER 4 METHODS All protocols were reviewed and approved by the University of Florida Health Science Center's Institutional Review Board (IRB). No financial incentives were offered to the subjects for their participation in the study. Demographics One hundred and eight patients were contacted about participating in the study. Sixty-six subjects (61% of those contacted) were included in the analyses. Of these patients, 42% were male and 58%) were female. The mean age of the patients at the time of BMT was 35 years. Patients had an average of 14 years of education. Mean length of time from diagnosis to time of transplant was 15 months (standard deviation =14 months). Forty-seven percent of the patients were in their first remission at the time of BMT, 39%i were in a subsequent remission or relapse and no data were obtained for 14%o of patients. Thirty-four percent of patients underwent allogeneic transplantation, with 66%) undergoing autologous transplantation. At the time of post-BMT data collection, 70% of the study sample (n=46) were alive and 30%) (n=20) were deceased. Patients completed post-BMT measures 3 months to six years after receiving their transplant. Mean survival time post-BMT was 18.5 months (sd==17.09 months). Forty-two patients refijsed to participate. Of these patients, two refused telephone interviews, five were not able to be 33

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34 reached by telephone and did not return telephone messages, and the rest of the patients did not return mailed questionnaires. (See Table 1) Table 1 : Demographic, Disease, and Medical Data Variable Percentage or value SD and Range (if applicable) Male 42% Female 58% Diagnosis ALL or myelodysplasia 16% CML or aplastic anemia 24% other diagnoses 60% Disease status First remission 47% Second remission or relapse 40% Missing data 13% Transplant Type Allogeneic 34% Autologous 66% Mortality Alive at follow-up 70% Deceased at follow-up 30% Mean age at BMT Mean years of education Mean months from diagnosis to BMT 35.4 years (sd=12.74, range=17-60) 13.7 years (sd=2 3 range=9-20) 15.0 months (sd=13.95, range=4-75)

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35 Subjects Eligibility criteria for participation in the study were as follows: (1) Subjects had completed a pre-BMT assessment in the Psychology Clinic at Shands Hospital, University of Florida, during the period from 1990-1995, (2) Subjects had subsequently undergone allogeneic or autologous bone marrow transplantation, (3) Subjects were at least 16 years old at time of transplantation and (4) Subjects were currently at least 2 months post-BMT. During the time period from 1990-1995, approximately 165 bone marrow transplantations were performed on adult patients at Shands Hospital. Subjects were recruited from this patient population. Procedures As per the eligibility criteria, all patients were seen for a pre-transplant psychological assessment in the Psychology Clinic at Shands Hospital. The pre-transplant assessment typically lasts 2-3 hours and consists of a clinical interview and psychological testing. All psychological testing data were combined with interview data to form a composite: the Transplant Candidate Evaluation Rating Form (TCERF), which summarized assessment data relevant to transplantation. Similar instruments have been described in the literature as a way of assessing transplant candidates in terms of pretransplant psychosocial variables (Olbrisch & Levenson, 1989; Twillman et al, 1993). The format of the TCERF is quite similar to these instruments.

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36 In the current study, the TCERF was rated by two advanced graduate students who received training to ensure their understanding of the rating scale. One student served as the primary reviewer and the other served as a reliability check. Prior to beginning the ratings of study subjects, raters practiced completing the TCERF on ten "mock" subjects independently. Interrater reliability was then measured to assure the training was adequate. As recommended by Hartmann (1982), lower limits of acceptable percentage agreement ranged from .60-. 75. During the study, every fifth subject was evaluated by both raters as a check of interrater reliability. Initially, data collection was planned to occur by telephone interviews. All potential subjects were notified by mail that they would be contacted by phone regarding a research study. A brief description of the study was given in this letter and elaborated on in a follow-up phone call. This phone call served to inform the patients about the purpose of the study, answer any questions they had, inform them of any possible risks and benefits of participating, and obtain their consent to be involved in the study. Patients giving their consent were asked to fill out a number of measures over the phone (see Measures section below). These measures consisted of a symptom checklist, a generic QOL instrument, and a cancer-specific QOL instrument. The assessment lasted approximately one half hour. Due to difficulties contacting patients by telephone, the entire packet of the above questionnaires was sent to most subjects (n=54) and they were provided with stamped envelopes in which to return the completed questionnaires. This inconsistency in data I ,^-^tt,H'>t^--^.l>V>Mjw^-^4

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37 collection methods is a potential confounding variable. However, two of the measures used, the FACT and the SF-36 were designed to be administered either in a structured interview or by patient self-report and have demonstrated reliability in both settings (MacKeigan & Pathak, 1992; Ware & Sherbourne, 1992). Measures Independent Variables As indicated previously, all prospective BMT candidates are interviewed clinically at the time of pre-BMT assessment. However, the battery of psychological tests administered varies considerably across patients because until recently, there has been no specific assessment battery guidelines in the literature. Specific tests administered typically (but not always) include subtests of the Wechsler Adult Intelligence ScaleRevised (WAIS-R) (Wechsler, 1981), the Minnesota Multiphasic Personality Inventory (MMPI) (Hathaway & McKinley, 1970), the State-Trait Anxiety Inventory (STAI) (Spielberger et al., 1970), and the Beck Depression Inventory (BDI) (Beck et al., 1988). The MMPI is often used to assess personality functioning in bone marrow transplantation candidates. The MMPI is an empirically derived measure and contains 10 clinical scales, four validity scales, and four supplementary scales. The MMPI has been extensively used in many populations and has adequate reliability and validity. For a detailed description of the MMPI, see Dahlstrom, Welsh and Dahlstrom (1972).

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Negative affect is typically measured by the STAI and the BDI. The STAI is a 40item questionnaire which measures two components of anxiety: state anxiety and trait anxiety (Spielberger, Gorsuch & Lushene, 1970). State anxiety is anxiety which is caused by a person's response to certain, specific conditions. Trait anxiety is defined as anxiety which is characterologic in nature and is not situation specific. Reliability and validity have been established (Turner et al., 1986; Spielberger & Vagg, 1984) and the STAI has been used extensively in a wide variety of populations (Novy, Nelson, Goodwin, & Rowzee, 1993; Sutker, Bugg, & Allain, 1991; Donham, Ludenia, Sands, & Holzer, 1984). The BDI is a 21 -item questionnaire that measures depressive symptomatology such as insomnia, weight loss, feelings of sadness, pessimism, guilt, suicidal ideation, etc. The measure yields a summary score, which can then be compared to normative samples to derive an index of depression. Reliability and validity of the measure have been extensively reviewed and are adequate (Beck, Steer, & Garbin, 1988). While these tests are typically administered as part of the pre-BMT screening, there is nonetheless a fair amount of variability and these tests are sometimes not used. The variability in psychological testing may be seen as a problem; however, this was compensated for by combining psychological test results and interview data into a composite of psychosocial functioning using the Transplant Candidate Evaluation Rating Form (TCERF), The TCERF rates psychosocial fianctioning in a variety of domains including affect, compliance and social support. Each domain is rated on a five point.

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39 Likert-type scale. Raters were aided by a guide sheet wiiich provided detailed descriptions of criteria for each numeric rating. The descriptions are described below. As noted earlier, interrater reliability data was gathered to ensure the scientific rigor of this measure. Also, in clinical practice there is no standard battery of tests used to assess pre-BMT patients. Similar rating scales to the TCERF are just beginning to be described in the literature (Olbrisch & Levenson, 1993; Twillman, et al., 1993). Therefore, this study is in line with current clinical practice, and hopefully will serve to demonstrate a useful way in which clinical interview data can be combined with variable psychological testing data. Three variables from the TCERF were analyzed as potential independent variables: affect, social support and compliance history. Also measured as secondary variables were: psychological or psychiatric treatment and life events/stress. Patients were asked about past history of psychological treatment, as well as several questions regarding the occurrence of significant life events since BMT. As noted above, TCERF variables were rated on a five point scale. Raters were trained to use the scale using an expanded description form. On the affect domain, a score of one on the affect scale is described as follows: "At least two of the following criteria met: a) concerns about anxiety or depression or other emotion mentioned in psychological evaluation which is severe enough to merit concern about the recipient's suitability for transplant, b) history of one or more psychiatric hospital admissions or c) suicidal ideation or attempt mentioned in psychological evaluation." A score of five is described as

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40 follows: "Psychological evaluation mentions appropriate fears, anxiety, anger and sadness. Anxiety and depression are within normal limits." Similarly detailed descriptions of the ratings are listed for all numbered ratings on all three scales. For the social support variable, a score of one represents the following; "Both of the following criteria met: a. patient reports that s/he does not know who will be the primary caretaker following BMT and b. patient reports no strong relationships or very unstable relationships." A score of five represents the following: "Stable, committed relationships, good mental health in social supporters, caretaker in town with patient throughout BMT process." For the compliance variable, a score of one is described as follows: "Concerns with all of the following are mentioned in the psychological evaluation: a. difficulty being compliant with medications, b. frequent missed appointments with medical, psychological services or tardiness to appointments and c. problems with dietary, exercise and smoking domains. A score of five represents that the patient "Has an excellent compliance history." No concerns are noted in the psychological evaluation." For all variables, a score of zero indicates that the rater is "unable to rate" for that domain. Also measured were disease, treatment, and demographic variables that have been shown to have either an empirical or theoretical association with BMT mortality and morbidity. These variables included: age at BMT, months from diagnosis to BMT, extent of marrow graft match (histocompatible vs. haploidentical or matched unrelated donor (MUD)), type of transplant (autologous vs. allogeneic) and disease state (first remission or

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41 first chronic phase vs. all other later stages). Secondary demographic and medical variables measured were; socioeconomic status (SES), sex, diagnosis (within the allogeneic BMT group) and remission status (in the autologous BMT group). Dependent Variables Three variables were measured post-transplant: survival, quality of life (QOL), and physical functioning/somatic symptoms. Two methods were used to determine survival data for subjects. First, survival data is kept on record at Shands Hospital, and if the patient was deceased, the death date was noted. If the patient's survival status is unknown, this was obtained via telephone interview with the patient, or the spouse or significant other if the patient was deceased. If the patient was deceased, the date of death was obtained from the spouse or significant other. Two Heahh Related Quality of life (HRQOL) measures were used. First, the Medical Outcomes Study 36-item Short Form (SF-36), a generic HRQOL measure, was administered. This measure was both rationally and empirically developed by Ware and colleagues (Ware & Sherbourne, 1992; McHorney, Ware, Rogers, Raczek, & Lu, 1992; McHorney, Ware, Lu, & Sherbourne, 1994). The SF-36 assesses eight health concepts including: limitations in physical activities because of health problems, limitations in social activities because of physical or emotional problems, limitations in role activities because of health problems, limitations in role activities due to emotional problems, pain, general mental health (psychological distress and well-being), vitality (energy and fatigue), and

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42 patient perception of general health status. The survey is designed to be a self-report measure, or to be administered over the telephone by an interviewer. In a sample of 3,053 adults, the internal reliabilities of the subscales ranged from .77 to .92 (Stewart et al., 1992). Also, a cancer-specific HRQOL measure was given. The literature is practically non-existent on QOL measures specifically assessing QOL in a bone marrow transplantation population. Therefore, a cancer-specific QOL instrument will be substituted. The FACT-G is a cancer-specific instrument which includes a total QOL score, as well as four subscale scores for physical, fianctional, social, and emotional wellbeing, and a satisfaction with treatment relationship score. The measure has demonstrated adequate internal consistency and reliability (Cella, et. al, 1993). A symptom checkHst was added to the post-transplantation battery in order to attain information about post-transplant physical/medical condition. The Transplant Symptom Frequency Questionnaire, which has been modeled after the work of Lough et al. (1987), was used for assessment. This questionnaire assesses the frequency of 35 symptoms using a 0-4 rating (0=never have symptom and 4=always have symptom). In addition, for each symptom, the questionnaire inquires, "Is this a problem for you?" The symptom frequency checklist yields two scores. The first is a "total frequency score" (sum of 0-4 ratings on all questions). The second is a "total problem score" (number of "yes"

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43 responses on the questionnaire). These 2 scores were analyzed as relevant physical functioning outcome variables. Finally, the Transplant Recipient Information Questionnaire provided a structured format for inquiring about socioeconomic status (SES), prior psychiatric or psychological treatment, and significant life events/life stress in the past 6 months. Socioeconomic status was measured on a 4 point Likert-type scale, while prior psychiatric treatment and 1 significant life events were analyzed as dichotomous variables (yes/no). Means and standard deviations for dependent and independent measures are presented in Table 2. Statistical Analysis Interrater reliability data were gathered on the TCERF by computing percentage agreement (Cohen, 1969). First, it was hypothesized that negative psychosocial indicators (higher pre-BMT levels of anxiety and depression, lower levels of family/social support, a history of inadequate compliance with medical regimens pre-BMT), negative demographic indicators (increased age at BMT, increased time from initial diagnosis to BMT) and negative medical indicators (poor marrow-graft match, later disease state and allogeneic transplantation) would be associated with decreased survival time. Correlation coefficients were computed to examine the association of various psychosocial, demographic and medical variables to survival time. Those variables showing at least a slight trend toward association (p<.20) were included in a stepwise Cox proportional

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44 Table 2; Means and standard deviations of measures Measure Mean Transplant Candidate Evaluation Rating Form (TCERF) Social Support Aifect Compliance Life Stress 4.18 4.18 4.26 1.77 SD .89 .91 .90 1.54 Functional Assessment of Cancer (FACT) Physical Well-Being 5.20 5.07 Emotional Well-Being 5.39 2.10 Satisfaction with Doctor 7.07 1.36 Family Well-Being 14.74 3.87 Total Score 53.61 5.43 SF-36 General Health Scale 68.37 23.54 General Mental Health 79.83 14.36 Symptom Checklist Problem Score 6.17 7.04 Frequency Score 1 27.54 16.26 hazards linear regression model. The stepwise Cox model is a multivariate measure to determine the relative contribution of each psychosocial, demographic and medical variable to prediction of survival time post-BMT.

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45 Second, it was hypothesized that these negative psychosocial indicators, demographic indicators and medical indicators would be associated with poorer quality of life post-BMT. Again, correlation coefficients were computed to asses the relationship between psychosocial, demographic and medical variables with quality of life. Variables showing at least a trend (p<.20) toward an association with QOL and symptom self-report were included in a number of multiple linear regression models analyzing the utility of psychosocial variables in predicting post-BMT quality of life. Specifically, multiple regression equations were analyzed for two domains of the SF-36: 1) general mental health and 2) patient perception of general health status. These domains were chosen because of their adequate internal reliability and because they address the most general and relevant variables of interest to this study. This yielded a total of 2 multiple regression equations measuring the contribution of relevant demographic, psychosocial, and medical variables to the prediction of general mental health and patient perception of general health status. For the FACT-G analysis, one multiple regression equation was used to measure the association of various demographic, medical, and psychosocial variables with the total score on the FACT-G. Also, five multiple regression equations were used to examine the association of the independent variables with each of the domain scores: 1) physical wellbeing; 2) fianctional well-being; 3) social well-being; 4) emotional well-being and; 5) satisfaction with treatment relationship.

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46 Third, it was hypothesized that negative psychosocial, demographic and medical variables would be associated with increased symptom self-report. Again, correlation coefficients were computed measuring the association of psychosocial, demographic and medical variables with symptom self-report. Variables demonstrating at least a slight trend toward a significant association (p<.20) were included in multiple regression equations. A total of two multiple regressions were performed to examine the Symptom Checklist variables. These multiple regressions measured the association of relevant demographic, psychosocial, and medical variables to: 1) the total frequency score, and 2) the total problem score. Several secondary hypotheses were also investigated. First, it was hypothesized that patients undergoing psychological or psychiatric treatment either during BMT or post-BMT would experience increased mortality and morbidity post-BMT. A t-test was run to examine this hypothesis. Second, it was hypothesized that patients experiencing significant life stress post-BMT would experience increased mortality and morbidity postBMT. This was examined by computing correlation coefficients measuring the association of life stress with survival time, quality of life and symptom self-report. If life stress were found to be at least slightly correlated to mortality or morbidity (p<.20) it would be included in Cox regression analysis or multiple regression analysis as described above. Several hypotheses regarding the effect of medical variables on outcome (see Chapter 3) had to be dropped from the analyses due to lack of data.

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47 T-tests were performed to investigate whether deceased and still-living subjects differed in terms of their pre-BMT aflFect, social support and compliance. T-tests were also run comparing subjects having psychological treatment in terms of their outcome (quality of life, survival time, physical functioning).

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CHAPTER 5 RESULTS Interrater Reliability Interrater reliability was calculated as described above. Every fifth subject (20% of the entire sample) was evaluated by both raters to cross-check validity. This yielded a sample of 13 subjects for whom percentage agreement was computed. Percentage agreement was .60 for Social Support, .73 for Affect and .80 for Compliance. These values are within the guidelines suggested by Hartmann (1982) for acceptable interrater reliability in the social sciences. Variables Included/Excluded from Multiple Regressions and Survival Analyses As noted in the Statistical Analysis Plan, correlation coefficients were computed to investigate the association between pre-BMT demographic, physical/medical and psychosocial variables (independent variables) and post-BMT survival time, quality of life and physical functioning (dependent variables). Independent variables showing at least a slight trend toward an association with outcome variables were included in either Cox regression analysis or multiple regression analysis. Survival Time: The following variables showed a trend toward an association with survival time and were therefore included in the Cox regression analysis: education (r=.18, p=.15) and SES (r=.22, p=.08) (demographic variables); treatment type (r=-.21, p=.04), remission status (r=-.23, p=.04), diagnosis (in allogeneic transplant) (r=-.15, p=.17) and 48

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49 number of remissions (r=.15, p=.17) (medical variables). Affect, social support, and compliance history were also included in the Cox regression analysis since they were the primary psychosocial variables of interest. Variables demonstrating no relationship (p>.20) to survival time and therefore not included in the Cox analysis are as follows: lifestress, age at BMT, gender and time from diagnosis to BMT, Quality of marrow-graft match was dropped from the analysis due to the low number of subjects for whom this information could be procured from medical records. OOL and Symptom Self-Report: The following variables showed a trend toward an association with quality of life variables or symptom report variables and were therefore included in a number of multiple regression equations: age at BMT (r=-.2152, p=.08), education (r=.20, p=.ll), SES (r=.29, p=.02) (demographic variables), and pre-BMT affect (r=,50, p<.001), social support (r=.27, p=.07), compliance (r=.28, p=.06) and life stress (r=-.32, p=.009)(psychosocial variables). The following variables did not show an association to quality of life or symptom report (p>.20) and therefore were eliminated from multiple regression analyses: gender, psychological or psychiatric treatment history, diagnosis, treatment type, remission status (again, likely an artifact), disease state and time from diagnosis to BMT. Quality of graft-match was eliminated as a variable due to insufficient sample size for which this information could be procured.

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50 Survival Analysis and Multiple Regressions In terms of survival time analysis, none of the medical, demographic, or psychosocial variables significantly predicted post-BMT survival time. Given the robustness of the literature, it is likely that extent of graft-match does have significant predictive value (Andrykowski, et al, 1994), however, this variable was dropped from the analysis due to difficulty procuring this information from medical records. In terms of the multiple regression analyses performed, none of the demographic, medical or psychosocial variables was predictive of responses on the SF-36 General Mental Health Scale, although pre-BMT affect showed a trend toward significance (F=2.0, p=.09). Patients experiencing higher levels of affective distress pre-BMT were more likely to rate their mental health as poor following treatment. None of the medical variables was predictive of patient responses on the SF-36 General Health Scale. However, patients experiencing fewer life stresses were more likely to rate their post-BMT health in a positive manner (F=2.8, p<.05). Also, patients experiencing lower levels of negative affect pre-BMT affect were more likely to rate their post-BMT health highly (F=3.22, p<.01). Interestingly, patients who reported lower levels of social support pre-BMT were more likely to rate their health in a positive manner post-BMT (F=2.7, p<.05). Also, patients who ranked poorly in terms of pre-BMT compliance were more likely to view their general health as good post-BMT (F=2.4, p<.05).

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51 None of the medical, demographic, or psychosocial variables was significantly correlated to subjects' Functional Assessment of Cancer (FACT-G) Total score, the FACT-G Family Weil-Being Scale or the Emotional Weil-Being Scale. However, preBMT affect was predictive of post-BMT scores on the FACT-G Physical Well-Being Scale (F=3.05, p<.05). Pre-BMT social support (F=2,6, p<.05) and compliance (F=2A, p<.05) also significantly predicted physical well-being. In sum, subjects judged to have lower levels of negative affect pre-BMT affect, higher levels of social support and better compliance history were more likely to report feeling physically healthy on the FACT-G Physical Well-Being Scale. Several medical, demographic and psychosocial variables were associated with increased scores on the FACT-G Satisfaction with Doctor scale. The following variables were significantly associated with increased satisfaction with the treating physician: male gender (r=.39, p<.05), lower SES (r=-.43, p<.05), allogeneic transplant (F=3.5, p<.05), decreased life stress (F=3.8, p<.01), decreased negative affect pre-BMT (F=3.5, p<.01), lower levels of pre-BMT social support (F=3.2, p<.01) and poorer pre-BMT compliance (F=3.1,p<.01). No medical or demographic variables were significantly correlated with Frequency of Symptoms (on Symptom Checklist). However, patients experiencing more life stress experienced greater frequency of symptoms (F=3. 1, p<.05), as did patients with more symptoms of anxiety and depression pre-BMT (F=3.0, p<.05) and poorer compliance

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52 (F=2.7, p<.05). Patients judged to have higher levels of social support pre-BMT surprisingly reported greater frequency of symptoms post-BMT (F=2.6, p<.05). In terms of how distressing subjects reported their physical symptoms to be (Symptom Checklist Total Problem Score), subjects with higher levels of negative affect pre-BMT (F=2.9, p<.05) and poorer compliance (F=3.4, p<.01) judged their symptoms to be more problematic than did subjects with higher ratings of pre-BMT affect and compliance. AJso, subjects with higher levels of pre-BMT social support rated their symptoms as more disturbing than did individuals with lower levels of social support (F=2.6, p<.05). T-Tests T-tests were run comparing deceased individuals with individuals still living in terms of their pre-BMT affect, compliance and social support. Individuals with lower levels of social support pre-BMT were more likely to be deceased at the time of follow-up (one tailed t=1.72, p<.05). Individuals with higher levels of negative affect pre-BMT showed a trend toward being more likely to expire during the follow-up period compared with individuals with lower levels of negative affect pre-BMT (one tailed t=l,58, p=.06). T-tests were also performed comparing individuals who had received psychological or psychiatric treatment with those who had not in terms of their survival time, likelihood of being alive at time of follow-up, quality of life and symptom report. The only significant result was that individuals who had received psychological treatment

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53 reported greater frequency of symptoms (2-tailed t=3.07, p<.01) and greater distress about these symptoms (2-tailed t=2.58, p<.05) than individuals who had not received psychological treatment (See Tables 3 and 4).

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54 Table 3: Results of regression analyses on predictors of quality of life and symptom report Outcome variable Significant predictors Beta Adjusted R^ F SF-36 General Health .22 2.38 Lifestress -.37 Affect .29 Social Support -.03 Compliance -.04 FACT Physical Well-Being .23 2.41 Affect -.39 Social Support -.01 Compliance -.16 FACT Satisfaction with M.D. .30 3.09 Gender .39 SES -.43 Transplant Type .16 Lifestress -.27 Affect .18 Social Support -.16 Compliance -.19 Symptom Checklist-Frequency .27 2.74 Lifestress .44 j Affect -.21 Social Support .03 Compliance 1 -.27 Symptom Checklist-Problem .33 3.39 1 Affect -.41 Social Support ,13 Compliance -.39

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55 Table 4: Psychosocial Variables significantly associated with mortality, QOL and symptom report Variable Association Social support Affect Compliance 1. Subjects with poor pre-BMT social support more likely to be deceased at followup 2, Adequate pre-BMT social support predicts decreased self-reported activity level, increased symptom frequency and symptom distress at follow-up 1. Subjects with fewer symptoms of depression and anxiety pre-BMT have more positive perceptions of their health, decreased symptom frequency and symptom distress at follow-up 1 Increased pre-BMT compliance predicts decreased symptom frequency and symptom distress Lifestress 1 Increased life stress predicts poorer perception of general health, increased symptom frequency and symptom distress

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CHAPTER 6 DISCUSSION No psychological, demographic or medical variables were predictive of survival time. This is likely an artifact, because in other studies (e.g. Andrykowski et al, 1994) quality of marrow-graft match was significantly predictive of survival time. In the current study, however, difficulty obtaining medical record data forced the removal of this variable from analysis. Based on the literature (Murphy, Jenkins & Whittaker, 1996; Andrykowski et al., 1994; Jenkins et al., 1994), it does appear that survival time is mediated predominantly by medical variables rather than psychosocial or demographic variables. Jenkins et al. (1994) notes that psychosocial variables appear to have a more prominent effect on quality of life and post-BMT emotional state than mortality. Murphy, Jenkins & Whittaker (1996) failed to find a significant link between depression and survival. Gregurek et al. (1996) found that an elevated level of anxiety during the first week of BMT was significantly predictive of developing acute GVHD (Stage II-IV) but was not predictive of eventual mortality. This suggests that psychological factors may play a role in medical morbidity, but may have too subtle an effect to actually influence mortality. These studies are in contrast to the only study to date which has linked psychosocial factors (depression and low family support) to mortality (Colon, et al., 1991). It should be noted that there are methodologic problems with the Colon et al. study and the results have not been replicated. 56

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57 In the current study, subjects who were judged to have lower levels of social support were more likely to be deceased at time of follow up compared to subjects with adequate social support. Although there is a great deal of literature linking social support to emotional adjustment to cancer (see Rowland, 1989 for a review), few studies have investigated the relationship between naturally occurring social support (i.e. families, friends in the community) and mortality. To date, only Colon et al. (1991) has examined naturally occurring social support networks and their outcome on survival time or mortality. Colon et al. (1991) found that individuals undergoing BMT who reported adequate family support were more likely to be alive at the time of follow up compared to individuals who rated their family support as poor. Gregurek et al. (1996) has suggested that psychosocial factors (such as emotional state and social support) may influence alloreactivity through the action of cytokines, which play a role in connecting the neuroendocrine and immune systems. Research has also investigated the effect of social support interventions on mortality. According to Holland (1991) over 20 intervention studies have been conducted that involved social interactions, the majority of which demonstrated an improvement in psychological adjustment. However, the data on mortality are more equivocal. Most of the social support intervention studies lacked theoretical frameworks and had serious methodological flaws. These studies focused on either peer discussion or education (see Helgeson & Cohen, 1996 for a review of these studies). Helgeson & Cohen conclude that

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58 although their review includes several studies that found effects of social support interventions on mortality (Fawzy et al, 1993; Morgenstern et al., 1984; Spiegel et al., 1989), the number of studies focusing on mortality or symptom report are not sufficient to assess the effectiveness of these interventions or to speculate on responsible mechanisms for the protective effect of social support. In sum, it appears that social support may protect people to some extent from mortality. However, the most helpful type of social support (i.e. family support vs. peer discussion group vs. peer education group) has not yet been determined. The "protective" components of a peer discussion group may be very different from the "protective" components in a naturally occurring social support group (like a family). Further research needs to clarify exactly what components of naturally occurring social support and social support interventions protect people from mortality and morbidity. This would enable identification of individuals at increased risk of mortality due to decreased social support and would allow interventions designed to address the specific component of social support which protects individuals from mortality. People who reported elevated levels of life stress (e.g. divorce, death of a friend or relative, loss of job) at the time of follow-up reported poorer perceptions of their general health and more frequent symptoms of illness than did individuals who reported little or no life stress. This again points to a connection between an individual's psychological state and his or her perceptions of physical health. Stress has been found to activate the

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59 sympathetic nervous system and HP A axis, thereby decreasing immune functioning (Maier, Watkins & Fleshner, 1994; Stein, Keeler & Schleifer, 1985). Consistent with this, it was also found that subjects who had lower levels of negative affect pre-BMT had more positive perceptions of their general health at the time of follow-up. Further, individuals with lower levels of negative affect pre-BMT reported decreased symptom frequency and were less distressed by the symptoms which they did experience. This is consistent with Gregurek et al. (1996) who found that subjects undergoing BMT who had elevated anxiety levels were more likely to develop acute GVHD. Some have suggested (Baker et al., 1994; Hobfoll & Walfisch, 1984; cited in Baker et al., 1994) that self-esteem may play a large role in determining adaptive functioning and perception of physical health following BMT. Individuals with improved self-esteem seem to fare better post -BMT than individuals with low self-esteem. While self-esteem was not measured in the current study, it would be expected that self-esteem would play a large role in determining pre-BMT affective state. Since having adequate self-esteem may enable people to experience improved affect, both preand post-BMT, this is an area meriting further research. Learning how certain people maintain their selfesteem and improve post-BMT quality of life in the face of many physical, mental status and emotional changes could foster the development of interventions designed to aid those with poor self-esteem both pre-BMT and during BMT.

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60 Conflicting data was found with regard to the impact of social support and compliance on perceptions of physical health. On the SF-36, patients who had lower levels of social support and compliance rated their physical health as better than individuals with higher levels of social support and compliance. However, on the FACTG, patients were more likely to report good physical health who had higher levels of social support and compliance pre-BMT. This may be due to the fact that the SF-36 and the FACT-G measure subtly different things. The SF-36 is a general health survey, while the FACT-G is a cancer-specific quality of life instrument. As a result, the SF-36 focuses on general activity level as a way of measuring physical health, while the FACT-G focuses on cancer-specific physical symptoms as a measure of physical health. Looked at in this light, individuals with lower levels of social support may be forced to be more active and independent than those subjects with social support networks to help them complete activities. Therefore, based on reports of physical activity, individuals with less social support would appear to view themselves as healthier than individuals with more social support. At any rate, the relationship between social support, compliance and perception of physical health remains unresolved at this time. With regard to symptom frequency and distress related to symptoms, individuals with higher levels of pre-BMT social support and poorer compliance reported higher levels of symptoms and more emotional distress over these symptoms. It would be expected that individuals with poorer compliance histories would experience more

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61 symptoms. However, the relationship between social support and symptom report is not entirely clear. It is possible that caretakers tend to focus on symptoms in an attempt to take care of patients, leading the patient to "notice" symptoms more than he or she would if forced to function independently of family and friends. However, it is also possible that individuals' level of social support changed from preto post-BMT. Little research has focused on what changes take place in terms of family relationships during and following BMT. One study (Syrjala, et al., 1993) found that there was little change in social support over time; however, another study (Zabora, et al., 1992) found that there were great changes in social support over time with some patients reporting increased social support and others reporting decreased support. This means that level of social support prior to BMT may not even predict level of social support post-BMT. This in turn would make it difficult to predict quality of life postBMT based on pre-BMT social support. Zabora and colleagues found that families tended to set goals and time periods in which they expected the BMT patient to resume family and career roles, and when these goals were not fulfilled, family conflict was typical. They also found that, in general, BMT patients' significant others experienced a significant worsening in their emotional state up to six months after BMT as well as reporting increased physical fatigue. In sum, the fact that little is known about changes in social support over time for BMT patients makes it difficult to make inferences about the

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62 relationship of pre-BMT social support to post-BMT report of physical symptoms in BMT patients. Social support was not found to correlate with post-BMT affective state. Individuals with lower levels of social support were no more likely to report emotional distress at follow up. This is in contrast to Baker et al. (1994) who found that patients with less social support were more likely to experience high levels of anger and negative affect post-transplant. However, in the Baker et al. study, patients were reporting social support post-BMT. Therefore, these patients may be expected to experience anger and negative affect in response to the current stress of low family support. As noted above, it is unclear at the present time how or if social support changes during the time between pre-transplant and one year post-transplant (Wingard, 1994). Patients in our study were rated on social support pre-BMT and those with low levels of support pre-BMT may have improved their level of social support during and after transplantation. Indeed, at least one study has found that social adjustment post-BMT is comparable with a healthy community sample overall in various domains of work, family, marital and leisure activities (Wolcott, Wellisch & Fawzy, 1986), suggesting that BMT patients acclimate well into their communities following BMT. Individuals in the current study who had undergone psychological or psychiatric treatment in the past were more likely to rate their frequency of physical symptoms as high. This is likely due to the fact that individuals with more severe physical symptoms

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63 may be more emotionally distressed than individuals with few symptoms and therefore, more likely to receive psychiatric treatment. Individuals on the Bone Marrow Treatment Unit at the University of Florida are monitored closely by the staff, who notify the Psychology Dept. if psychological distress appears to be in excess of normal levels. At that time, psychotherapy is typically initiated. A relatively new area of investigation is the FACT-G Satisfaction with Doctor scale. In the current study, males, people with lower socioeconomic status, lifestress, social support and compliance, people with fewer symptoms of anxiety and/or depression pre-BMT, and people undergoing allogeneic treatment were more likely to have higher ratings of satisfaction with their doctor. This suggests that patients who have lower levels of social support may look for this support in their treating physician. Also, patients with lower SES and fewer affective symptoms pre-BMT may be more likely to trust their physician and therefore, report increased satisfaction. Individuals receiving allogeneic treatment may report higher patient satisfaction due to having increased contact with their doctors compared to autologous BMT patients. This would likely be due to the fact that allogeneic BMT survivors are more likely to experience GVHD, necessitating closer follow-up after BMT and increased contact with medical staff. It is unclear why males or individuals with poor pre-BMT compliance would have higher physician satisfaction. In summary, pre-BMT psychosocial variables appear linked to outcome in terms of both mortality and psychological morbidity. People with higher levels of anxiety and/or

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64 depression pre-transplant were more likely to report poorer perceptions of physical health, greater frequency of symptoms and greater distress about these symptoms. People with lower levels of social support appear to be at increased risk for mortality compared to those with higher levels of social support. However, higher levels of social support may cause individuals to focus on their symptoms more than they otherwise would and to decrease their activity level accordingly. Individuals with higher levels of social support reported more frequent symptoms and more distress about these symptoms than did individuals with lower levels of social support. The current findings are very encouraging, as they suggest that psychosocial factors do have a strong influence on outcome in terms of quality of life and possibly mortality. This is important because interventions designed to modify patients' affective state, level of social support and compliance behavior are existent in the literature, but only now are beginning to receive strong empirical support (e.g. Andrykowski et al., 1994; Gregurek et al., 1996). The clinical implications for the current study are important. First, the role of psychologists in screening patients for risk factors in BMT is strengthened given the current data. Also, treating physicians should know that outcome may be improved if a patient's affective state is closely monitored and interventions put in place at the first sign of affective distress in excess of normal. There are several limitations of the current study. The first is the retrospective nature of the design. The second is the use of a subjective rating scale to measure

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65 subjects' pre-transplant psychological functioning. However, the subjective rating scale is modeled after several other rating scales found to have adequate reliability and validity in a BMT population (Presberg, et al, 1995). Third, the sample size was somewhat small, limiting statistical power. Difficulty in obtaining medical information was another limiting factor, necessitating the elimination of several important medical predictor variables from the analysis. Future studies should use a prospective design and standardized psychological measures (as in the Gregurek et al., 1996 and Andrykowski et al, 1994 studies). Related to the limitations above is the response rate of the current study. Since only 61% of those contacted to participate in the study actually participated, it is interesting to question whether a self-selected sample such as this one is significantly different from a true cross-section of BMT survivors. While there is no research examining this issue in a BMT population, it is not expected that there would be many differences between study participants and non-participants. Anecdotally, participants in the study had a wide range of experiences in terms of quality of life. Some were quite pleased with the results, reporting few side effects and few lingering symptoms, while other BMT patients reported chronic GVHD, difficulty returning to work, and problems in physical and emotional functioning. It is therefore suspected that the sample in our study is fairly representative of BMT survivors as a whole.

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66 Future research should also address the complex relationship between social support and mortality. It seems plausible that higher levels of social support protect patients from mortality (Helgeson & Cohen, 1996). It is not yet clear which types of social support (i.e. family support vs. peer discussion or educational support groups) are the most helpful in decreasing mortality. However, it may be true that particular types of social support (for example, cancer support groups) which motivate patients to increase their independence and take an active role in maintaining social support networks may be the most effective in decreasing psychosocial morbidity (i.e. quality of life, symptom report) as well as mortality. Based on the current study, interventions such as group or individual psychotherapy which (hopefully) increase patient independence, provide social support and decrease depression and anxiety could "inoculate" people against mortality and morbidity post-BMT. The complex role between social support, role retention, and quality of life should also be further examined. It appears that role retention is a critical component in determining not only BMT patients' quality of life, but also family functioning post-BMT (Baker, et al, 1994). The sooner a BMT patient is able to resume roles such as family caretaker, parent, employee, etc., the faster the family unit is able to resume normal functioning. While medical variables certainly play the largest role in an individual's ability to resume typical role functioning, psychological variables also play a part. Since it is unclear what changes occur in social support over time following BMT, it is critical to

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67 examine ways to allow BMT patients to exert control over their treatment and life style following BMT, thereby increasing their ability to resume role functioning, increase social support and hopefully protect themselves from increased risk of mortality and morbidity. Finally, continued research into the development and refinement of rating scales similar to the one used in this study (see Presberg, 1995) would be helpful. Since the current state of clinical practice in this area involves the use of a multitude of psychosocial assessment techniques and instruments, finding a means of summarizing testing and interview data in a valid and reliable way is essential to identifying patients at high risk for negative outcome in BMT. Particular issues to focus on include the measurement of reliability between samples of BMT patients and between raters.

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BIOGRAPHICAL SKETCH Timothy Pearman was born in Allentown, Pennsylvania, on October 5, 1969. He received a Bachelor of Arts degree from the Pennsylvania State University in May, 1991, and entered the University of Florida in August, 1991. He received a Master of Science degree from University of Florida in May, 1994. He completed his clinical internship at Tulane University Medical Center and is currently living in New Orleans, Louisiana. 78

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I certify that I have read this study and that in my opinion it conforms to acceptable standards of scholarly presentation and is fully adequate, in scope and quality, as a dissertation for the degree of Doctor of Philosophy. II' jan/es Rodrigue, Chair Kssociate Prof \/Psychology Kssociate Professor of Clinical and Health I certify that I have read this study and that in my opinion it conforms to acceptable standards of scholarly presentation and is fully adequate, in scope and quality, as a dissertation for the degree of Docter^^of Philosophy. | Duane Dede, Cochair Assistant Professor of Clinical and Health Psychology I certify that I have read this study and that in my opinion it conforms to acceptable standards of scholarly presentation and is fiilly adequate, in scope and quality, as a dissertation for the degree of Doctor of Philosophy. ^e^^,,/^ B ^ ; Stephen Boggs Associate Professor of Clinical and Health Psychology I certify that I have read this study and that in my opinion it conforms to acceptable standards of scholarly presentation and is fully adequate, in scope and quality, as a dissertation for the degree of Doctor of Philosophy. KarolynGodSy ^ Associate Professor of Nursing

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I certify that I have read this study and that in my opinion it conforms to acceptable standards of scholarly presentation and is fully adequate, in scope and quality, as a dissertation for the degree of Doctor of Philosophy. ) (,v/v,A ^A.,^?v Jan Moreb Associate Professor of Hematology and Oncology This dissertation was submitted to the Graduate Faculty of the College of Health Professions and to the Graduate School and was accepted as partial fulfillment of the requirements for the degree of Doctor of Philosophy. August 1997 r^-^l^^ ^ ^.c^/c Dean, College of Health Professions, I > I 1/ i Dean, Graduate School / \


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