Prev: IMRT anyone?
Next: Dave's path report
From: Boney Maroni on 4 May 2006 19:51
*Chemotherapy and Novel Agents for Patients With Advanced Prostate
Cancer: New Developments*
Robert Dreicer, MD, FACP ??

Introduction

The demonstration in 2 randomized trials that a modest but real
survival benefit can be derived from docetaxel-based chemotherapy (when
compared with the benefit seen in patients receiving mitoxantrone and
prednisone) has forced physicians to reevaluate the management of
patients with advanced prostate cancer.[1,2] While docetaxel-based
chemotherapy is an important first step toward increased survival,
androgen-resistant, metastatic prostate cancer remains an incurable
disease. Many challenges remain, including the optimal timing and
duration of therapy and options for patients whose disease progresses
following docetaxel-based therapies. Significant efforts are under way
to augment the activity of taxane-based therapies and to evaluate novel
agents in various settings of advanced disease.

Presented here is an overview of a series of abstracts addressing
refinements in the use of chemotherapy in advanced disease and early
results using novel agents presented at the 2006 Prostate Cancer
Symposium in San Francisco.

Chemohormonal Therapy

Over the years, investigators have been intrigued by the possibility of
augmenting the response to chemotherapy by integrating hormonal therapy
cycling into a novel treatment paradigm. Rathkopf and colleagues[3]
conducted a phase 2 trial of docetaxel in combination with rapid
hormonal therapy cycling in 60 patients with noncastrate metastatic
prostate cancer. Patients with evidence of progressive
prostate-specific antigen (PSA) values with or without radiographic
evidence of metastatic disease and noncastrate levels of testosterone
received six 28-day cycles of leuprolide (7.5 mg intramuscularly) and
docetaxel 75 mg/m2 on day 1, followed by topical testosterone repletion
on days 22 through 28. The primary endpoint was the proportion of
patients at 6 and 18 months who achieved PSA values 0.05, 0.5, or 2.0
ng/mL or less following surgery or radiotherapy, or who had untreated
metastatic disease, respectively. Nine of 25 (36%) patients with
increasing PSA and 13 of 37 (35%) patients with noncastrate metastatic
disease achieved the primary end point at 6 months. Therapy was
relatively well-tolerated, although grade 3 and 4 neutropenia occurred
in 61% of patients, and 10% of patients had febrile neutropenia. The
authors speculate that the increased incidence of neutropenia may be
related to decreased clearance of docetaxel in the setting of
noncastrate levels of testosterone.

Intermittent Chemotherapy Administration

In an effort to gain further insight into the role of "intermittent"
chemotherapy -- that is, re-treatment of patients with taxane-based
therapy after a clinical response is achieved and treatment is
discontinued -- Beer and colleagues[4] presented data collected
prospectively from the ASCENT study in which docetaxel (36 mg/m2) was
administered weekly 3 out of 4 weeks with or without calcitriol
(DN-101) for 10 to 12 cycles. Patients enrolled in the ASCENT study
could suspend treatment if they had a confirmed reduction in serum PSA
of 50% or more and a serum PSA 4 ng/mL or less. Patients underwent
planned serial imaging and PSA monitoring, and therapy was resumed when
serum PSA levels rose by 50% or more and was greater than 2 ng/mL or
for any other evidence of disease progression. Of the 250 patients
enrolled in the study, 18% received intermittent therapy (DN-101 +
docetaxel 20%, docetaxel alone 16%). The median duration of the first
chemotherapy holiday was 16 weeks. On resumption of treatment after the
first chemotherapy holiday, 50% of patients had a reduction in serum
PSA levels of 50% or more, with 35% meeting criteria for stable PSA and
15% progression.[5] This experience suggests that a subset of patients
undergoing chemotherapy with docetaxel can be given a holiday from
therapy with the expectation of a response when therapy is restarted.
The impact of this intermittent strategy on patient survival and
overall quality of life remains undefined.

Second-Line Chemotherapy for Androgen-Resistant Metastatic Prostate
Cancer

A modest survival benefit from docetaxel-based chemotherapy has
recently been shown.[1,2] As a result, investigators around the world
are actively studying therapeutic options for second-line therapies.

Saad and coworkers[6] evaluated the utility of docetaxel and prednisone
in patients with androgen-resistant metastatic disease with evidence of
progression following chemotherapy with mitoxantrone and prednisone. In
an interim report of this ongoing study, 30 patients with disease
progression following standard mitoxantrone and prednisone received
docetaxel 75 mg/m2 every 3 weeks with prednisone 5 mg twice a day. At
study entry, 80% had bone pain and a median PSA of 112 ng/mL. At the
time of this report, PSA reductions greater than 50% were seen in 70%
of patients, and a 57% decline in analgesic scores indicated some
degree of pain improvement in 80% of patients. Two patients had
experienced febrile neutropenia. Progression-free survival is currently
7 months, and median survival has not yet been determined.

Ohlmann and colleagues[7] evaluated 25 patients with androgen-resistant
metastatic prostate cancer with PSA progression following
docetaxel-based chemotherapy. Progression was defined as continuous
increase in PSA level measured at 3 consecutive time points 2 weeks
apart and a level higher than 2 x nadir after the first 12-week cycle
of chemotherapy. A PSA response was seen in 18 of 25 (72%) of patients,
and the mean duration of response was 5.8 months. Five and 3 patients,
respectively, experienced grade 3 to 4 anemia and leukopenia. Grade 3
to 4 nonhematologic toxicities included nail bed changes in 20%,
diarrhea in 12%, and fluid retention in 12%.

Rosenberg and colleagues[8] performed a randomized phase 2 trial of
ixabepilone, a novel epothilone, compared with mitoxantrone and
prednisone in patients with disease progression during or within 60
days of stopping docetaxel chemotherapy. Patients were randomized to
either mitoxantrone 14 mg/m2 administered every 3 weeks with daily
prednisone 5 mg twice daily or ixabepilone 35 mg/m2 given every 3
weeks. Crossover at time of progression was permitted. The study
accrued 41 evaluable patients in each arm. With a median follow-up of 5
months, confirmed posttherapy PSA decreases of 50% or more were
observed in 17% of the patients receiving ixabepilone and in 20% of
those receiving mitoxantrone and prednisone. Median survival from
protocol entry was 12.5 months for ixabepilone and 13 months for
mitoxantrone. Hematologic toxicity included grade 3 and 4 neutropenia
in 41% of patients receiving ixabepilone and in 54% of patients treated
with mitoxantrone. One patient treated with ixabepilone died of a
therapy-related complication. The authors concluded that both agents
have only modest activity in this setting with acceptable toxicity
profiles.

Novel Agents

FK 228 is a bicyclic depsipeptide that inhibits histone deacetylase.
Such inhibition can result in G1/G2/M arrest, differentiation, and
apoptosis. Molife and colleagues[9] presented early results from an
ongoing phase 2 trial of FK 228 administered intravenously at 13 mg/m2
on days 1, 8, and 15 of a 4-week cycle for up to 6 cycles. Eligible
patients had castrate metastatic prostate cancer and were
chemotherapy-naive. Of the 16 patients included in this interim report,
12 were evaluable for radiologic response. One patient achieved a
confirmed radiographic partial response, and 4 others had stable PSA
values on treatment. The most common adverse events were grade 1 and 2
fatigue, nausea, and vomiting.

Lin and coworkers[10] reported a phase 2 trial of ketoconazole and
granulocyte-macrophage colony stimulating factor (GM-CSF). Eligible
patients had progressive castrate metastatic prostate cancer and were
immunotherapy-naive. Ketoconazole 400 mg was given 3 times daily with
hydrocortisone at replacement doses. GM-CSF at 250 mcg/m2 was
administered subcutaneously on days 15 through 28 of each 28-day cycle.
The study was powered to detect a 50% prolongation of the median
response duration relative to historical controls (5 to 7.5 months). At
the time of this interim report, 42 of the planned 48 patients had been
enrolled (30 with metastatic disease and 12 with PSA evidence of
disease only). The 35 patients evaluable for response were treated for
a median of 5.1 months. Twenty-four (69%) have experienced a reduction
in serum PSA of 50% or more associated with stable scans. Sixteen of 30
patients with metastatic disease and 8 of the 12 patients with only PSA
progression have also had a reduction in serum PSA of 50% or greater.
Therapy was very well-tolerated; the most common adverse events were
grade 1 injection site reactions and fatigue. Accrual and follow-up for
this study are ongoing.

A report by Wu and colleagues[11] of the National Cancer Institute
reminds us that relying on PSA response alone may be misleading in the
assessment of novel agents. These researchers conducted a phase 2 trial
of sorafenib, a potent inhibitor of Raf-1 and multiple receptor kinases
involved in tumor progression, that was recently approved by the FDA
for advanced kidney cancer. Twenty-two patients with androgen-resistant
metastatic prostate cancer were treated twice daily with 400 mg of
sorafenib. The primary end point of this study was a 50%
progression-free interval at 4 months. Nineteen of 22 patients had
evidence of disease progression, with 10 on the basis of PSA criteria
alone. Of interest, 5 of the patients with PSA progression alone were
noted to have decreased PSA levels after discontinuing therapy. Two
patients with disappearance of metastatic bone disease on serial bone
scan assessment had concomitant PSA progression.

Conclusions

Although the data presented at the 2006 ASCO prostate meeting will not
necessarily change clinical practice standards, a growing body of
evidence suggests that there is a subgroup of patients with advanced
prostate cancer previously treated with docetaxel who will respond to
reintroduction of this agent. This observation will need to be
confirmed but will probably have clinical relevance given the current
lack of a standard, effective, second-line therapy and the likelihood
that patients will increasingly receive docetaxel-based therapy earlier
in the disease course. Three upcoming studies involving docetaxel will
be exploring chemotherapy in the following settings: 1) neoadjuvant
(CALGB-90203, which will involve neoadjuvant docetaxel followed by
radical prostatectomy vs prostatectomy), 2) adjuvant (a 3-arm study
evaluating chemotherapy vs hormonal therapy vs treatment at
progression), and 3) metastatic (ECOG "CHARTED"-untreated patients with
metastatic disease randomized to receive standard androgen deprivation
therapy with or without 6 cycles of docetaxel-based therapy).

Several novel agents have interesting early activity in advanced
disease, and we are again reminded that understanding how these agents
work at the molecular level will be increasingly important to avoid
abandoning active agents because they alter PSA expression in the wrong
direction while having direct antitumor effects.

References
1 Tannock I, de Wit R, Berry W, et al. Docetaxel plus prednisone or
mitoxantrone plus prednisone for advanced prostate cancer. N Engl J
Med. 2004;351:1502-1512. Abstract
2 Petrylak D, Tangen C, Hussain M, et al. Docetaxel and
estramustine compared with mitoxantrone and prednisone for advanced
refractory prostate cancer. N Engl J Med. 2004;351:1513-1520. Abstract
3 Rathkopf D, Carducci MA, Slovin SF, et al. A phase II trial of
docetaxel with rapid hormonal cycling for patients with non-metastatic
prostate cancer. Program and abstracts of the 2nd Annual
Multidisciplinary Prostate Cancer Symposium; February 24-26, 2006; San
Francisco, California. Abstract 207.
4 Beer TM, Ryan CW, Venner PM, et al. Interim results from ASCENT:
A double-blinded randomized study of DN-101 (high-dose calcitriol) plus
docetaxel vs. placebo plus docetaxel in androgen-independent prostate
cancer (AIPC). Proc Am Soc Clin Oncol 2005;23:382. Abstract 4516.
5 Beer TM, Ryan CW, Venner PM, et al. Intermittent chemotherapy in
metastatic androgen-independent prostate cancer. Initial results from
ASCENT. Program and abstracts of the 2nd Annual Multidisciplinary
Prostate Cancer Symposium; February 24-26, 2006; San Francisco,
California. Abstract 216.
6 Saad F, Reuther D, Ernst S, et al. Canadian Urologic Oncology
Group phase II study using docetaxel/prednisone in the second line
setting for metastatic androgen independent prostate cancer in patients
progressing after first line mitoxantrone and prednisone. Program and
abstracts of the 2nd Annual Multidisciplinary Prostate Cancer
Symposium; February 24-26, 2006; San Francisco, California. Abstract
231.
7 Ohlmann CH, Azgar E, Engelmann U, et al. Second-line chemotherapy
with docetaxel for prostate specific antigen relapse in men with
hormone-refractory prostate cancer previously treated with
docetaxel-based chemotherapy. Program and abstracts of the 2nd Annual
Multidisciplinary Prostate Cancer Symposium; February 24-26, 2006; San
Francisco, California. Abstract 248.
8 Rosenberg JE, Weinberg VK, Kelly WK, et al. Randomized phase II
study of ixabepilone or mitoxantrone and prednisone in patients with
taxane resistant hormone refractory prostate cancer. Program and
abstracts of the 2nd Annual Multidisciplinary Prostate Cancer
Symposium; February 24-26, 2006; San Francisco, California. Abstract
253.
9 Molife R, Patterson S, Riggs C, et al. Phase II study of FK228 in
patients with metastatic hormone refractory prostate cancer. Program
and abstracts of the 2nd Annual Multidisciplinary Prostate Cancer
Symposium; February 24-26, 2006; San Francisco, California. Abstract
217.
10 Lin AM, Ryan CJ, Rosenberg JE, et al. A phase II trial of
ketoconazole and granulocyte-macrophage colony stimulating factor for
androgen-independent prostate cancer. Program and abstracts of the 2nd
Annual Multidisciplinary Prostate Cancer Symposium; February 24-26,
2006; San Francisco, California. Abstract 219.
11 Wu S, Posadas E, Scripture C, et al. Bay 43-9006 (sorafenib)
can lead to improvement of bone lesions in metastatic
androgen-independent prostate cancer despite rises in serum PSA levels.
Program and abstracts of the 2nd Annual Multidisciplinary Prostate
Cancer Symposium; February 24-26, 2006; San Francisco, California.
Abstract 259.





*Hormonal and Bone-Targeted Therapies for Patients With Advanced
Prostate Cancer: Recent Advances*
Robert Dreicer, MD, FACP ??

Introduction

It has been more than 6 decades since androgen-deprivation therapy
(ADT) was first shown to be effective in management of advanced
prostate cancer. During the past 15 years, there have been major
refinements in the clinical application of hormonal therapy, which in
combination with the widespread measurement of prostate-specific
antigen (PSA) levels in serum, has dramatically increased both the
number of patients treated and the length of time that they receive
hormonal therapy.

One of the characteristic features of advanced prostate cancer is the
high incidence of metastatic bone disease. The past decade has seen an
increased focus in both basic and clinical investigation of the biology
and clinical management of this debilitating disease.

This brief overview will discuss a series of abstracts dealing with
various aspects of ADT and bone-targeted approaches presented at the
2006 Prostate Cancer Symposium held in San Francisco.

Hormonal Therapy

The early prostate cancer (EPC) program[1] comprises 3 randomized,
double-blind, placebo-controlled trials designed for combined analysis.
These trials investigated the addition of bicalutamide 150 mg to
standard care (radical prostatectomy, radiotherapy, or watchful
waiting). See and colleagues[2] presented findings from the EPC
program's third analysis of data, which had a median follow-up for the
radiotherapy-treated subgroup. In this subgroup, 699 men received
bicalutamide 150 mg and 671 received placebo. In a subset of patients
with locally advanced disease (n = 305), bicalutamide 150 mg adjuvant
to radiotherapy significantly improved objective progression-free
survival (hazard ratio, 0.56; P < .001) and overall survival (hazard
ratio, 0.65; P = .03) compared with placebo. There were no significant
differences seen in either of these end points in patients with
localized disease. The authors noted that this study was the first to
show a significant overall survival benefit in patients with locally
advanced disease treated with any noncastration-based hormonal adjuvant
therapy. However, Dr. Mario Eisenberger of Johns Hopkins cautioned
against overinterpretation of the results from this very small subset
of patients.

Bianco and coworkers[3] analyzed a large consecutive cohort of patients
with rising PSA levels following radical prostatectomy. Their goal was
to better define a tool to predict the utility of ADT. The study group
was drawn from a cohort of 4500 men who underwent radical prostatectomy
for clinically localized disease, of which 693 subsequently had
evidence of increasing PSA. Of the 693 men, 355 received ADT and were
followed prospectively for a median of 12 years from the time of
radical prostatectomy and a median of 5.3 years following initiation of
hormonal therapy. During this time, 93 men developed evidence of
metastatic prostate cancer and 36 died from causes unrelated to
prostate cancer with an undetectable PSA. The median response time to
ADT until development of metastatic disease was 12.4 years. Within 8
months of ADT, PSA nadir was less than 0.2 in 285 (80%) of the men. The
median time to metastatic disease for those who did not reach an
undetectable PSA level was 35 months. The authors concluded that many
men treated for a rising PSA after radical prostatectomy have a
prolonged duration of response to ADT and that they have developed a
model that can identify patients with a shorter-term response to this
approach who would be candidates for additional interventions.

Shipley and colleagues[4] examined the question of the optimal timing
of ADT in patients with PSA progression following radiotherapy by
performing a secondary analysis of data from the RTOG 86-10 trial.[5]
This trial randomized 471 patients with bulky-stage T2 to T4 disease to
receive either 70-Gy radiotherapy alone or combined with neoadjuvant
and concomitant ADT. It demonstrated that patients with prostate
carcinoma of 2 to 6 on the Gleason scale showed a highly significant
improvement in local control, reduction in disease progression, and
overall survival after a short course of androgen ablation administered
before and during radiotherapy. In the secondary analysis, 247 (54%)
patients have received subsequent salvage hormonal therapy. Median
follow-up was 9 years, and patients were followed for a median of 5.5
years following initiation of ADT. For patients with metastatic disease
present at the start of ADT, overall survival and disease-specific
survival were significantly reduced when compared with those without
metastases at the start of ADT (P < .001). An important limitation of
this retrospective study is that it did not evaluate PSA doubling time,
which may better predict long-term survival than absolute PSA.

Impact of Androgen-Deprivation Therapy on Bone

Saad and colleagues[6] performed a retrospective analysis on the
patients in their prospective, placebo-controlled, randomized trial of
zoledronic acid.[7] Using a Cox regression model, they assessed the
correlation between fractures or bone markers (urinary N-telopeptide
and bone alkaline phosphatase) and death or skeletal events, adjusting
for treatment group. They found that patients who had a fracture while
they were in the study had a shorter survival time than those who did
not, and that patients with high urinary N-telopeptide levels seemed to
have a significantly increased risk for skeletal events.

Three other abstracts provided additional insight into the potential
role of bisphosphonates in patients receiving ADT. Casey and
colleagues[8] conducted an open-label, placebo-controlled, multicenter
study to determine whether treatment with zoledronic acid can prevent
bone loss in patients undergoing ADT with goserelin acetate. Two
hundred men with locally advanced prostate cancer were randomized in a
1:1 ratio to receive goserelin acetate with or without zoledronic acid
4 mg every 3 months for a year. The primary end point was the
percentage change from baseline in bone mineral density of the femoral
neck and hip, changes in height, and interval development of metastatic
disease. Interim results at 1 year are available on 80 patients and
show decreased bone mineral density at all measured sites in patients
receiving goserelin alone. Overall, patients treated with zoledronic
acid in addition to goserelin experienced improvement in bone mineral
density up to 4% compared with up to 2% in men treated with goserelin
alone.

Nelson and colleagues[9] enrolled 112 men with nonmetastatic prostate
cancer who were on ADT for at least 6 months in a 2-year, randomized,
double-blind, placebo-controlled study of oral alendronate 70 mg once
weekly. All patients received calcium and vitamin D supplementation. In
this interim report at 1 year of follow-up, only 9% of men had normal
bone mass at baseline, 39% had osteoporosis, and 52% had low bone mass.
In men treated with alendronate, bone mass increased significantly (P <
..05) after 12 months at the spine and hip compared with significant
loss in those locations in men in the placebo group. Therapy was
well-tolerated; no differences in adverse events were noted between the
2 groups.

Ryan and colleagues[10] evaluated the role of bisphosphonates initiated
later in the course of ADT. One hundred-twenty men without metastatic
bone disease who had received ADT for fewer than 12 months were
randomized to receive either zoledronic acid 4 mg administered
intravenously every 3 months or placebo. Patients were stratified
according to duration of ADT. The primary end point was bone mineral
density in the femoral neck and lumbar spine at 6 and 12 months.
Patients in the placebo group lost more than 2% of bone mineral density
at both measured sites over the 12-month study period. Compared with
placebo, therapy with zoledronic acid increased bone mineral density at
both sites by 3.6% and 6.7%, respectively (P = .0004 and P < .0001),
per year. The effects of zoledronic acid on bone mineral density were
not differentiated by the duration of ADT. The authors concluded that
their findings support current guidelines that recommend initial
monitoring of bone mineral density with delayed initiation of
bisphosphonates until evidence of bone mineral density loss appears.

An important clinical question regarding the role of bisphosphonates is
their utility in patients who have already had a skeletal event while
receiving hormonal therapy. Saad and coworkers[11] conducted a series
of retrospective analyses on selected cohorts of patients enrolled in
their prospective, placebo-controlled, randomized trial of zoledronic
acid. Data for this analysis were analyzed from a 15-month core study
and a 9-month extension study. End points included the percentage of
patients with a first or second in-study skeletal event and mean annual
incidence of skeletal events. The investigators found that among
patients who had experienced a skeletal event before study entry, fewer
patients in the zoledronic acid arm had 1 or more skeletal events
during the entire study (24 months) than those in the placebo arm (41%
vs 51%; P = .215). After 15 months of therapy, zoledronic acid
significantly reduced the percentage of patients who had a second
in-study skeletal event (21% vs 31%; P = .017) and reduced the mean
annual incidence of skeletal events. The authors concluded that
zoledronic acid appears to provide ongoing benefits to men with
prostate cancer and bone metastases even after they have a skeletal
event. This observation is clearly of interest but will require
prospective validation because of the implications for both
therapy-related toxicity and costs.

References
1 McLeod DG, Iversen P, See WA, et al. Bicalutamide 150 mg plus
standard care vs. standard care alone for early prostate cancer. BJU
Int. 2006;97:247-254. Abstract
2 See WA, McLeod DG, Iverson P, et al. Adding bicalutamide 150 mg
to radiotherapy significantly improves overall survival in men with
locally advanced prostate cancer. Program and abstracts of the 2nd
Annual Multidisciplinary Prostate Cancer Symposium; February 24-26,
2006; San Francisco, California. Abstract 136.
3 Bianco FJ, Scardino PT, Scher HI, et al. Studies on androgen
deprivation therapy for a rising PSA post prostatectomy: Development of
castrate metastases (hormonally refractory prostate cancer). Program
and abstracts of the 2nd Annual Multidisciplinary Prostate Cancer
Symposium; February 24-26, 2006; San Francisco, California. Abstract
182.
4 Shipley WU, DeSilvio M, Pilepich MV, et al. Early initiation of
salvage hormone therapy influences survival in patients who failed
initial radiation for locally advanced prostate cancer. A secondary
analysis of RTOG phase III protocol 86-10. Program and abstracts of the
2nd Annual Multidisciplinary Prostate Cancer Symposium; February 24-26,
2006; San Francisco, California. Abstract 186.
5 Pilepich MV, Winter K, John MJ, et al. Phase III radiation
therapy oncology group (RTOG) trial 86-10 of androgen deprivation
adjuvant to definitive radiotherapy in locally advanced carcinoma of
the prostate. Int J Radiat Oncol Biol Phys 2001;50:1243-1252.
6 Saad F, Coleman RE, Cook R, et al. Pathologic fractures and bone
markers are predictors of clinical outcome in patients with prostate
cancer and bone metastases. Program and abstracts of the 2nd Annual
Multidisciplinary Prostate Cancer Symposium; February 24-26, 2006; San
Francisco, California. Abstract 150.
7 Saad F, Gleason D, Murray R, et al. Long-term efficacy of
zoledronic acid for the prevention of skeletal complications in
patients with metastatic hormone-refractory prostate cancer. J Natl
Cancer Inst 2004;96:879-82.
8 Casey R, Love W, Mendoza C. Zoledronic acid reduces bone loss in
men with prostate cancer undergoing androgen deprivation therapy.
Program and abstracts of the 2nd Annual Multidisciplinary Prostate
Cancer Symposium; February 24-26, 2006; San Francisco, California.
Abstract 184.
9 Nelson JB, Greenspan SL, Resnick NM, et al. Once weekly
alendronate prevents bone loss in men on androgen deprivation therapy
for prostate cancer. Program and abstracts of the 2nd Annual
Multidisciplinary Prostate Cancer Symposium; February 24-26, 2006; San
Francisco, California. Abstract 139.
10 Ryan CW, Huo D, Demers LM, et al. Zoledronic acid initiated
during the first year of androgen deprivation therapy increases bone
mineral density and suppresses bone turnover markers in prostate cancer
patients. Program and abstracts of the 2nd Annual Multidisciplinary
Prostate Cancer Symposium; February 24-26, 2006; San Francisco,
California. Abstract 192.
11 Saad F, Gleason D, Murray R, et al. Zoledronic acid provides
long-term reductions in skeletal morbidity for men with prostate cancer
and bone metastases. Program and abstracts of the 2nd Annual
Multidisciplinary Prostate Cancer Symposium; February 24-26, 2006; San
Francisco, California. Abstract 149.





*Balancing Interventions With Quality of Life in Advanced Prostate
Cancer*
Hossein Jadvar, MD, PhD ??

Prostate cancer is the most common type of cancer affecting men in the
United States. In 2003, the estimated incidence of and deaths from this
disease were 220,900 and 28,900, respectively.[1] In this report, we
summarize selected data related to the treatment of locally advanced,
recurrent, and metastatic disease that were presented at the 2nd Annual
Meeting of the Multidisciplinary Prostate Cancer Symposium held in San
Francisco, California, February 24-26, 2006. The meeting was
cosponsored by the American Society of Clinical Oncology (ASCO), the
American Society for Therapeutic Radiology and Oncology (ASTRO), the
Prostate Cancer Foundation (PCF), and the Society of Urologic Oncology
(SUO).

Androgen-independent metastatic prostate cancer is incurable. However,
a host of new treatments have entered clinical trials that are designed
to improve clinical outcomes while safeguarding quality of life for
patients with this disease.

Aspects of Docetaxel Therapy

The findings of several ongoing studies of docetaxel-based chemotherapy
were presented. This therapy has been shown to confer a significant
survival benefit in this clinical setting. Unfortunately, about 80% of
men with androgen-independent metastatic disease have PSA relapse
within 12 months; median time to progression is about 6 months after
the initial response to docetaxel. In 1 investigation, 25 patients with
PSA relapse after docetaxel-based chemotherapy received repeated
treatment with low-dose docetaxel; the primary endpoint was a decline
greater than 50% in PSA levels.[1] A PSA response was noted in 72% of
patients, with a mean duration of response of 5.8 (range, 3 to 10)
months. These findings suggested that rechallenge with low-dose
intermittent docetaxel may be a well-tolerated, effective treatment
option in men with hormone-refractory disease and PSA progression
following initial response to docetaxel-based chemotherapy.

Another study combined standard docetaxel-based chemotherapy with
capecitabine in a phase 2 clinical trial.[2] The results of the first
stage of this trial have suggested that capecitabine combined with
docetaxel is efficacious, showing a 67% partial remission rate and a
decline in PSA level of at least 50%. Another randomized phase 2 trial
showed that the combination of docetaxel and estramustine has
significant therapeutic efficacy in men with hormone-refractory
disease.[3] Similar favorable results were reported by G. Gravis MD,
and coworkers, who showed that docetaxel combined with estramustine on
a weekly basis can achieve a clinical benefit response of 33%, has a
median response duration of 74 days, and is associated with a PSA
response of 53%.[4]

S. Tomek, MD, and colleagues reported the findings of a phase 2
clinical trial on the use of weekly docetaxel vs weekly vinorelbine as
first-line chemotherapy in patients with androgen-independent
metastatic prostate cancer.[5] The authors concluded that weekly
docetaxel was more efficacious than vinorelbine in terms of 50% PSA
decline (62.5% vs 11.1%, respectively), while the overall toxicity
profile of both regimens was mild. The results of a phase 2 clinical
trial of combined diethylstilbestrol (DES) and docetaxel were reported
by B. Montgomery, MD, and coworkers.[6] This trial included 26 men with
metastatic hormone-refractory disease, and response was assessed by
RECIST criteria and by PSA decline greater than 50% maintained over 4
weeks. To date, the median number of treatment cycles has been 6, with
a median follow-up after chemotherapy of 6 months (range, 1 to 18
months). The overall response rate for 23 patients was 74%. Six
patients had toxicity greater than grade 3, 1 died of unrelated causes,
and 1 died due to steroid-induced ulcer complications. The authors of
this paper concluded that DES improves the therapeutic index of
docetaxel and should be considered as part of a combination regimen for
future trials.

The combination of docetaxel and gefitinib was assessed by a group from
Switzerland.[7] This phase 2 trial enrolled 37 chemotherapy-naive
patients who received the combined treatment. Gefitinib was given
continuously while docetaxel was limited to up to 6 cycles. PSA
response (defined as at least a 50% decline in PSA) was 43.2% at 2
months and 45.9% at 4 to 6 months. Median duration of PSA response was
215 days, median time to PSA or radiologic progression was 165 days,
and median survival was 447 days. About 38% of patients discontinued
combination therapy due to significant adverse events.

The initial results of the multicenter ASCENT trial were reported by T.
Beer, MD, and colleagues.[8] ASCENT was a multi-institution,
randomized, clinical trial designed to compare the effectiveness and
safety of weekly DN-101 plus docetaxel to placebo plus docetaxel in
patients with chemotherapy-naive metastatic androgen-independent
prostate cancer. Patients were allowed to suspend treatment if they had
a confirmed decrease in PSA exceeding 50% and a PSA level 4 ng/mL or
less. PSA was monitored every 4 weeks. Treatment was resumed when PSA
increased more than 50% and was 2 ng/mL or higher. The study concluded
that this strategy results in clinically meaningful chemotherapy
holidays and can be offered to about one fifth of men who, when
treatment is restarted, will again respond (85%, as evaluated by stable
or declining PSA levels).

Hormonal Therapies Show Promise

The role of adjuvant androgen-deprivation therapy (ADT) in surgically
treated men with prostate cancer invading the seminal vesicles was
discussed by B. Inman, MD, and coworkers from the Mayo Clinic.[9] Men
who received immediate postoperative ADT had considerably better
outcomes than those who did not receive ADT (10-year biochemical-free
survival, 60% vs 23%; 10-year cancer-specific survival, 97% vs 90%).
These findings suggested that immediate adjuvant ADT should be strongly
considered in men with prostate cancer invading the seminal vesicles.

A group of Belgian and Danish researchers evaluated the use of
degarelix (a gonadotrophin-releasing hormone-receptor blocker) in 187
men with prostate cancer (19% metastatic, 32% locally advanced, 22%
localized, and 27% M0/MX and not T-staged).[10] Degarelix therapy for 1
year resulted in rapid, sustained suppression of testosterone and PSA
decline without untoward complications.

The efficacy of atrasentan therapy was also evaluated by M. Carducci,
MD, and colleagues.[11] Patients underwent a randomized, double-blind,
placebo-controlled multinational trial of atrasentan. Disease
progression was defined as radiographically identified new lesions, or
by clinical criteria (eg, pain requiring significant opioids). This
study showed that, in men with hormone-refractory osseous metastatic
disease, the administration of atrasentan can forestall disease
progression.

The results of a phase 2 trial of low-dose (LD, 1.25 mg once daily) and
high-dose (HD, 1.25 mg three times daily) conjugated estrogens was
reported by W. Oh, MD, and coworkers from Harvard Medical School.[12]
Patients were encouraged to receive prophylactic breast irradiation,
and warfarin anticoagulation was also given unless it was
contraindicated. HD estrogen therapy was associated with a 32% response
rate, while no response was observed in the LD group. The median time
to progression was 3.2 to 3.3 months for both regimens. Toxicity was
modest, although thromboembolism was seen despite prophylactic
anticoagulation with warfarin.

Stanford researchers examined the potential synergistic effect of
calcitriol and naproxen in men with recurrent prostate cancer.[13] The
underlying physiologic basis for this investigation was that calcitriol
and nonsteroidal antiinflammatory drugs (such as naproxen) exert
antiproliferative effects by decreasing prostaglandins. The early
results of this study demonstrated that the combination of calcitriol
(0.5 mcg/kg per week) and naproxen (400 mg twice daily) may be an
effective therapy for prostate cancer recurrence after primary therapy.
Additional studies, which are under way, are necessary to confirm and
support these early encouraging findings.

Postradiation Salvage Surgery: Dealing With Bone Pain and Posttherapy
PSA Spikes

Salvage prostatectomy in men with locally recurrent prostate cancer
after definitive radiation therapy is a challenging course of action.
C. Ohlmann, MD, and colleagues performed salvage prostatectomy in 21
men with radio recurrent prostate cancer and no evidence of metastatic
disease.[14] These researchers concluded that, in this subset of
patients, salvage prostatectomy is a technically challenging but
feasible approach when used in selected patients. However, as the
researchers noted, patient follow-up was too short to evaluate outcomes
with a high degree of accuracy. More extensive information on outcomes
would be helpful in deciding whether salvage prostatectomy is a viable
option in selected patients.

Control of bone pain is important in men with osseous metastatic
prostate cancer. O. Sartor, MD, reported the findings of a multicenter
trial designed to examine the safety and efficacy of single and
repeated dosing of Sm-153 lexidronam (Sm-153).[15] Sm-153 (1.0 mCi/kg)
was given to 157 patients for treatment of bone pain. There were 48
patients given repeated dosing. Adverse events were assessed at
baseline, weeks 1 to 6, and 8 weeks after dosing. Repeated dosing was
offered to men who had an initial palliative response and recovery of
leukocyte and platelet counts. The median interval between first and
second treatments was 137 days and 78 days after the second infusion.
The authors of this study concluded that repeated dosing of Sm-153 is
well-tolerated and is a reasonable palliative option in the appropriate
clinical setting. The same investigators analyzed a series of variables
that may predict a palliative response in patients receiving Sm-153 for
painful osseous metastases.[16] They found no particular clinical
variables that could predict the success of palliative response to
Sm-153. This suggests that the variables that contribute to response
may be multifactorial, complex, and at least partially related to
difficult-to-measure considerations, such as the patient's tolerance of
pain and subjective pain assessment.

The outcome of men with rapidly rising PSA after definitive local
therapy was investigated by a multicenter team led by N. Rodrigues,
MD.[17] The study population included 67 men with PSA doubling time 6
months or less after radical prostatectomy or external-beam radiation
therapy for localized prostate cancer. Men were followed for 2.9 years
beginning 8 months after ADT initiation. A PSA nadir greater than 0.2
ng/mL and a Gleason score of 8 or higher were significantly associated
with short time to prostate cancer-specific mortality (PCSM). The study
concluded that men with PSA doubling time 6 months or less and at high
risk for PCSM would be candidates for phase 3 chemotherapy clinical
trials. In another study, it was determined that pretreatment PSA
doubling time may be a useful predictor of response to chemotherapy in
men with androgen-sensitive PSA progression after local therapy.[18] In
this study, a PSA doubling time of 70 days was associated with a
sensitivity of 70% and specificity of 71%.

In summary, all phases of clinical trials are being conducted to
address the difficult problem of treating men with hormone-refractory
disease. The general goals of these studies are to find ways to
increase survival while maintaining a reasonable quality of life and
minimizing toxicity and complications.

References
1 Ohlmann CH, Azgar E, Engelmann U, et al. Second-line chemotherapy
with docetaxel for prostate-specific antigen (PSA) relapse in men with
hormone refractory prostate cancer (HRPCA) previously treated with
docetaxel-based chemotherapy. Program and abstracts of the 2nd Annual
Multidisciplinary Prostate Cancer Symposium; February 24-26, 2006; San
Francisco, California. Abstract 248.
2 Vaishampayan UN, Kucuk O, Heilbrun L, et al. Clinical efficacy of
docetaxel and capecitabine therapy in metastatic androgen independent
prostate cancer (AIPC). Program and abstracts of the 2nd Annual
Multidisciplinary Prostate Cancer Symposium; February 24-26, 2006; San
Francisco, California. Abstract 230.
3 Nelius T, Kaltte T, Reiher F, et al. randomized study of
docetaxel (D) and dexamethasone (DX) with low- or high-dose (E) for
patients with low- or high-dose estramustine (E) for patients with
advanced hormone-refractory prostate cancer (HRPC). Program and
abstracts of the 2nd Annual Multidisciplinary Prostate Cancer
Symposium; February 24-26; 2006. San Francisco, California. Abstract
242.
4 Gravis G, Protiere C, Salem N, et al. Weekly administration of
docetaxel (D) and estramustine (E) for symptomatic metastatic
hormone-refractory prostate cancer. Program and abstracts of the 2nd
Annual Multidisciplinary Prostate Cancer Symposium; February 24-26,
2006; San Francisco, California. Abstract 244.
5 Tomek S, Elandt K, Horak P, et al. A prospective, open-label
randomized phase II trial of weekly docetaxel versus weekly vinorelbine
as first-line chemotherapy in patients with androgen-independent
prostate cancer. Program and abstracts of the 2nd Annual
Multidisciplinary Prostate Cancer Symposium; February 24-26, 2006; San
Francisco, California. Abstract 218.
6 Montgomery B, Lin DW, Ryan CW, et al. Diethylstilbestrol and
docetaxel: a phase II study in patients with metastatic
androgen-independent prostate cancer. Program and abstracts of the 2nd
Annual Multidisciplinary Prostate Cancer Symposium; February 24-26,
2006; San Francisco, California. Abstract 256.
7 Borner MM, Morant R, Rochlitz C, et al. An open-label phase II
trial to evaluate the efficacy and safety of combination docetaxel with
gefitinib in patients with metastatic hormone-refractory prostate
cancer. Program and abstracts of the 2nd Annual Multidisciplinary
Prostate Cancer Symposium; February 24-26, 2006; San Francisco,
California; Abstract 258.
8 Beer TM, Ryan CW, Venner P, et al. Intermittent chemotherapy in
metastatic androgen-independent prostate cancer (AIPC): initial results
from ASCENT. Program and abstracts of the 2nd Annual Multidisciplinary
Prostate Cancer Symposium; February 24-26, 2006; San Francisco,
California. Abstract 216.
9 Inman BA, Kwon ED, Myers RP, et al. Adjuvant androgen ablation
therapy improves survival in patients with prostate cancer invading the
seminal vesicles. Program and abstracts of the 2nd Annual
Multidisciplinary Prostate Cancer Symposium; February 24-26, 2006; San
Francisco, California. Abstract 180.
10 Tombal B, de la Rosette J, Persson B, et al. Testosterone and
PSA response in a one-year, multi-center randomized study of degarelix,
a gonadatrophin-releasing hormone (GnRH) receptor blocker, in patients
with prostate cancer. Program and abstracts of the 2nd Annual
Multidisciplinary Prostate Cancer Symposium; February 24-26, 2006; San
Francisco, California. Abstract 187.
11 Carducci MA, Nelson JB, Petrylak DP, et al. Clinical benefit
of atrasentan for men with metastatic hormone-refractory prostate
cancer metastatic to bone. Program and abstracts of the 2nd Annual
Multidisciplinary Prostate Cancer Symposium; February 24-26, 2006; San
Francisco, California. Abstract 220.
12 Oh WK, Manola J, Taplin M, et al. Phase II study of low-dose
(LD) and high-dose (HD) premarin in androgen independent prostate
cancer (AIPC). Program and abstracts of the 2nd Annual
Multidisciplinary Prostate Cancer Symposium; February 24-26, 2006; San
Francisco, California. Abstract 238.
13 Srinivas SS, Colocci N, Feldman D, et al. A phase II trial of
calcitriol and naproxen in recurrent prostate cancer. Program and
abstracts of the 2nd Annual Multidisciplinary Prostate Cancer
Symposium; February 24-26, 2006; San Francisco, California. Abstract
212.
14 Ohlmann CH, Azgar E, Wille S, et al. Salvage radical
prostatectomy in locally recurrent prostate cancer following radiation
therapy. Program and abstracts of the 2nd Annual Multidisciplinary
Prostate Cancer Symposium; February 24-26, 2006; San Francisco,
California. Abstract 210.
15 Sartor O, Reid RH, Bushnell DL, et al. Single and repeated
dose samarium Sm-153 lexidronam in prostate cancer: a safety
assessment. Program and abstracts of the 2nd Annual Multidisciplinary
Prostate Cancer Symposium; February 24-26, 2006; San Francisco,
California. Abstract 266.
16 Sartor O, Sartor EA, Davis N, et al. Predictors of palliative
response for samarium Sm-153 lexidronam: analysis of data from three
randomized controlled blinded trials. Program and abstracts of the 2nd
Annual Multidisciplinary Prostate Cancer Symposium; February 24-26,
2006; San Francisco, California. Abstract 267.
17 Rodrigues NA, Chen M, Catalona WJ, et al. Mortality following
androgen deprivation therapy in patients with a rapidly rising PSA
after local therapy. Program and abstracts of the 2nd Annual
Multidisciplinary Prostate Cancer Symposium; February 24-26, 2006; San
Francisco, California. Abstract 204.
18 Stein MN, Mehta A, Goodin S, et al. Pre-treatment PSA doubling
time (PSADT) predicts biochemical responses to chemotherapy in patients
with androgen sensitive PSA progression after local therapy. Program
and abstracts of the 2nd Annual Multidisciplinary Prostate Cancer
Symposium; February 24-26, 2006; San Francisco, California. Abstract
208.




Authors and Disclosures

Author

Hossein Jadvar, MD, PhD
Assistant Professor of Radiology and Biomedical Engineering, Keck
School of Medicine, University of Southern California, Los Angeles

Disclosure: Hossein Jadvar, MD, PhD, MPH, has disclosed no relevant
financial relationships.

Robert Dreicer, MD, FACP
Professor of Medicine; Chairman, Department of Solid Tumor Oncology,
Cleveland Clinic Lerner College of Medicine, Cleveland, Ohio

Disclosure: Robert Dreicer, MD, FACP, has disclosed that he has
received grants for clinical research from Sanofi-Aventis, Millennium,
Berlex, and Celgene, and has received grants for educational activities
from Sanofi-Aventis and Novartis. Dr. Dreicer has also disclosed that
he has served as an advisor or consultant to Berlex and Bristol-Myers
Squibb.

Editor

Margie Miller
Program Director, Hematology-Oncology

Disclosure: Margie Miller has disclosed no relevant financial
relationships.
 | 
Pages: 1
Prev: IMRT anyone?
Next: Dave's path report