Group Title: BMC Urology
Title: Focal therapy for prostate cancer: revolution or evolution?
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Abstract: The face of prostate cancer has been dramatically changed since the late 1980s when PSA was introduced as a clinical screening tool. More men are diagnosed with small foci of cancers instead of the advanced disease evident prior to PSA screening. Treatment options for these smaller tumors consist of expectant management, radiation therapy (brachytherapy and external beam radiotherapy) and surgery (cryosurgical ablation and radical prostatectomy). In the highly select patient, cancer specific survival employing any of these treatment options is excellent, however morbidity from these interventions are significant. Thus, the idea of treating only the cancer within the prostate and sparing the non-cancerous tissue in the prostate is quite appealing, yet controversial. Moving forward if we are to embrace the focal treatment of prostate cancer we must: be able to accurately identify index lesions within the prostate, image cancers within the prostate and methodically study the litany of focal therapeutic options available.
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Focal therapy for prostate cancer: revolution or evolution?
Ryan Turpen and Charles J Rosser*


Address: Department of Urology, University of Florida, Gainesville, Florida, USA
Email: Ryan Turpen ryan.turpen@urology.ufl.edu; Charles J Rosser* charles.rosser@urology.ufl.edu
* Corresponding author


Published: 23 April 2009
BMC Urology 2009, 9:2 doi: 10.1186/1471-2490-9-2


Received: 13 January 2009
Accepted: 23 April 2009


This article is available from: http://www.biomedcentral.com/1471-2490/9/2
2009 Turpen and Rosser; licensee BioMed Central Ltd.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.ore/licenses/by/2.0),
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.



Abstract
The face of prostate cancer has been dramatically changed since the late 1980s when PSA was
introduced as a clinical screening tool. More men are diagnosed with small foci of cancers instead
of the advanced disease evident prior to PSA screening. Treatment options for these smaller
tumors consist of expectant management, radiation therapy (brachytherapy and external beam
radiotherapy) and surgery cryosurgicall ablation and radical prostatectomy). In the highly select
patient, cancer specific survival employing any of these treatment options is excellent, however
morbidity from these interventions are significant. Thus, the idea of treating only the cancer within
the prostate and sparing the non-cancerous tissue in the prostate is quite appealing, yet
controversial. Moving forward if we are to embrace the focal treatment of prostate cancer we
must: be able to accurately identify index lesions within the prostate, image cancers within the
prostate and methodically study the litany of focal therapeutic options available.


Background
As defined by the International Task Force on Prostate
Cancer and the Focal Lesion Paradigm, the goal of focal
therapy for prostate cancer would be to "selectively
ablate(s) known disease and preserve(s) existing func-
tions, with the overall objective of minimizing lifetime
morbidity without compromising life expectancy" [1].
Several, new treatment modalities for localized prostate
cancer with encouraging efficacy and reduced morbidity
compared to conventional treatment options may have
the potential of accomplishing this goal [2].

Focal therapy for the treatment of prostate cancer has been
called the 'male lumpectomy', an analogue to women's
breast lumpectomy for the treatment of breast cancer [3].
In a lumpectomy, the breast tumor and some of the nor-
mal tissue that surrounds it are rejected, thus sparing sig-


nificant portion of the breast. This breast conserving
surgery is associated with less morbidity. However, most
women opting for breast lumpectomy receive 5 to 7 weeks
of local radiation therapy shortly after lumpectomy in
order to eliminate any cancer cells that may linger in the
conserved breast. Two large prospective randomized con-
trol trials showed that women with small breast cancers
(under 4 centimeters) treated with lumpectomy plus radi-
ation therapy were just as likely to be alive and disease-
free 20 years later as women who had had mastectomies.
Additional, neoadjuvant chemotherapy may be part of the
treatment regimen when breast lumpectomy is performed
[4,5]. To date, most discussions on 'male lumpectomy' are
devoid of radiation therapy or chemotherapy. With that
said, is focal therapy for prostate cancer really similar to
breast lumpectomy? Furthermore, is the talk of focal ther-
apy for prostate cancer, heresy? Herein, we discuss critical




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pathologic and radiologic findings conducive to focal
therapy and we briefly discuss the results of a variety of
therapeutic options utilized for focal therapy.

Discussion
Successful adoption of focal therapy for the treatment of
prostate cancer will hinge on several critical issues: 1) can
we accurately identify index lesions within the prostate, 2)
can we reliably image cancers within the prostate, 3) long-
term efficacy of the technology to eradicate cancer, 4)
appropriate follow-up of patients treated with focal ther-
apy, and 5) limitations of PSA following therapy and how
to detect recurrent/persistent disease.

Pathology
Extensive, bilateral disease precludes focal therapy. Multi-
focal prostate cancer has been reported in 67% to 87% of
all cases of contemporary radical retropubic prostatec-
tomy [6]. Thus, the ideal candidate considered for focal
therapy should have unilateral disease. A recent study out
of Duke University reported that in 1,386 prostatectomy
specimens, 18% of the tumors were unilateral only. On
multivariate analysis, race, pathologic Gleason score, sur-
gical margin status and percentage of tumor involvement
as independent predictors of unilateral disease [7]. It is
noted that pathologic Gleason score and surgical margins
are not known when selecting patients for focal therapy.

In order to implement focal therapies, cancer must be
accurately and reliably mapped within the gland. Initially,
transperineal 3D mapping biopsies were reported to effec-
tively exclude patients with clinically significant unsus-
pected cancer outside the area destined to be ablated more
so than repeat transrectal ultrasound (TRUS) guided biop-
sies [8]. Though not corroborated by whole-mount pros-
tatectomy specimens, Onik reported the use of
transperineal 3D mapping biopsy used as an additional
staging procedure prior to focal prostate cancer therapy.
One hundred ten patients, all of whom had unilateral dis-
ease on TRUS biopsies, were restaged using the 3D map-
ping method prior to focal therapy. Bilateral cancer was
demonstrated in 60 patients (55%, all of whom had only
unilateral cancer shown on TRUS biopsy). The Gleason
score was increased in 25 patients (23%) over the Gleason
score found on TRUS biopsy [9], thus suggesting transper-
ineal prostate mapping provides better pathologic assess-
ment of the entire prostate gland.

Perhaps the 3D nature in which the biopsies are obtained
not the route the biopsies are obtained (i.e., transrectal
versus transperineal) is not the critical factor. Researchers
using the TargetScan 3D transrectal ultrasound and pros-
tatic biopsy system correctly characterize 88% of ex vivo
prostatic octants in regards to whether or not they con-
tained cancer [101. These 3-D mapping biopsies have been


suggested in some of the focal therapy clinical trials dis-
cussed at the 1st International Workshop on Focal Therapy
and Imaging of Prostate Cancer.

Though standard imaging with ultrasound have limited
sensitivity of identifying pathologic proven tumor within
the prostate gland, novel techniques are being investi-
gated with prostate biopsying, including the use of ultra-
sonographic contrast agents, color Doppler, power
Doppler, and MR spectroscopy image-directed TRUS-
guided biopsy in hopes of better identifying cancer at the
time of prostate biopsy [11,12].

Imaging
Equally important to the success of focal therapy of local-
ized prostate cancer is imaging and its ability to more
accurately provide information regarding tumor presence
and localization before and after treatment. Tumor local-
ization using imaging modalities allows for treatment of
the areas) involved with cancer and sparing of the nor-
mal, non-cancerous tissue. Our current radiologic staging
modalities (i.e., prostate ultrasound and computed tom-
ography of the pelvis) lack sensitivity in depicting the
presence and location of localized disease [13].

Previous studies reported a variable sensitivity of mag-
netic resonance imaging (MRI) in localizing disease
within the prostate [14,15]. Recently, the introduction of
functional imaging techniques such as dynamic contrast-
enhanced (DCE) MRI, diffusion-weighted imaging (DWI)
and magnetic resonance spectroscopic imaging (MRSI)
have been studied to improve the detection and localiza-
tion of prostate cancer. Specifically, DCE MRI was
assessed in 53 patients with suspected prostate cancer. The
wash-in rate value was greater in cancer tissue (9.2/sec-
ond) than in three normal tissues (3.3/second, 6.7/sec-
ond, and 3.2/second, respectively; P < 0.001). The
sensitivity and specificity of detecting prostate cancer were
greater on parametric imaging of the wash-in rate com-
pared to T2-weighted imaging in the entire prostate (96%
and 82% vs. 65% and 60%, respectively) [ 16]. As for DWI
MRI, T2-weighted imaging and DWI were performed in
49 patients before radical prostatectomy using an
endorectal coil at 1.5 T in a prospective trial. Sensitivity for
prostate cancer detection was significantly higher with T2
plus DWI (81%) than with T2 imaging alone (54%), with
T2 plus DWI showing only a slight loss in specificity com-
pared with T2 imaging alone (84% vs. 91%, respectively)
[171.

MRI, MRSI and DCE-MRI with a 3-Tesla whole-body scan-
ner were performed in 30 patients with biopsy-proven
prostate cancer before radical prostatectomy. The high sig-
nal-to-noise ratio (SNR) at 3 Tesla provided T2-weighted
turbo spin echo (TSE) images with excellent anatomical


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detail (in-plane voxel size of 0.22 x 0.22 mm) and good
T2 contrast, whereas dynamic contrast-enhanced images
showed good temporal resolution [18]. The combination
of vascular information from DCE-MRI or DWI MRI and
metabolic data from MRSI has excellent potential for
improved accuracy in delineating and staging prostate car-
cinoma.

Cryotherapy
Though fascinating, delving into the history and biology
of cryotherapy is not part of this review. Recently, the AUA
released its best practice statement on cryosurgery for the
treatment of localized prostate cancer [ 19]. A cornerstone
of this report was the large, retrospective series reported by
Cohen with a median follow-up of greater than 12 years.
In this report, 370 patients with TI to T3 prostate cancer
treated consecutively from 1991 to 1996 with cryosurgery
as primary monotherapy was analyzed. Kaplan-Meier
analysis demonstrated a biochemical disease-free survival
rate at 10 years of 80.56%, 74.16%, and 45.54% for low,
moderate, and high-risk groups, respectively. The 10-year
negative biopsy rate was 76.96% [20]. Another large, ret-
rospective series was reported by Bahn and colleagues. In
this report, the charts of 590 consecutive patients who
underwent primary cryosurgical ablation for definitive
management were reviewed. The mean follow-up of the
cohort was 5.4 years. The percentages of patients with
low-, medium-, and high-risk prostate cancer were 15.9%,
30.3%, and 53.7%, respectively. Using a PSA-based defi-
nition of biochemical failure of 0.5 ng/mL, results were as
follows: the 7-year actuarial bDFS for low-, medium-, and
high-risk patients were 61%, 68%, and 61%, respectively.
The rate of positive biopsy was 13%. Hormonal therapy
was given to 91.5% of the subjects before treatment to
downsize the gland and consisted of luteinizing hor-
mone-releasing hormone, combined with an antiandro-
gen agent 3 months to 1 year before cryoablation. Though
hormonal therapy was not continued on any patient after
cryoablation, it is still difficult to interpret early serum
PSA results in this cohort. Lastly it was noted that 4.3% of
subjects reported post-operative incontinence, 94.9%of
subjects reported post-operative erectile dysfunction and
< 0.1% of subjects developed a post-operative fistula.
Thus, the rates of morbidity were modest, and no serious
complications were observed [21]. These encouraging
results with whole gland treatment have sparked an inter-
est in utilizing this treatment modality for the focal treat-
ment of prostate cancer.

Focal cryoablation was planned to encompass the area of
known tumor based on staging biopsies. Forty-eight
patients with at least 2-year follow-up had focal cryoabla-
tion. Mean follow-up was 4.5 years. Ninety-four percent
of the patients treated had stable PSAs according to Amer-
ican Society of Therapeutic Radiology and Oncology


(ASTRO) criteria. Of the 24 patients with stable PSAs who
were routinely biopsied (n = 24) all were negative. No
local recurrences were noted in areas treated. Potency was
maintained to the satisfaction of the patient in of 36 of 40
patients who were potent preoperatively. Of the 48, all
were continent [22]. It is the limited morbidity that makes
this treatment option quite attractive. These encouraging
results have prompted the initiation of two large, multi-
center trials assessing the feasibility and efficacy of per-
forming focal cryotherapy in subjects with localized, low-
risk prostate cancer.

The use of hormone therapy must be accounted for when
interpreting the results from the above studies. In the
study by Onik, patients on combined hormone therapy
had therapy stopped immediately after treatment in all
cases. Nonetheless, the 3-month data should be cau-
tiously interpreted due to potential residual effects of neo-
adjuvant hormone therapy [22]. A 2005 study evaluating
men with high-risk features for prostate carcinoma, the
majority of study participants (67.7%) received neoadju-
vant hormones. Despite this, no significant difference was
seen in biochemical recurrence-free survival between
those who received hormones and those who did not
[23]. Regardless, use of hormones must be taken into con-
sideration when interpreting PSA-recurrence or biopsy
results in these patients.

High-intensity focused ultrasound
First introduced in the 1940s, high-intensity focused
ultrasound (HiFU) uses energy focused to a specific point
within the prostate, thus enabling targeted destruction of
prostatic tissue. Currently, two HiFU devices are attempt-
ing to get FDA approval for the treatment of prostate can-
cer in the US. However, HiFU therapy for localized
prostate cancer has been widely accepted in Europe and
Asia. In a large Phase II/III prospective multicenter study,
Thuroff reported the results of 402 patients with stage Tl-
2, Nx-0, MO prostate cancer treated with HiFU. Follow-up
was extremely short at approximately 1 year, but the neg-
ative biopsy rate observed in the T1-2 primary-care popu-
lation was 87.2% [24]. The HiFU series with the longest
follow-up comes out of the University of Regensburg in
Germany. In their report, Blana reports on the outcomes
of 163 patients with clinical Stage T1-T2NOMO, biopsy-
proven, localized prostate cancer, with a serum prostate-
specific antigen (PSA) level of < 20 ng/mL, Gleason score
of< 7, treated with HiFU. Median follow-up was 4.8 years.
Of the 163 patients, 86.4% achieved a PSA nadir of< 1 ng/
mL and 92.7% had negative post-treatment biopsy find-
ings. The biochemical recurrence free survival rate at 5
years was 75 %, with salvage treatment initiated for 12% of
the patients. On multivariate analysis, the pretreatment
PSA level was the only statistically significant predictive
factor of recurrence (P = 0.005) [25].


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Similar to focal cryoablation, focal HiFU is planned to
encompass the area of known tumor based on staging
biopsies. In 2008, Muto and others published a study on
70 patients treated with HiFU. Twenty-nine of these
patients had unilateral disease as determined by multi-
regional biopsies. These patients received focal therapy
while the remaining patients received whole organ abla-
tion. Scheduled biopsies were performed at 6 and 12
months following treatment. After 12 months 84% of
patients who received whole therapy were biopsy negative
versus 77% in the focal therapy group. Using the ASTRO
definition, the 2-year biochemical recurrence free survival
rates for patients at low and intermediate risk were 91%
and 50% for whole therapy, respectively. For the focal
therapy group, biochemical recurrence free survival rates
were 83% and 54%, respectively at 2 years. The authors
also noted in this study that whole, but not focal therapy,
resulted in a continuous decline in serum testosterone lev-
els. Of the 52 patients who were continent prior to HiFU,
49 (94%) subjects were continent after HiFU therapy.
Morbidity of whole gland HiFU compared to focal gland
HiFU was not significantly different [26]. These results are
promising and support focal cryotherapy as a therapeutic
modality in subjects with localized, low-risk prostate can-
cer.

Similar with cryosurgery, in patients who received hor-
mone therapy, caution must be taken when interpreting
these results. The study by Thuroff excluded patients who
had previous orchiectomy or hormone therapy [24]. Muto
does not account for hormone therapy in his results
despite reporting 24 of 70 patients with hormone therapy
at time of treatment [26].

Vascular Targeted Photodynamic Therapy
Vascular targeted photodynamic therapy (VTP) involves
the generation of cytotoxic agents in situ that results in cell
death and tissue ablation. This is achieved by systemic or
local administration of a photosensitizing drug that is
activated with light of a specific wavelength. The photo-
sensitizer Tookad] (WST09) has been studied in the VTP
of prostate cancer. Huang and colleagues demonstrated
that Tookad-VTP could destroy a clinically-significant vol-
ume of normal canine prostate tissue [27]. In a phase I
clinical trial conducted in Europe and Canada, Trachten-
berg and others report the safety and efficacy of VTP in 28
patients with histological proven recurrent prostate cancer
after definitive radiotherapy. In the study, response to VTP
was assessed using contrast-enhanced MRI and transrectal
ultrasound guided biopsies targeting areas of lesion for-
mation in addition to monitoring serum PSA levels. Areas
of necrosis were documented on MRI scans. Serum PSA
levels decreased in the complete responders, however,
PSA levels in partial and nonresponders remained similar
to baseline levels, regardless of light doses received. Side-


effects of the TOOKAD-VTP treatment were modest, gen-
erally self-limited, and compared favorably with other sal-
vage methods. However, two patients did develop a
rectourethral fistula, which translates into a remarkably
high fistula rate. The authors speculate that this high fis-
tula rate may be explained by an EBRT induced prostatitis,
resulting in higher drug concentration in blood pooling
within the rectum [28]. Regardless, efforts must be aimed
at decreasing the morbidity reported in this most recent
study.

Recently, Emberton presented results of a phase I trial
using VTP to treat low volume, primary prostate cancer.
Preliminary results are encouraging, however the authors
readily admit refinements in the technique are needed
prior to embarking on a larger clinical trial [29]. The
encouraging finding in this study was that Tookad-VTP
induced lesions were able to be accurately shaped using a
single light source, thus highlighting its potential role in
focal prostate therapy.

Summary
The face of prostate cancer has been dramatically changed
since the late 1980s when PSA was introduced as a clinical
screening tool. More men are diagnosed with localized
prostate cancer [30] and smaller volume, non-aggressive
prostate cancers [31]. It is unlikely that these cancers will
adversely affect the individuals overall survival, thus
expectant management or now focal therapy may be an
excellent treatment modality for this very select cohort. A
key remains the ability to identify candidates for focal
therapy. The International Task Force on Prostate Cancer
and the Focal Lesion Paradigm has proposed a clinical
definition of suitable candidates for focal therapy (Table
1) [32]. But for those individuals opting for definitive
therapy, perhaps focal therapy utilizing any of the modal-
ities discussed above may be an option [33]. It is noted
that advancements in the delivery of external beam radia-
tion and brachytherapy are enabling these therapies to be
considered in the focal therapy armamentarium.

Though focal therapy of the prostate only treats a portion
of the prostate it has been referred to as the 'male lumpec-
tomy', but one must remember women who undergo
lumpectomy usually will have other local or systemic
therapies to ensure eradication of disease. Since men who
are undergoing 'male lumpectomy' rarely undergo these
addition therapies, comparison with women undergoing
a lumpectomy should be limited. However, through rigor-
ous clinical scrutiny the ideal treatment combinations
were identified for breast cancer that successfully treated
the cancer and limited the morbidity associated with
more radical therapies. A strong push must be made in the
Urologic community to rigorously scrutinize focal therapy
in men with prostate cancer.


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Table I: Ideal Candidates for Focal Therapy*

Serum PSA PSA < 10 ng/mL, PSAD < 0.15 ng/mL/g

Clinical Stage T I NxMx or T2aNxMx

Pathologic evaluation/Gleason score" 3+3 or less (no grade 4 or 5)

No more than 2 adjacent regions positive for cancer

Total length of cancer < 10 mm total and < 7 mm in any I core; < 1/3 of cores positive for cancer


Radiologic Imaging (MRI +/- MRSI)


Largest dimension < 15 mm if prostate volume > 25 grams or < 10 mm if volume < 25 grams. Capsular
contact < 5 mm on axial imaging. No signs of extracapsular extension or seminal vesicle invasion


* adapted from Sartor, 2008.
"10 core minimum biopsy schema, plus 2 additional cores for every 10 grams of prostate > 40 grams (max of 18 cores)


As previously stated, successfully adoption of focal ther-
apy for the treatment of prostate cancer will hinge on two
critical issues: 1) accurately identifying index lesions
within the prostate, 2) reliably imaging cancers within the
prostate, 3) long-term efficacy of the technology to eradi-
cate cancer, 4) appropriate follow-up of patients treated
with focal therapy, 5) limitations of PSA following ther-
apy and how to detect recurrent/persistent disease. Solv-
ing these critical issues not only will assist with
pretreatment counseling of these patients, but could be
used as effective monitors for ideal end points in cancer
therapy. In addition, optimal patient selection using pre-
treatment risk stratification must be developed to ensure
the treatment of subjects who would gain the most out of
focal therapy. Despite our limitations in identifying dis-
ease that can be treated by focal therapy, several clinical
trials utilizing some of the promising therapeutic modali-
ties mentioned above are on the horizon. Hopefully with
careful monitoring and critical review of these trials we
can better determine if focal therapy is an appropriate
treatment option to offer patients with localized, low-
grade prostate cancer.

Abbreviations
PSA: prostate specific antigen; 3D: 3 dimension; TRUS:
transrectal ultrasound; MRI: magnetic resonance imaging;
DCE: dynamic contrast-enhanced; MRSI: magnetic reso-
nance spectroscopic imaging; DWI: diffusion-weighted
imaging; SNR: signal-to-noise ratio; AUA: American Uro-
logical Association; ASTRO: American Society of Thera-
peutic Radiology and Oncology; HiFU: high-intensity
focused ultrasound; FDA: Food and Drug Administration;
DFS: disease free survival; VTP: Vascular targeted photody-
namic therapy; TSE: turbo spin echo.

Competing interests
The authors declare that they have no competing interests.


Authors' contributions
RT gathered all data and wrote the manuscript. CJR devel-
oped and was responsible for overseeing the project.

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