Conversations with Urologic Oncology Investigators PCU 2006 VOL 5 ISSUE 2

PCU 2006
VOL 5 ISSUE 2
Conversations with Urologic Oncology Investigators
Bridging the Gap between Research and Patient Care
EDITOR
Neil Love, MD
FAC U LT Y
Judd W Moul, MD
SPECIAL EDITION
Daniel P Petrylak, MD
Case-Based
Roundtable Discussion
Download MP3 files of this audio program at ProstateCancerUpdate.com
Prostate Cancer Update
A Continuing Medical Education Audio Series
S TAT EM EN T O F N EED / TA RG E T A U D I EN C E
Prostate cancer is one of the most rapidly evolving fields in urologic oncology. Published results from clinical
trials lead to the emergence of new surgical and radiation therapy techniques and therapeutic agents, along
with changes in the indications for existing treatments. In order to offer optimal patient care — including the
option of clinical trial participation — the practicing urologist and radiation oncologist must be well informed of
these advances. To bridge the gap between research and practice, Prostate Cancer Update utilizes one-on-one
discussions with leading urologic oncology and radiation oncology investigators. By providing access to the latest
research developments and expert perspectives, this CME program assists urologists and radiation oncologists in
the formulation of up-to-date clinical management strategies.
GLOBAL LEARNING OBJECTIVES
• Critically evaluate the clinical implications of emerging clinical trial data in prostate cancer screening,
prevention and treatment and incorporate these data into management strategies in the local and advanced
disease settings.
• Counsel appropriately selected patients about the availability of ongoing clinical trials.
• Inform prostate cancer patients about the specific risks and benefits of local and systemic therapies.
• Provide individualized counseling to patients regarding the choice and timing of endocrine therapy.
• Counsel appropriately selected patients in the high-risk or advanced disease settings about the risks and
benefits of chemotherapy, including emerging data on taxane-based regimens.
P U R P O S E O F T H I S I S S U E O F P R O STATE C A N C E R U P D ATE
The purpose of Issue 2 of Prostate Cancer Update is to support these global objectives by offering the perspectives
of Drs Moul and Petrylak on the integration of emerging clinical research data into the management of prostate
cancer.
AC C R ED I TAT I O N S TAT EM EN T
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continuing medical education for physicians.
C R ED I T D E S I G N AT I O N S TAT EM EN T
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Physicians should only claim credit commensurate with the extent of their participation in the activity.
HOW TO USE THIS CME ACTIVITY
This CME activity contains both audio and print components. To receive credit, the participant should listen to the
CDs or tapes, review the monograph and complete the Post-test and Evaluation form located in the back of this
monograph or on our website. This monograph contains edited comments, clinical trial schemas, graphics and
references that supplement the audio program. ProstateCancerUpdate.com includes an easy-to-use, interactive version of this monograph with links to relevant full-text articles, abstracts, trial information and other web
resources indicated here in blue underlined text.
Prostate Cancer Update — Issue 2, 2006
TA B L E O F C O N T EN T S
MEE T THE PRO FESSO RS C ASE DISCUSSIO NS
3
Case 1: A 62-year-old man who presented with a PSA of five ng/mL underwent
radical prostatectomy and had a pathologic Stage T2B, Gleason 7 (4 + 3)
prostate cancer with 40 to 50 percent involvement of the gland and a focal
positive margin at the anterior edge of the apex (from the practice of
Alan M Nieder, MD)
5
Case 2: A 53-year-old man with a history of colon cancer whose PSA level
rose from 3.8 to 7.9 ng/mL in one year, with pathologic T3 Gleason 4 + 5
prostate cancer with extracapsular extension, negative nodes, seminal vesicles
and margins after nerve-sparing prostatectomy (from the practice of
Michael A Simon, MD)
7
Case 3: A 50-year-old man with an abnormal DRE (slightly indurated left
lobe), a PSA level of 0.2 ng/mL with 1/12 positive cores (one percent) and
Gleason 6 prostate cancer (from the practice of Richard Davi, MD)
9
Case 4: An 84-year-old man who underwent external beam radiation
therapy 10 years ago for Gleason 7 prostate cancer and was treated with an
LHRH agonist and then MAB therapy for PSA recurrences. Currently, he has
bone metastases, with a PSA of 50 ng/mL, and he is receiving docetaxel and
prednisone for bone pain (from the practice of Dr Nieder)
13
Case 5: A 71-year-old man with a PSA rising from five to 18.1 ng/mL in
the year prior to diagnosis of Gleason 6-7 prostate cancer, with 9/13 positive
cores (85 percent) and DRE abnormal bilaterally. Bone and CT scans were
negative (from the practice of Benjamin M Tripp, MD)
16
Judd W Moul, MD
INTERVIE WS
Professor and Chief
Division of Urologic Surgery
Duke University Medical Center
Durham, North Carolina
21
Daniel P Petrylak, MD
Associate Professor of Medicine
Director, Genitourinary Oncology Program
Columbia Presbyterian Medical Center
New York, New York
26
P OST-TEST
23
E VALUATIO N FO RM
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MEDICAL ONCOLOGIST COMMUNIT Y PANEL
Richard Davi, MD
Michael A Simon, MD
Miami, Florida
Pembroke Pines, Florida
Alan M Nieder, MD
Benjamin M Tripp, MD
Miami, Florida
Boca Raton, Florida
C O N T E N T VA L I D AT I O N A N D D I S C L O S U R E S
Research To Practice is committed to providing its participants with high-quality, unbiased and stateof-the-art education. We assess potential conflicts of interest with faculty, planners and managers of
CME activities. Real or apparent conflicts of interest are identified and resolved by a peer review content
validation process. The content of each activity is reviewed by both a member of the scientific staff
and an external independent reviewer for fair balance, scientific objectivity of studies referenced and
patient care recommendations.
The scientific staff and consultants for Research To Practice are involved in the development and review
of content for educational activities and report the following real or apparent conflicts of interest for
themselves (or their spouses/partners) that have been resolved through a peer review process: Richard
Kaderman, PhD, Neil Love, MD, Douglas Paley, Michelle Paley, MD, Margaret Peng, Lilliam Sklaver
Poltorack, PharmD, Chris Thomson, MD, MS and Kathryn Ault Ziel, PhD — no real or apparent conflicts
of interest to report; Marie Bialek, PharmD — Freelance/Contract Medical Writer: McNeil Consumer
& Specialty Pharmaceuticals, Janssen Pharmaceutica Products LP; salary (spouse): AstraZeneca
Pharmaceuticals LP; Sally Bogert, RNC, WHCNP — shareholder of Amgen Inc. Research To
Practice receives education grants from Abraxis Oncology, Amgen Inc, AstraZeneca Pharmaceuticals
LP, Bayer Pharmaceuticals Corporation/Onyx Pharmaceuticals Inc, Genentech BioOncology/
OSI Pharmaceuticals Inc, Genomic Health Inc, Roche Laboratories Inc and Sanofi-Aventis, who have
no influence on the content development of our educational activities.
In addition, the following faculty (and their spouses/partners) have reported real or apparent conflicts
of interest that have been resolved through a peer review process:
Dr Moul — Consulting Fees: AstraZeneca Pharmaceuticals LP, Sanofi-Aventis; Fees for Non-CME Services
Received Directly from Commercial Interest of their Agents: AstraZeneca Pharmaceuticals LP, Sanofi-Aventis.
Dr Petrylak — Consulting Fees: Abbott Laboratories, Bristol-Myers Squibb Company, Celgene Corporation,
Cell Genesys Inc, Centocor Inc, Dendreon Corporation, Eli Lilly and Company, GPC Biotech Inc, Novartis
Pharmaceuticals, Roche Laboratories Inc, Sanofi-Aventis; Fees for Non-CME Services Received Directly from
Commercial Interest of their Agents: Sanofi-Aventis; Contracted Research: Abbott Laboratories, Cell Genesys Inc,
Eli Lilly and Company, GPC Biotech Inc, Sanofi-Aventis.
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U P C O M I N G E D U C AT I O N A L E V E N T S
Advances in Urology 2006
December 1-2, 2006
Atlanta, Georgia
Event email: [email protected]
AUA Annual Meeting
May 19-24, 2007
Anaheim, California
Event website: auanet.org
54th Annual James C Kimbrough Urological
Seminar
January 14-19, 2007
Houston, Texas
Event website: sgsu.org
2007 Prostate Cancer Symposium
February 22-24, 2007
Orlando, Florida
Event website: asco.org/prostate2007
ASCO 2007 Annual Meeting
June 1-5, 2007
Chicago, Illinois
Event website: asco.org
35th Annual American College of Surgeons
Meeting
April 22-25, 2007
Las Vegas, Nevada
Event website: facs.org
2
MEE T THE PRO FE S S O RS
SELECT EXCERPTS FROM CASE DISCUSSIONS
Editor’s Note
The driving force behind our CME group’s work has been the daily practice application of emerging clinical research data, and over the years, we have experimented
with various education platforms to meet these needs. One of the most successful
strategies has been to juxtapose physicians practicing in a community setting with
clinical investigators. For this issue, we asked four community-based urologists to
select challenging cases from their practices to present to Dr Judd Moul and Dr Dan
Petrylak. After this highly interesting meeting, I met individually for one-on-one
interviews with both faculty members to further explore their thoughts on the cases
they had just discussed. We hope you enjoy this adventure in cancer education and
appreciate your feedback.
— Neil Love, MD
[email protected]
CASE 1: A 62-year-old man who presented with a PSA of five ng/mL underwent
radical prostatectomy and had a pathologic Stage T2B, Gleason 7 (4 + 3) prostate
cancer with 40 to 50 percent involvement of the gland and a focal positive margin at
the anterior edge of the apex (from the practice of Alan M Nieder, MD)
Tracks 1-4
Track 1
Track 2
Introduction
Case discussion: A 62-year-old
man with Stage T1c, Gleason 7
prostate cancer
Track 3
Track 4
Management of focal positive
margins
Radiation therapy after prostatectomy for patients with positive
margins
Tracks 2-4
DR MOUL: I would observe this patient and repeat a PSA test every three
months for the first year, every six months for the next two years and then
annually thereafter. If the PSA stayed undetectable, I would leave him alone.
DR LOVE: Dan, can you review the evolution of clinical trial data evaluating
postprostatectomy radiation therapy, particularly the studies reported in the
last couple of years?
DR PETRYLAK: The most recent study was performed by the Southwest
Oncology Group. Patients were randomly assigned to immediate versus
deferred radiation therapy postprostatectomy. An improvement occurred in
disease-free survival but not overall survival. The problem with the study is
that the event rate in the control arm was a lot lower than originally antici3
pated. So with further follow-up, we may see a survival benefit in favor of the
postoperative radiation therapy.
DR LOVE: Dr Simon, you published a paper, based on your experience at the
University of Miami with Mark Soloway, examining the effect of positive
margins on outcome (Simon 2006). What did your study show?
DR SIMON: It included approximately 1,000 patients who underwent radical
prostatectomy and an average of five years of follow-up, assessing whether
positive margins led to increased recurrence rates (Simon 2006; [1.1]). In
general, a positive margin is an adverse prognostic factor, and it is a significant
variable in increasing risk for recurrence of disease.
However, the recurrence rates were still very low. Among our patients, the
recurrence rate for patients with positive margins during that five-year followup was only 19 percent. So 81 percent had no recurrence of cancer; therefore,
if they were all treated with radiation therapy, you’d be radiating 81 percent of
patients for no reason, with all the added side effects.
Positive margins are a significant prognostic factor that you have to discuss
with patients. However, following patients closely is certainly reasonable, and
you may avoid additional costs, treatments and side effects for a majority of the
patients, at least according to our series.
1.1
PSA Recurrence Rates After Radical Retropubic
Prostatectomy (RRP) and Positive Margins
“The finding of a positive margin after a cancer operation has generally been thought to
portend a poor prognosis. Our data suggest otherwise. Of the 350 patients with 1 or more
positive margins in our series only 67 (19%) had recurrence. Therefore, if all patients with
a positive margin were treated in adjuvant fashion, 81% would be treated unnecessarily
and subjected to potentially damaging side effects and loss of quality of life. Death from
prostate cancer is rare after radical prostatectomy. There have been only 2 deaths in our
series (1 of 936 or 0.2%) and 1 of these patients had a positive margin (1 of 350 or
0.3%).”
SOURCE: Simon MA et al. J Urol 2006;175(1):140-5. Abstract
DR MOUL: Dr Simon’s paper is a really good one with 1,000 patients, but it
points out that we’ve seen a stage migration even with positive margins. It’s
so frustrating. We have the SWOG positive-margin trial and the one from
Europe presented by Dr Bolla (Bolla 2005), but they’re probably out of date
because those were “rip-roaring” positive margins. Now we have these “itsybitsy” positive margins in many cases, with the recurrence rate at 19 percent.
DR PETRYLAK: The same can be said for the Messing study because of the
issue of positive lymph nodes (Messing 1999). There were probably more
grossly positive lymph nodes than what we’re seeing now, because of the stage
migration from PSA testing. The randomized SWOG-S9921 chemotherapy
study allows patients to receive postoperative radiation therapy. So this patient
4
would be eligible for that particular study.
DR LOVE:
What happened with this patient, Dr Nieder?
DR NIEDER: He recovered very well postoperatively, and we saw him after
six weeks for our first PSA test, which was undetectable. We decided just
to follow him, and we will follow his PSA level every three months. He’s
comfortable with that decision.
SELECT PUBLICATIONS
Blute ML et al. Anatomic site-specific positive margins in organ-confined prostate
cancer and its impact on outcome after radical prostatectomy. Urology 1997;50(5):733-9.
Abstract
Bolla M et al; European Organization for Research and Treatment of Cancer. Postoperative
radiotherapy after radical prostatectomy: A randomised controlled trial (EORTC trial
22911). Lancet 2005;366(9485):572-8. Abstract
Kamat AM et al. Identification of factors predicting response to adjuvant radiation
therapy in patients with positive margins after radical prostatectomy. J Urol
2003;170(5):1860-3. Abstract
Messing EM et al. Immediate hormonal therapy compared with observation after radical
prostatectomy and pelvic lymphadenectomy in men with node-positive prostate cancer.
N Engl J Med 1999;341(24):1781-8. Abstract
Obek C et al. Positive surgical margins with radical retropubic prostatectomy: Anatomic
site-specific pathologic analysis and impact on prognosis. Urology 1999;54(4):682-8.
Abstract
Simon MA et al. Prostate specific antigen recurrence rates are low after radical retropubic prostatectomy and positive margins. J Urol 2006;175(1):140-5. Abstract
CASE 2: A 53-year-old man with a history of colon cancer whose PSA level rose from
3.8 to 7.9 ng/mL in one year, with pathologic T3 Gleason 4 + 5 prostate cancer with
extracapsular extension, negative nodes, seminal vesicles and margins after nervesparing prostatectomy (from the practice of Michael A Simon, MD)
Tracks 1-8
Track 1
Track 2
Track 3
Track 4
Case discussion: A 53-year-old
man with Gleason 9 prostate
cancer and extracapsular
extension
High-volume versus low-volume
Gleason 9 disease
Hormonal therapy after radical
prostatectomy for high-risk
prostate cancer
Trials of chemotherapy in the
adjuvant setting
Track 5
Track 6
Track 7
Track 8
5
Combined androgen blockade
as adjuvant therapy after radical
prostatectomy
Role of postoperative radiation
therapy after radical prostatectomy
Incidence of sexual dysfunction
with postoperative radiation
therapy
PSA threshold for initiating
hormonal therapy
Tracks 1-8
DR MOUL: Without question, he will need something beyond radical prostatectomy. I would try to get him onto SWOG-S9921, on which he’d be
randomly assigned to two years of combined hormonal therapy or two years of
hormones and mitoxantrone-based chemotherapy.
Some would argue that if he doesn’t want to go on the trial, you could use
two years of complete hormonal therapy. He’s only 53 and probably wants to
maintain his libido. This might be a patient for whom you would consider
adjuvant bicalutamide. The high-risk pT3 patients in the trials seemed to
benefit from two years of adjuvant bicalutamide.
DR PETRYLAK: He is an excellent candidate for SWOG-S9921, and a second
study, evaluating docetaxel, is being opened nationally and internationally.
The docetaxel study is very similar to the SWOG study, but the question of
early versus delayed therapy is being addressed.
Patients receive immediate hormones or chemotherapy with hormones versus
delayed hormones or chemotherapy with hormones at the time of PSA
progression. The androgen deprivation used is combined blockade.
We don’t know whether starting the hormones at the first rise in PSA level is
the same or worse than starting the hormones immediately. For a 53-year-old
patient like this, you consider maintenance of sexual function as well as the
long-term chronic effects of hormones on bone mineral density and muscle
mass. It’s difficult without the actual data to make any real conclusions.
DR MOUL: If a patient is not concerned about hormonal therapy side effects
and is not interested in a protocol, I have no qualms about putting him on
a year or two of complete hormonal therapy adjuvantly, in the immediate
postoperative period. I don’t do it routinely, but if this is truly Gleason 9
disease, it probably is systemic disease. If he wants something done, it wouldn’t
be wrong to give him a year or two of complete hormonal therapy.
DR PETRYLAK: I agree with Judd on the issue of early hormone therapy.
It’s very reasonable to consider a year or two of combined blockade. The
chemotherapy issue is somewhat more problematic because of the possibility
of toxic deaths.
In the rare cases in which patients absolutely insist on chemotherapy, I always
raise the issue that you can potentially die from neutropenia or neutropenic
sepsis. I’m a little less inclined to give patients off-protocol treatment. Again,
we also don’t know how this will affect the disease in the long term.
DR LOVE: What is your threshold to treat PSA-only disease? What would it
take for you to initiate endocrine therapy, Dan?
DR PETRYLAK: If I started seeing a rapid doubling time or if it started getting
up into the range of an absolute value of two to three ng/mL, I would treat.
DR MOUL:
We’re all biased by the fact that this patient had Gleason 9 disease.
6
Any jump in PSA level is likely to be real. However, I agree with Dan. The
key would be trying to follow PSA velocity. In this case, we were arguing
back and forth about whether we wanted to use two years of hormone right
from the get-go with an undetectable PSA. You might “pull the trigger”
quicker with this patient than you would with another.
SELECT PUBLICATIONS
Bolla M et al. Improved survival in patients with locally advanced prostate cancer
treated with radiotherapy and goserelin. N Engl J Med 1997;337(5):295-300. Abstract
Crawford ED. Early versus late hormonal therapy: Debating the issues. Urology
2003;61(2 Suppl 1):8-13. Abstract
Loblaw DA et al. American Society of Clinical Oncology recommendations for the initial
hormonal management of androgen-sensitive metastatic, recurrent, or progressive
prostate cancer. J Clin Oncol 2004;22(14):2927-41. Abstract
Messing E. The timing of hormone therapy for men with asymptomatic advanced
prostate cancer. Urol Oncol 2003;21(4):245-54. Abstract
Messing EM et al. Immediate hormonal therapy compared with observation after radical
prostatectomy and pelvic lymphadenectomy in men with node-positive prostate cancer.
N Engl J Med 1999;341(24):1781-8. Abstract
Walsh PC et al. A structured debate: Immediate versus deferred androgen suppression in
prostate cancer — Evidence for deferred treatment. J Urol 2001;166(2):508-15. Abstract
Wirth MP et al; Casodex Early Prostate Cancer Trialists’ Group. Bicalutamide 150 mg in
addition to standard care in patients with localized or locally advanced prostate cancer:
Results from the second analysis of the early prostate cancer program at median followup of 5.4 years. J Urol 2004;172(5 Pt 1):1865-70. Abstract
CASE 3: A 50-year-old man with an abnormal DRE (slightly indurated left lobe), a
PSA level of 0.2 ng/mL with 1/12 positive cores (one percent) and Gleason 6 prostate
cancer (from the practice of Richard Davi, MD)
Tracks 1-6
Track 1
Track 2
Track 3
Case discussion: A 50-year-old
man with PSA at 0.2 ng/mL and
small volume disease
Rationale for biopsy of patients
with a low PSA level
Watchful waiting for patients with
a small volume disease
Track 4
Track 5
Track 6
Incidence and challenges of
nonsignificant prostate cancer
Watchful waiting for patients with
low-risk disease
Role of dietary modification and
vitamins for patients on watchful
waiting
Tracks 1-6
DR MOUL: This patient has a very small volume of disease. Ninety to 95
percent of urologists would say he should undergo a radical prostatectomy.
Laury Klotz, Bal Carter or even Peter Carroll would probably try to teach us
that we should not look at him as age 50 but rather as a patient with extremely
small-volume prostate cancer, and we should offer him watchful waiting. He
7
would end up with a radical prostatectomy in my practice because he would
be “freaking out” and wouldn’t tolerate a watch-and-wait approach.
DR LOVE: Dr Davi, was it your assessment that this patient could have tolerated a watch-and-wait approach emotionally?
DR DAVI: I didn’t think so, especially with his wife crying and saying, “Let’s
do something.” I leaned strongly toward the radical prostatectomy.
DR LOVE:
Dan, what would you have suggested?
DR PETRYLAK: I believe you can offer him all modalities, including watchful
waiting, but the practicality of this patient undergoing watchful waiting is low
based on what you’re saying about his family situation.
DR NIEDER: I used to think watchful waiting was for 75-year-old men with
lots of comorbidities, who were likely going to die from some other disease
manifestation.
When I think about a 50-year-old healthy guy with very low-volume disease
and favorable parameters, I believe it would be reasonable to rebiopsy him in a
year. If he had truly very low-volume, low-grade disease, maybe the abnormal
DRE was driven by prostatitis or some other factor besides a bulky tumor. If
the volume and the Gleason score were still the same, it wouldn’t be unreasonable to keep following him like that.
He still has cancer, but it’s clearly not life-threatening cancer. You might be
able to hold off on a prostatectomy or radiotherapy for five years or so.
DR MOUL: The problem is that we’ve opened Pandora’s box. The patient and
family are extremely concerned about the “C” word. We know from Wael
Sakr’s study (Sakr 1993, 1996) that at 50, a man has a 30 to 35 percent chance
of having autopsy prostate cancer, yet most of those men never die of prostate
cancer.
From an academic standpoint, you may have found autopsy prostate cancer, but
from a practical standpoint, you’re dealing with a guy who knows he has cancer.
DR TRIPP: I have a completely different take on this, and I have a similar
patient in my practice. We’re watching him, and he’s highly anxious. We
had the exact same conversation on autopsy cancers — studies show that 30
percent of patients at the age of 50 have cancer, but is that the same cancer
that we’re discussing?
I don’t know if I agree that this gentleman has cancer. Obviously, he has
several glands that have cancer, but what is the significance of it? I did exactly
what Dr Nieder suggested. I waited a year and did another 12 biopsies, which
were completely normal. So I have 23.9 biopsies out of 24 that are completely
benign. We’ll probably take another biopsy in the next year or two — his PSA
has been stable — to see exactly where we are and whether he has cancer.
DR LOVE: I was intrigued by the follow-up with this patient and what
actually happened with him.
8
DR DAVI: His sexual functioning was important to him, because he was only
50 years old. After I provided him with all of the treatment options, I suggested
that he see a very well-known urologist in Maryland to get a second opinion.
The urologist wasn’t certain that this was, in fact, cancer, so he had his pathologist confirm the diagnosis. He recommended the patient have a PSA and
rectal examination every six months and a biopsy every year. At that point, he
seemed comfortable with that strategy, and I was also.
DR LOVE:
Judd, any closing comments?
DR MOUL: Bal Carter has the prospective watchful waiting study at Johns
Hopkins, and I don’t know if that’s the particular urologist he saw, but it’s a
great academic study for patients like this man. The most significant issue is
the psychological well-being of the patient. Can he and his family accept this
active surveillance approach?
We did several studies evaluating the outcome of watchful waiting when I was
in the military. The dropout rate for men under age 70 was almost 75 percent
at five years. So, if that study holds, this man would probably have about a
25 percent chance of being maintained on active surveillance five years from
now. On the other hand, if they educated him and counseled him properly,
perhaps his chance of dropping out would be less.
SELECT PUBLICATIONS
Bill-Axelson A et al; Scandinavian Prostate Cancer Group Study No. 4. Radical prostatectomy versus watchful waiting in early prostate cancer. N Engl J Med 2005;352(19):1977-84.
Abstract
Holmberg L et al; Scandinavian Prostatic Cancer Group Study Number 4. A randomized trial
comparing radical prostatectomy with watchful waiting in early prostate cancer. N Engl
J Med 2002;347(11):781-9. Abstract
Sakr WA et al. Age and racial distribution of prostatic intraepithelial neoplasia. Eur Urol
1996;30(2):138-44. Abstract
Sakr WA et al. The frequency of carcinoma and intraepithelial neoplasia of the prostate
in young male patients. J Urol 1993;150(2 Pt 1):379-85. Abstract
Steineck G et al; Scandinavian Prostatic Cancer Group Study Number 4. Quality of life after
radical prostatectomy or watchful waiting. N Engl J Med 2002;347(11):790-6. Abstract
CASE 4: An 84-year-old man who underwent external beam radiation therapy 10
years ago for Gleason 7 prostate cancer and was treated with an LHRH agonist and
then MAB therapy for PSA recurrences. Currently, he has bone metastases, with a
PSA of 50 ng/mL, and he is receiving docetaxel and prednisone for bone pain (from
the practice of Dr Nieder)
9
Tracks 1-5
Track 1
Track 2
Track 3
Future directions in immune
therapy of prostate cancer
Track 5 Benefit of input from medical
oncologists in management of
prostate cancer
Case discussion: An 84-year-old
man with hormone-refractory
metastatic prostate cancer
Symptom improvement
associated with docetaxel
Side effects of docetaxel
Track 4
Tracks 1-5
DR LOVE:
How did this older man tolerate the docetaxel?
DR NIEDER:
He did relatively well. He looks relatively robust and feels okay.
DR LOVE: Dan, what do we know about the ability of chemotherapy, particularly the docetaxel regimens, to relieve tumor-related symptoms?
DR PETRYLAK: Bone pain improved in both large randomized studies of
docetaxel. It was more pronounced in the TAX-327 study, which showed
significant improvement in bone pain compared to mitoxantrone and prednisone (1.2, 1.3).
We didn’t see it in the SWOG study, but the experimental arm did not have
prednisone. So it’s a little bit of an unfair comparison. Nonetheless, there is a
better palliation of bone pain with docetaxel and prednisone versus mitoxantrone and prednisone.
DR LOVE: In patients with measurable disease, how often do you see objective
tumor shrinkage?
DR PETRYLAK: In the SWOG study and the TAX-327 study, it was in the
range of 15 percent — a little bit lower than what we had seen in our Phase II
experience. But we do see objective responses.
DR LOVE: Judd, another interesting aspect to this case was that he had PSA
progression on an LHRH agonist. The PSA further decreased when bicalutamide was added. How often do you see that, and what do you think the
implications are?
DR MOUL: The literature more strongly supports using MAB up front and
then withdrawing the oral anti-androgen when the patient progresses. In this
case, they used the LHRH at the beginning and added the anti-androgen
when he progressed.
Many urologists do that. If you evaluate the data on objective progression
rates, you’re better off using MAB up front and then pulling it away, to save
you money later. My argument would be if you’re going to use MAB, use it
up front and then pull the anti-androgen away if the patient progresses.
DR PETRYLAK: An interesting question is, “When is the optimal time to
administer chemotherapy to these patients?” Clearly, in this case, the chemo10
therapy was administered when the patient was symptomatic. Can you achieve
a better response with these patients using docetaxel earlier? We really don’t
know the answer to that question.
I think the best way to think about this is using an analogy to baseball. You
can use your best pitcher in the first couple of innings of the game and then
move other pitchers in as needed, or you can save your best pitcher for later
and try more experimental approaches to begin with.
I’ve treated a 92-year-old with chemotherapy, and he’s lived three years with
a good quality of life. I think every patient with metastasis really should be
offered this. It’s up to them to decide whether it’s appropriate. If the oncologist
is experienced in administering the treatments and knows when to push and
when not to push, I believe the patient certainly can benefit.
1.2
Quality of Life Improvements with Docetaxel/Prednisone
“The percentage of patients who had an improvement in the quality of life was similar in
the two docetaxel groups (22 percent in the group given docetaxel every three weeks and
23 percent in the group given weekly docetaxel) and significantly higher than that in the
mitoxantrone group (13 percent; P=0.009 and P=0.005, respectively)...
The greatest benefit in the docetaxel groups was in the subscale representing prostatespecific concerns (including weight loss, appetite, pain, physical comfort, and bowel and
genitourinary function).”
SOURCE: Tannock IF et al; TAX 327 Investigators. N Engl J Med 2004;351(15):1502-12. Abstract
1.3
Randomized Trials Comparing a Docetaxel-Containing Regimen
to Mitoxantrone/Prednisone in Hormone-Refractory
Metastatic Prostate Cancer
SWOG-S99161
Median survival
TAX-3272*
D+E
(n = 338)
M+P
(n = 336)
D q3wk
(n = 332)
D qwk
(n = 330)
M
(n = 335)
17.5 mo
15.6 mo
18.9 mo
17.4 mo
16.5 mo
Survival†
36%
30%
50%
43%
40%
PSA response rate
(≥50 percent decline)
50%
27%
45%
48%
32%
Partial response rate
17%
11%
12%
8%
7%
Decreased pain
—
—
35%
31%
22%
Increased
quality of life
—
—
22%
23%
13%
D = docetaxel; E = estramustine; M = mitoxantrone; P = prednisone
* All patients in TAX-327 received prednisone in addition to chemotherapy.
†
Median follow-up 32 months for SWOG-S9916 and 20.7 months for TAX-327
SOURCES: 1 Petrylak DP et al. N Engl J Med 2004;351(15):1513-20. Abstract
2
Tannock IF et al; TAX 327 Investigators. N Engl J Med 2004;351(15):1502-12. Abstract
11
SELECT PUBLICATIONS
Armstrong AJ, Carducci MA. Chemotherapy for advanced prostate cancer: Results of new
clinical trials and future studies. Curr Oncol Rep 2005;7(3):220-7. Abstract
Berry W, Eisenberger M. Achieving treatment goals for hormone-refractory prostate
cancer with chemotherapy. Oncologist 2005;10(Suppl 3):30-9. Abstract
Berthold DR et al. Management of advanced prostate cancer after first-line chemotherapy. J Clin Oncol 2005;23(32):8247-52. Abstract
Bill-Axelson A et al; Scandinavian Prostate Cancer Group Study No. 4. Radical prostatectomy versus watchful waiting in early prostate cancer. N Engl J Med 2005;352(19):1977-84.
Abstract
Chodak GW, Warren KS. Watchful waiting for prostate cancer: A review article. Prostate
Cancer Prostatic Dis 2006;9(1):25-9. Abstract
Donohue KM, Petrylak DP. Chemotherapy agents and timing of chemotherapy in
prostate cancer management. Curr Urol Rep 2005;6(3):224-7. Abstract
Gilbert DC, Parker C. Docetaxel for the treatment of prostate cancer. Future Oncol
2005;1(3):307-14. Abstract
Gleave M, Kelly WK. High-risk localized prostate cancer: A case for early chemotherapy.
J Clin Oncol 2005;23(32):8186-91. Abstract
Hainsworth JD et al. Weekly docetaxel/estramustine phosphate in patients with
increasing serum prostate-specific antigen levels after primary treatment for prostate
cancer: A Phase II trial of the Minnie Pearl Cancer Research Network.
Clin Genitourin Cancer 2006;4(4):287-92. Abstract
Holmberg L et al; Scandinavian Prostatic Cancer Group Study Number 4. A randomized trial
comparing radical prostatectomy with watchful waiting in early prostate cancer.
N Engl J Med 2002;347(11):781-9. Abstract
Kibel AS. An interdisciplinary approach to treating prostate cancer. Urology 2005;65(6
Suppl):13-8. Abstract
Kirby R. Management of clinically localized prostate cancer by radical prostatectomy
followed by watchful waiting. Nat Clin Pract Urol 2005;2(6):298-303. Abstract
Klotz L. Active surveillance with selective delayed intervention for favorable risk
prostate cancer. Urol Oncol 2006;24(1):46-50. Abstract
Klotz L. Active surveillance for prostate cancer: For whom? J Clin Oncol 2005;23(32):81659. Abstract
Michels J et al. First- and second-line chemotherapy with docetaxel or mitoxantrone in
patients with hormone-refractory prostate cancer: Does sequence matter?
Cancer 2006;106(5):1041-6. Abstract
Petrylak DP et al. Evaluation of prostate-specific antigen declines for surrogacy in
patients treated on SWOG 99-16. J Natl Cancer Inst 2006;98(8):516-21. Abstract
Petrylak D. Therapeutic options in androgen-independent prostate cancer: Building on
docetaxel. BJU Int 2005;96(Suppl 2):41-6. Abstract
Petrylak DP et al. Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. N Engl J Med 2004;351(15):1513-20. Abstract
Pienta KJ, Smith DC. Advances in prostate cancer chemotherapy: A new era begins.
CA Cancer J Clin 2005;55(5):300-18. Abstract
Ryan CJ, Eisenberger M. Chemotherapy for hormone-refractory prostate cancer: Now it’s
a question of “when?”. J Clin Oncol 2005;23(32):8242-6. Abstract
Tannock IF et al; TAX 327 Investigators. Docetaxel plus prednisone or mitoxantrone plus
prednisone for advanced prostate cancer. N Engl J Med 2004;351(15):1502-12. Abstract
Walsh PC. Radical prostatectomy versus watchful waiting in early prostate cancer. J Urol
2005;174(4 Pt 1):1291-2. No abstract available
12
CASE 5: A 71-year-old man with a PSA rising from five to 18.1 ng/mL in the year
prior to diagnosis of Gleason 6-7 prostate cancer, with 9/13 positive cores (85
percent) and DRE abnormal bilaterally. Bone and CT scans were negative (from the
practice of Benjamin M Tripp, MD)
Tracks 1-11
Track 1
Track 2
Track 3
Track 4
Track 5
Track 6
Case discussion: A 71-yearold man with high-risk prostate
cancer
Treatment options for patients
with high-risk disease
Difference in quality of life on
androgen deprivation therapy and
bicalutamide monotherapy
Side effects of androgen
deprivation therapy
Clinical use of bicalutamide
monotherapy
Adverse effects associated with
bicalutamide monotherapy
Clinical use of therapies without
definitive clinical trial data
Track 8 Cardiovascular morbidity in
patients receiving androgen
deprivation therapy
Track 9 Use of PSA and PSA doubling
time to determine treatment
approach
Track 10 Challenges of accruing patients to
clinical trials in prostate cancer
Track 11 Tolerability of single-agent
docetaxel
Track 7
Tracks 1-11
DR MOUL: This is an interesting case. He had a high PSA velocity the year
before diagnosis. We now know that this rapid doubling time is a poor
prognostic factor. Clinically, this is probably T2b/T2c disease, but realistically,
he probably had T3 disease and a negative metastatic workup.
He’s a healthy individual with no other comorbidities. My favored approach
would be radical prostatectomy. However, in fairness to our colleagues in
radiation oncology, he is more than 70 years old and he probably has locally
advanced disease.
I suspect if he had a family member who was a radiation oncologist, they
would probably lean toward a combination of external beam radiation therapy
and two to three years of hormonal therapy.
The role of brachytherapy with external beam radiation therapy is controversial, but certainly it should be mentioned, along with some form of hormonal
therapy for a period of time.
DR PETRYLAK: He’s an active, vigorous, healthy man, with a rapid increase
in PSA velocity. I believe he will eventually get into trouble because his life
span may be another 10 or 15 years. This is a common dilemma: How do you
approach a patient who is potentially at high risk?
Radical prostatectomy is the one way to conclusively stage this case, with the
caveat that this patient should strongly consider a high-risk adjuvant protocol,
13
such as SWOG-S9921 — a randomized trial of two years of hormones versus
two years of hormones with mitoxantrone and prednisone.
DR LOVE:
Dr Tripp, can you follow up on what happened with the patient?
DR TRIPP: He was treated with external beam radiation therapy, IMRT
and a boost with seed implants. In addition, an initial decision was made
to administer a total of three years of hormonal therapy — the first year he
received leuprolide, and during the last two years we changed to bicalutamide
monotherapy.
A huge difference in his quality of life occurred between the first year and the
second and third years of treatment. During the first year — while receiving
the LHRH agonist — the patient gained 25 to 30 pounds, his exercise tolerance was severely impaired and his sexual functioning and interest were nil.
He really had a tough year, with depression, anxiety and the other changes in
his life.
We changed to bicalutamide after one year. Remarkably, within three or
four months, he shed his weight and his energy level, sense of well-being and
sexual functioning were much better. The improvement in quality of life was
dramatic. He received external beam radiation therapy for breast tenderness
and enlargement and responded well.
DR LOVE:
Judd, what are your thoughts about this strategy?
DR MOUL: I want to applaud Dr Tripp and his colleagues’ multimodality
approach to this patient at high risk. This patient was treated with a twist on
the Bolla trial (Bolla 1997).
The patient received radiation therapy, although as opposed to external beam,
only his local dose was increased with the implant. Then, “á la Bolla,” he
would have received three years of hormonal therapy, but for this patient it
was adjusted nicely to improve his quality of life.
DR PETRYLAK: He was having severe difficulty after his first year. Obviously,
you want to cure the patient, but you want a reasonable quality of life. In that
he couldn’t tolerate androgen blockage, I believe it was reasonable to try the
next best step — peripheral blockade with bicalutamide.
SELECT PUBLICATIONS
Benecchi L. PSA velocity and PSA slope. Prostate Cancer Prostatic Dis 2006;[Epub ahead of
print]. Abstract
Bolla M et al. Improved survival in patients with locally advanced prostate cancer
treated with radiotherapy and goserelin. N Engl J Med 1997;337(5):295-300. Abstract
Chodak GW, Warren KS. Watchful waiting for prostate cancer: A review article. Prostate
Cancer Prostatic Dis 2006;9(1):25-9. Abstract
D’Amico AV et al. Identifying patients at risk for significant versus clinically insignificant postoperative prostate-specific antigen failure. J Clin Oncol 2005;23(22):4975-9.
Abstract
D’Amico AV et al. Pretreatment PSA velocity and risk of death from prostate cancer
following external beam radiation therapy. JAMA 2005;294(4):440-7. Abstract
14
D’Amico AV et al. Preoperative PSA velocity and the risk of death from prostate cancer
after radical prostatectomy. N Engl J Med 2004;351(2):125-35. Abstract
Kaisary AV. Evaluating the use of early hormonal therapy in patients with localised or
locally advanced prostate cancer. Prostate Cancer Prostatic Dis 2005;8(2):140-51. Abstract
Kirby R. Locally advanced prostate cancer treated with radiotherapy and androgen
deprivation. Nat Clin Pract Urol 2005;2(6):304-8. Abstract
Kirby R. Management of clinically localized prostate cancer by radical prostatectomy
followed by watchful waiting. Nat Clin Pract Urol 2005;2(6):298-303. Abstract
Klotz L, Schellhammer P. Combined androgen blockade: The case for bicalutamide.
Clin Prostate Cancer 2005;3(4):215-9. Abstract
Lee AK, D’Amico AV. Utility of prostate-specific antigen kinetics in addition to clinical
factors in the selection of patients for salvage local therapy. J Clin Oncol 2005;23(32):81927. Abstract
Sengupta S et al. Preoperative prostate specific antigen doubling time and velocity are
strong and independent predictors of outcomes following radical prostatectomy. J Urol
2005;174(6):2191-6. Abstract
Ward JF. Can PSA velocity serve as a surrogate endpoint in trials of hormone-refractory, metastatic prostate cancer? Nat Clin Pract Urol 2006;3(6):310-1. No abstract available
15
INTERVIEW
Judd W Moul, MD
Dr Moul is Professor and Chief of the Division of Urologic
Surgery at Duke University Medical Center in Durham,
North Carolina.
Tracks 1-12
Track 1
Track 2
Track 3
Track 4
Track 5
Track 6
Track 7
Potential role of chemotherapy
in the treatment of PSA-only,
hormone-refractory disease
Track 9 Case discussion: A 42-year-old
man treated with preoperative
docetaxel and hormonal therapy
Track 10 Cryotherapy and high-intensity
focused ultrasound
Track 11 Viral etiology associated with
prostate cancer
Track 12 Current controversies in the
management of prostate cancer
Introduction
Use of PSA velocity in screening
for prostate cancer
Potential role of biomarkers in the
diagnosis of prostate cancer
Disease management for patients
with PSA-only progression
Robotic versus open prostatectomy
Importance of experience in the
quality of robotic prostatectomies
Efficacy and tolerability of
docetaxel
Track 8
Select Excerpts from the Interview
Track 2
DR LOVE: Would you summarize what we know about PSA velocity
and prognosis?
DR MOUL: We’re now 15 years into the PSA era. At the beginning, it
was easy — we got the “low-hanging fruit.” Many patients had these big,
“whopping” PSAs, and it was easy to diagnose prostate cancer. As we’ve
moved through the PSA era, it has become more difficult and more controversial.
For example, Dr Tom Stamey, who’s contributed a tremendous amount to our
field and to the use of PSA, came out two years ago and basically said that
PSA was no good (Stamey 2004). That incident set the field on edge. The
reality is that PSA is still the best marker we’ve ever had, but it certainly isn’t
perfect, and we have to use it in a smarter way as we move further and further
into the PSA era.
With that background, we tried to see if the rate of change of PSA was more
16
predictive of prostate cancer than PSA itself. Most men that we see now
already know their PSA level. They’ve seen their primary care doctor or their
internist or even their urologist, and they have had a series of PSA tests. So
can we look at that change to predict prostate cancer?
The bottom line — with a large data set including men of various ages — is
that the rate of PSA change with or without cancer is different for younger
men than for older men. Younger men have a lower slope for their PSA
— slower-rising PSA levels.
Those subtle rises in young men are more predictive of prostate cancer because
BPH isn’t as common and there isn’t as much prostatitis in this group. Fewer
confounding conditions are present. We’re finding that if you measure PSA at
40 to 59 years of age — in that 20-year time span for a man — a change in
PSA of more than about a half a point per year is predictive of prostate cancer.
The reason that’s important is that 14 years ago, Bal Carter from Johns
Hopkins was the first person to propose PSA velocity as a screening tool for
prostate cancer (Carter 1992). Bal said that if a patient’s PSA level increased
more than about three quarters of a point per year, that was a red f lag for
prostate cancer.
We’re finding that Bal’s data do hold for older men, but for younger men in
their forties and fifties, it’s probably more appropriate to use a slightly lower
cut point for PSA velocity, to the tune of about 0.4 to 0.6 ng/mL. We’re
fine-tuning this right now in an effort to produce something that’s easy to
remember so doctors in the trenches can use it.
2.1
Baseline PSA as a Predictor of Prostate Cancer Risk in Younger Men
“In men younger than 60, a baseline PSA value between the age-specific median and
2.5 ng/mL was a significant predictor of later CaP and was associated with a significantly
greater PSA velocity. A young man’s baseline PSA value was a stronger predictor of CaP
than family history, race, or suspicious digital rectal examination findings. A greater
baseline PSA level was associated with significantly more adverse pathologic features and
biochemical progression.”
SOURCE: Loeb S et al. Urology 2006;67(2):316-20. Abstract
Track 4
DR LOVE: Would you summarize some of the key current issues in PSAonly recurrence?
DR MOUL: PSA recurrence or PSA progression continues to be a controversial
topic. From a clinical standpoint, for the average urologist in the trenches, the
$64,000 question is about the patient who has a rising PSA level after surgery
or radiation therapy. When do you “pull the trigger” on hormones?
The answer remains controversial. Our data from 2004 indicated that you
17
certainly couldn’t be criticized for starting hormonal therapy early for men at
high risk, such as those with a rapid PSA doubling time or those with higher
Gleason scores, because they’re not going to do well with watchful waiting
(D’Amico 2004).
More recently, Steve Freedland, who recently joined us at Duke, published
a nice paper in JAMA (Freedland 2005), in which he examined the Johns
Hopkins data set (2.2). It was actually a follow-up to the Pound paper (Pound
1999). The bottom line was that Steve created a nomogram, which showed
10-year mortality after PSA recurrence.
In other words, he evaluated patients who had a biochemical recurrence after
surgery and then asked what the chances were of dying from prostate cancer
10 years later. He found that PSA doubling time, Gleason score and time of
PSA recurrence (ie, earlier versus later than three years after the surgery) were
good predictors of death from prostate cancer.
The good news is that we can predict who will die of prostate cancer. The
bad news is that we’re still not sure if we can alter the natural history if we put
those patients on hormonal therapy.
Combining the data from Steve Freedland’s paper with those of our paper
from the military would suggest that using hormonal therapy for those highrisk PSA recurrences is reasonable, but we need a randomized trial to address
the question.
2.2
Factors Predictive of Prostate Cancer-Specific Death After
Biochemical Recurrence Following Radical Prostatectomy in a
Retrospective Cohort of 379 Men from a Single Tertiary Care Center
Variable
HR*
95% CI
p-value
PSA doubling time
<3 months
3 to 8.9 months
9 to 14.9 months
27.48
8.76
2.44
10.66 to 70.85
3.74 to 20.50
0.88 to 6.81
<0.001
<0.001
0.09
Years to recurrence
≤3 vs >3 years
3.53
1.59 to 7.84
0.002
Gleason score
≥8 vs <8
2.26
1.35 to 3.77
0.002
* HR = hazard ratio for time to death from prostate cancer
SOURCE: Freedland SJ et al. JAMA 2005;294(4):433-9. Abstract
Track 5
DR LOVE: Would you comment on robotic versus open radical
prostatectomy?
DR MOUL:
Robotic prostatectomy seems to be one of the most controver18
sial areas in urologic oncology right now for the average urologist. To set the
stage, the robotic prostatectomy came on the scene about three years ago.
From a marketing standpoint, it really caught on. Every hospital feels it has to
have the robot to “keep up with the Joneses” — the hospital down the street.
Nevertheless, the outcome comparisons between robotic prostatectomy and
what I still consider the gold standard — open radical prostatectomy through a
small, low, midline incision — have not demonstrated better outcomes with the
robotics (Tewari 2006). In fact, no good outcome studies have evaluated this.
We’re desperately trying to do that at Duke. It’s not a randomized study;
however, we’re trying to get all the patients who undergo either type of
surgery to fill out thorough quality-of-life instruments before the surgery and
then periodically over the first two years. So far, we’re not demonstrating any
statistically significant benefits in using the robot, except for lower blood loss
with no difference in transfusion rates. For those men who have strenuous,
physical-labor type jobs, the robotic surgery might confer about a five- to
seven-day benefit in the ability to return to full activity.
Other than that, we haven’t proved the difference in potency rates, and we
haven’t proved a difference in continence rates. We haven’t shown a difference
in hospital stay, but we’ve definitely shown a difference in cost. The robotic
surgery is a tremendously more expensive procedure for our country and our
healthcare system. The disposables associated with its use add to the cost, and
the operating room time alone — even in the best of hands — adds an hour to
an hour and a half to an open prostatectomy.
Track 8
DR LOVE: Do you believe the use of docetaxel chemotherapy has a role
in the treatment of patients who have PSA-only disease and are hormone
refractory?
DR MOUL: Honestly, I don’t know. PSA-only, hormone-refractory prostate
cancer is one of the hot topics in the field. In the PSA era, patients with PSA
recurrence were put on hormones. They had a negative bone scan and then
had a rising PSA level and still had a negative bone scan.
It is interesting that you bring that up because I’m trying to reevaluate that
issue using our database. When I was at Walter Reed, we made a first-pass
effort observing the natural history of that issue (Chen 2004). The bottom
line was that survival was much longer among those men than among the
traditional patients with hormone-refractory prostate cancer — to the tune
of about a five-year survival versus two to three years for the men with more
traditional hormone-refractory metastatic disease.
SELECT PUBLICATIONS
Carter HB et al. Longitudinal evaluation of prostate-specific antigen levels in men with
and without prostate disease. JAMA 1992;267(16):2215-20. Abstract
19
Chen Y et al. Contemporary experience with hormone refractory prostate cancer
(HRPC-Stage D3) in the PSA-era: Report from the DOD CPDR National Database.
Proc AUA 2004;Abstract 446.
D’Amico AV et al. Prostate specific antigen doubling time as a surrogate end point for
prostate cancer specific mortality following radical prostatectomy or radiation therapy.
J Urol 2004;172(5 Pt 2):42-6. Abstract
Freedland SJ et al. Risk of prostate cancer-specific mortality following biochemical
recurrence after radical prostatectomy. JAMA 2005;294(4):433-9. Abstract
Loeb S et al. Baseline prostate-specific antigen compared with median prostate-specific
antigen for age group as predictor of prostate cancer risk in men younger than 60 years
old. Urology 2006;67(2):316-20. Abstract
Pound CR et al. Natural history of progression after PSA elevation following radical
prostatectomy. JAMA 1999;281(17):1591-7. Abstract
Stamey TA et al. The prostate specific antigen era in the United States is over for
prostate cancer: What happened in the last 20 years? J Urol 2004;172(4 Pt 1):1297-301.
Abstract
Tewari A et al. Robotic prostatectomy: A pooled analysis of published literature.
Expert Rev Anticancer Ther 2006;6(1):11-20. Abstract
20
INTERVIEW
Daniel P Petrylak, MD
Dr Petrylak is Associate Professor of Medicine and
Director of the Genitourinary Oncology Program
at Columbia Presbyterian Medical Center in
New York, New York.
Tracks 1-4
Track 1
Track 2
Introduction
Case discussion: A 46-year-old
man with PSA-only, hormonerefractory disease
Track 3
Track 4
Chemotherapy for PSA-only
disease
Clinical use of intermittent
androgen therapy
Select Excerpts from the Interview
Tracks 2-3
DR LOVE: Would you present a patient from your practice who exemplifies the challenges of using chemotherapy for prostate cancer?
DR PETRYLAK: Sure. This is a 46-year-old man who had a radical prostatectomy four years ago with lymph node-positive Gleason 9 disease.
He underwent maximal androgen blockade, and approximately nine months
ago, he started having a rising PSA level. We withdrew bicalutamide and
started him on ketoconazole and cortisone, and he had a short response that
lasted four or five months. Now his PSA level is rising again. In fact, it rapidly
rose from about six or seven to 50 ng/mL in a four-week period and then to
70 ng/mL after another two weeks.
DR LOVE:
Why did you decide to treat him initially with maximal androgen
blockade?
DR PETRYLAK: In his situation, it was clearly supported by the Messing study,
in which early hormone therapy was better than delayed hormone therapy. It
came at the cost of losing his sexual function, but he wanted to live and he
wanted to see his son grow up.
DR LOVE:
How did he tolerate the androgen deprivation?
DR PETRYLAK: He tolerated it very well, with minimal hot f lashes, and he
gained only five pounds over the last couple of years.
21
DR LOVE:
What convinces you that combined blockade is “state of the art”?
DR PETRYLAK: When you look at the meta-analysis, you see a small —
approximately four percent — but detectable difference in survival in favor
of combined blockade. Other therapeutic interventions have been done for
similar benefit, and I believe it’s appropriate.
DR LOVE: So this patient was hormone refractory, although he still had PSAonly disease?
Correct. Based on this rapid PSA doubling, I was not comfortable with just waiting and watching until he developed metastatic disease. So
I started him on docetaxel, 75 mg/m 2 every three weeks as a single agent. He
has just completed his second cycle, so it’s too early to tell how well he will
respond, but he is tolerating it very well.
DR PETRYLAK:
DR LOVE: What are your thoughts about the use of chemotherapy for PSAonly disease?
DR PETRYLAK: We need to be selective. We don’t have trials to determine the
best time to use chemotherapy.
An interesting study that has come out over the last several years was done
by Matt Smith, in which he analyzed PSA doubling times and absolute PSA
values in relationship to the development of bone metastases in asymptomatic patients with a rising PSA. Only about a third of those patients eventually — at least in the time frame he analyzed — developed metastatic disease
(Smith 2005).
The most important prognostic factors for the development of metastatic
disease were a PSA doubling time of less than 6.3 months and an absolute PSA
value greater than 24 ng/mL (Smith 2005). But, again, we don’t know if those
are the patients who would benefit from early therapy.
DR LOVE: Do we know anything about the impact of chemotherapy, specifically docetaxel, in PSA-only disease?
DR PETRYLAK: We know we’ll see the PSA decline, but whether we can
delay the development of bone metastases is unclear at this point.
DR LOVE: What do you say to your patients about what to expect in terms of
the side effects and toxicity from docetaxel?
DR PETRYLAK: The major side effects are neutropenia, numbness in the
fingers and toes, edema, lacrimation and fatigue. I tell patients that they may
develop some of these side effects or no side effects whatsoever. We can also
sequence their treatment such that their most difficult day as far as fatigue is
concerned winds up on the weekend rather than during the week.
Track 4
DR LOVE:
What do we know about the efficacy of intermittent androgen
therapy?
22
DR PETRYLAK: Theoretically, it has good grounding. Some good preclinical
work evaluated this in the Shionogi tumor model (Akakura 1993) and in the
LNCaP (Sato 1996; Hobisch 2004; Eggener 2006). We will need to see the
clinical data, but it will be interesting to see the results from the SWOG trial
of intermittent therapy (SWOG-S9346; [3.1, 3.2]).
If intermittent therapy is inferior to combined androgen blockade administered continuously, questions will be raised as to whether the experimental
arm used in the SWOG study is as good as some of the other types of intermittent therapy used in the community. We’re all awaiting the results of that
trial because it will make a major impact on patient care.
DR LOVE:
Is that a strategy you use in your practice off protocol?
DR PETRYLAK: Yes. I tell patients up front, “I still believe the standard of care
is combined blockade administered continuously; however, if for any reason
you can’t tolerate the treatment, it’s acceptable to receive it intermittently.”
3.1
Phase III Study of Intermittent versus Continuous Combined Androgen
Deprivation (CAD) Therapy in Metastatic Stage IV Prostate Cancer
Protocol IDs: SWOG-S9346, CAN-NCIC-JPR8, INT-0162, CALGB-9594, ECOG-S9346,
EORTC-30985
Target Accrual: 1,500 (Open)
Continuous: CAD until
disease progression
Eligibility
Stage IV
prostate cancer
Induction
therapy
CAD x 8
Intermittent: Observation until
rising PSA or progressive disease,
then CAD; if PSA normalizes after
eight courses, then observation;
if not, then CAD
R
CAD = goserelin qmo + bicalutamide qd
Study Contact: Maha Hadi Hussain, MD; Southwest Oncology Group; tel: 800-865-1125
SOURCE: NCI Physician Data Query, June 2006.
3.2
Should Intermittent Androgen Deprivation (IAD)
Be Used in Routine Clinical Practice?
“While the studies to date have been mostly single-institution (phase II) uncontrolled case
series, they have shown the feasibility of IAD and some of the beneficial effects in terms
of quality of life and morbidity reduction. Well-designed phase III studies are ongoing,
which will provide definitive answers regarding survival, time to development of androgen
independence and possible quality-of-life benefits.”
SOURCE: Bhandari MS et al. J Clin Oncol 2005;23(32):8212-8. Abstract
23
SELECT PUBLICATIONS
Akakura K et al. Effects of intermittent androgen suppression on androgen-dependent tumors. Apoptosis and serum prostate-specific antigen. Cancer 1993;71(9):2782-90.
Abstract
Arlen PM, Gulley JL. Docetaxel-based regimens, the standard of care for metastatic
androgen-insensitive prostate cancer. Future Oncol 2005;1(1):19-22. Abstract
Beer TM et al. Multiple cycles of intermittent chemotherapy in metastatic androgenindependent prostate cancer. Br J Cancer 2004;91(8):1425-7. Abstract
Bhandari MS et al. Should intermittent androgen deprivation be used in routine clinical
practice? J Clin Oncol 2005;23(32):8212-8. Abstract
Burgess EF, Roth BJ. Changing perspectives of the role of chemotherapy in advanced
prostate cancer. Urol Clin North Am 2006;33(2):227-36. Abstract
Eggener SE et al. Enhancement of intermittent androgen ablation by “off-cycle”
maintenance with finasteride in LNCaP prostate cancer xenograft model. Prostate
2006;66(5):495-502. Abstract
Gulley JL et al. A prospective analysis of the time to normalization of serum androgens
following 6 months of androgen deprivation therapy in patients on a randomized phase
III clinical trial using limited hormonal therapy. J Urol 2005;173(5):1567-71. Abstract
Hainsworth JD et al. Weekly docetaxel/estramustine phosphate in patients with
increasing serum prostate- specific antigen levels after primary treatment for prostate
cancer: A phase II trial of the Minnie Pearl Cancer Research Network. Clin Genitourin
Cancer 2006;4(4):287-92. Abstract
Higano C et al. Bone mineral density in patients with prostate cancer without bone
metastases treated with intermittent androgen suppression. Urology 2004;64(6):1182-6.
Abstract
Hobisch A et al. Prostate cancer cells generated during intermittent androgen ablation
acquire a growth advantage and exhibit changes in epidermal growth factor receptor
expression. Prostate 2004;59(4):401-8.Abstract
Kramer G et al. Docetaxel induces apoptosis in hormone refractory prostate carcinomas
during multiple treatment cycles. Br J Cancer 2006;94(11):1592-8. Abstract
Mottet N et al. Intermittent androgen castration: A biological reality during intermittent
treatment in metastatic prostate cancer? Urol Int 2005;75(3):204-8. Abstract
Oh WK et al. Response to second-line chemotherapy in patients with hormone refractory prostate cancer receiving two sequences of mitoxantrone and taxanes. Urology
2006;67(6):1235-40. Abstract
Petrylak DP et al. Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. N Engl J Med 2004;351(15):1513-20. Abstract
Peyromaure M et al. Intermittent androgen deprivation for biologic recurrence after
radical prostatectomy: Long-term experience. Urology 2005;65(4):724-9. Abstract
Ryan CJ et al. Angiogenesis inhibition plus chemotherapy for metastatic hormone refractory prostate cancer: History and rationale. Urol Oncol 2006;24(3):250-3. Abstract
Sato N et al; Chiba Prostate Study Group. Intermittent androgen suppression for locally
advanced and metastatic prostate cancer: Preliminary report of a prospective multicenter study. Urology 2004;64(2):341-5. Abstract
Sato N et al. Intermittent androgen suppression delays progression to androgen-independent regulation of prostate-specific antigen gene in the LNCaP prostate tumour model.
J Steroid Biochem Mol Biol 1996;58(2):139-46. Abstract
Smith MR et al. Natural history of rising serum prostate-specific antigen in men with
castrate nonmetastatic prostate cancer. J Clin Oncol 2005;23(13):2918-25. Abstract
Spry NA et al. Adverse effects to quality of life arising from treatment can recover
with intermittent androgen suppression in men with prostate cancer. Eur J Cancer
2006;42(8):1083-92. Abstract
24
Tannock IF et al; TAX 327 Investigators. Docetaxel plus prednisone or mitoxantrone plus
prednisone for advanced prostate cancer. N Engl J Med 2004;351(15):1502-12. Abstract
Winquist E et al. Non-hormonal systemic therapy in men with hormone-refractory
prostate cancer and metastases: A systematic review from the Cancer Care Ontario
Program in Evidence-based Care’s Genitourinary Cancer Disease Site Group. BMC
Cancer 2006;6(1):112;[Epub ahead of print]. Abstract
Wright JL et al. Intermittent androgen deprivation: Clinical experience and practical
applications. Urol Clin North Am 2006;33(2):167-79, vi. Abstract
25
P O S T-TE S T
Prostate Cancer Update — Issue 2, 2006
QUESTIONS (PLEASE CIRCLE ANSWER) :
1. In a study at the University of Miami,
what percentage of patients with one
or more positive margins following
radical retropubic prostatectomy had a
recurrence?
a. Two percent
b. Seven percent
c. Nineteen percent
d. Thirty-seven percent
7. Compared to open radical prostatectomy, robotic prostatectomy has been
shown to result in __________________.
a. Improvements in potency rates
b. Improvements in continence rates
c. Decreased duration of hospitalization
d. Increased cost
8. Docetaxel is the first FDA-approved
chemotherapy that has demonstrated an
increased survival in men with hormonerefractory prostate cancer.
a. True
b. False
2. Dr Sakr demonstrated that by age 50,
men have less than a 10 percent chance
of having “autopsy” prostate cancer.
a. True
b. False
3. SWOG trial S9921 for patients with
high-risk prostate cancer treated with
radical prostatectomy randomly assigns
patients to _________________________.
a. [Goserelin + bicalutamide] x 2
years
b. [Mitoxantrone + prednisone x 6] +
[goserelin + bicalutamide] x 2 years
c. Docetaxel x 6
d. Both a and b
e. a, b and c
9. In a study reported by Smith and
colleagues, 66 percent of men with
prostate cancer and a rising PSA despite
having received androgen deprivation
therapy developed metastases within two
years.
a. True
b. False
10. Randomized Phase III clinical trials
have shown that the use of chemotherapy for patients with PSA-only recurrences delays the development of bone
metastases.
a. True
b. False
4. In TAX-327, patients treated with
docetaxel/prednisone had significant
improvements in bone pain compared
to those treated with mitoxantrone/
prednisone.
a. True
b. False
11. SWOG-S9346 is comparing intermittent
versus continuous combined androgen
blockade.
a. True
b. False
5. PSA velocity in men with or without
prostate cancer is essentially the same
for younger and older men.
a. True
b. False
6. A meta-analysis demonstrated approximately a four percent improvement in
overall survival for maximal androgen
blockade compared to an LHRH agonist
alone.
a. True
b. False
Post-test answer key: 1c, 2b, 3d, 4a, 5b, 6a, 7d, 8a, 9b, 10a, 11a
26
E VA LUATIO N F O RM
Prostate Cancer Update — Issue 2, 2006
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E VA LUATIO N F O RM
Prostate Cancer Update — Issue 2, 2006
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