NEW FRONTIERS IN PROSTATE CANCER MANAGEMENT
From Perspectives in Urology: Point/Counterpoint
| NOVEL NEW AGENTS: ATRASENTAN, SIPULEUCEL-T, AND SATRAPLATIN —E. David Crawford, MD,
Professor of Surgery, Urology, and Radiation Oncology, Head, Section of Urologic Oncology, and E. David and
Vicki M. Crawford Endowed Chair in Urologic Oncology, University of Colorado Health Sciences Center, Denver
|
| Metastatic prostate cancer: patients present with—relatively high tumor volume; elevated prostate-specific antigen
(PSA)
|
 | Lowering testosterone levels: usually involves administration of leuteinizing hormone–releasing hormone (LHRH)
agonist with or without antiandrogen; approach initially reduces PSA levels, improves bone scans, and can enhance
performance status; over time, cancer “escapes” and patient—receives secondary hormonal therapy,
which may prove effective initially; eventually progresses to androgen-independent prostate cancer (AIPC) or
hormone-refractory prostate cancer (HRPC)
|
| Chemotherapy: recent data show approach can affect overall survival in men with HRPC; when compared to combinations
of mitoxantrone and prednisone, docetaxel (Taxotere) alone or in combination with estramustine improved
survival by ≈2 mo; new advances needed to achieve significant improvement in treatment efficacy
|
| Targeted therapy: options—antigen-specific immunotherapy (opportunity exists to couple antigenic substances, ie,
PSA, prostate-specific membrane antigen [PSMA], and prostate acid phosphatase [PAP], with other factors that can
stimulate immune system to attack prostate cancer); organ-specific therapy (based on tendency for prostate cancer to
spread to bone; investigational agents include zoledronic acid and atrasentan); specific mechanistic approach (uses
antiangiogenesis-like agents that target tumor vasculature); therapy—targets cell surface, immune system, and vascular
antigens; works through intracellular pathways using tyrosine kinase inhibitors, antinuclear chemotherapy, antitubulin
agents, BcL-2 protein blockers (ie, antisense drugs block BcL-2 activity to facilitate apoptosis), and drugs
designed to target androgen receptors (eg, bicalutamide)
|
| Immunomodulation for treatment of prostate cancer: why developed—new approaches for managing advanced
and AIPC needed; patients with malignancy often demonstrate defects in immunologic tolerance; prostate tumors
characteristically immunogenic, ie, recent research has focused on improved methods for presenting antigens that
stimulate or restore immune system; approaches under development to treat AIPC from immunologic standpoint—
tumor androgen vaccine (antigens fairly specific for prostate cancer activate T cells); autologous dendritic cells
(DCs; only cells in body that stimulate native T and B cells to make antibodies); DCs and cytokines to directly
stimulate immune system; cytotoxic T-lymphocyte antigen 4 (CTLA4) to block compounds that impair immune
system; small molecules to stimulate immune system, eg, thalidomide has well known toxicity profile (safer, more
potent analogues under development)
|
| Tumor vaccines: immunotherapy; characteristics of candi-dates—PSA progression secondary to development of
androgen resistance; low tumor burdens; targeted tumor antigens—data show number of investigational compounds
work with PSA, PAP, and PSMA; Eastern Cooperative Oncology Group (ECOG) vaccine trial for advanced
prostate disease results—well-tolerated, nonhormonal immunomodulation can stabilize PSA levels and
exert therapeutic effect on prostate cancer; injection site reaction and hyperglycemia 2 most common side effects;
no evidence of specific or nonspecific autoimmunity; phase 3 trial planned
|
| Active cellular immunotherapy (ACI): involves new class of vaccines, in which patient’s immune system used to
target cancer cells; prostate cancer considered good target for ACI (gland highly differentiated and contains
many specific antigens); PAP—antigen highly expressed in >90% of prostate cancers; used in producing vaccine
|
| Sipuleucel-T (Provenge): uses body’s own “materials” to make antigen-presenting cells (APCs); process—patient
undergoes leukapheresis; blood processed to enable PAP to combine with and present on surface of APCs; patient
receives 3 infusions (week 0, week 2, and week 4) of fully activated APCs (ie, sipuleucel-T); T cells activated
by vaccine attack cancer cells; combined data from trials D9901 and D9902A—vaccine prolongs
survival; has favorable safety profile; side effects include mild chills and pyrexia; status—approval to be based
on updated survival data available in 2008
|
| Bone: favored site for disease spread (autopsy study detected bone involvement in 90% of cadavers with documented
prostate cancer); once disease spreads to bone, hypothetical “seed and soil” process occurs (cancer cells, osteoblasts,
and osteoclasts demonstrate complex interaction within bone microenvironment); endothelin-1 (ET-1)—produced by
prostate cancer cells; potent vasoconstrictor; interacts with bone environment; incites cell growth; inhibits apoptosis;
stimulates angiogenesis and osteoblastic remodeling of bone; immunoreactive endothelin assay—highly expressed in
men with HRPC; viable target
|
| Atrasentan: endothelin antagonist; data derived from men with metastatic HRPC—atrasentan effective when given in
10-mg dose; favorable results in bone-specific alkaline phosphatase (BAP) and N-telopeptide (NTx) bone marker
studies; Docetaxel and Atrasentan Hormone Refractory Prostate Cancer Trial (DAHRT)—under development;
will evaluate men with progressive metastatic AIPC randomized to combination of atrasentan, docetaxel, and prednisone
vs docetaxel and prednisone
|
| Angiogenesis: tumors—require blood supply to grow; use angiogenesis factors to stimulate blood vessel ingrowth;
may be treatable with drugs that block angiogenesis; bevacizumab (Avastin)—undergoing large randomized trial
in men with HRPC; other drugs under investigation
|
| Vitamin D: exerts antiproliferative effect on cancer cell lines; may be beneficial if added to other anticancer compounds
|
| AIPC Study of Calcitriol Enhancement of Docetaxel (Taxotere) (ASCENT) trial: builds on docetaxel enhanced
with calcitriol; participants had no history of previous chemotherapy and were free of kidney stones; key
finding—when compared to placebo, combination of docetaxel and DN101 proved beneficial for overall survival
and tumor and PSA response
|
| Second-line chemotherapy when primary docetaxel therapy fails
|
| Satraplatin: oral platinum agent; undergoing phase 3 trial involving men with refractory disease in which other chemotherapy
agents failed (participants randomized to satraplatin and prednisone); key observations—data show
oral platinum drug provided level of therapeutic activity; additional multicenter trials underway
|
| Conclusions: targeted therapy—promising new approach; potentially can achieve greater specificity with less toxicity;
phase 3 trials initiated; next generation of drugs will build on docetaxel experience
|
| PARALLELS BETWEEN PROSTATE AND BREAST CANCERS/THE ROLE OF EARLIER THERAPY FOR
PROSTATE CANCER —David C. Beyer, MD, Clinical Lecturer, University of Arizona College of Medicine,
Scottsdale, and Vice President, Arizona Oncology Services, Phoenix
|
| Demographic data on prostate and breast cancers: both cancers place first for incidence of new disease (prostate
cancer represents 33% of all new cancers in men; breast cancer 31% of all new cancers in women); mortality—
each year, 27,000 men die of prostate cancer, and 40,000 women die of breast cancer; lung cancer remains number
one cancer-related killer in both men and women; probability of developing disease—risk for breast cancer increases
at earlier age (substantial increase in incidence occurs in 40 to 59-yr-old age group); increase in prostate
cancer risk somewhat less among men in same age group; incidence of both cancers increases with age, eg, among
≥70 yr olds, women face ≈7% risk of developing breast cancer, and men face ≈14% risk of developing prostate
cancer; lifetime risk—prostate cancer, ≈18%; breast cancer, ≈13%; distribution at presentation—breast cancer
(≈60% of cases present as localized disease, ≈30% as regional disease, and 5%-10% as distant disease; blacks at
higher risk for metastatic and regional spread); prostate cancer (≈90% of cases present as localized disease, and
5%-7% as distant disease; regional disease rare; blacks have higher incidence of distant disease at presentation); 5-
yr survival rates—breast cancer (90%-95% for localized disease, ≈80% for regional disease, and ≈26% for distant
disease; for all stages, 80%-95% of women who develop disease survive 5 yr; race-based difference in 5-yr relative
survival considered significant); prostate cancer (≈100% of men with localized disease and ≈30% of men with distant
disease alive at 5 yr; differences in survival according to race less pronounced than with breast cancer); factors
that may correlate with risk for breast and prostate cancers—quantity of dietary fat and fiber; body mass index;
consumption of vitamins A, E, and C; dietary selenium; alcohol and caffeine consumption
|
| Breast cancer: concepts about disease spread have changed; current thinking suggests—breast cancer systemic disease
from early stage and has no orderly pattern of dissemination; positive lymph nodes indicators of distant metastases,
but do not instigate distant disease; lymph node chain in axilla and internal mammary does not provide
barrier to disease spread, but can signal that spread has taken place; blood stream plays key role in early disease
spread; local and regional management (although important) should be considered secondary to systemic treatment;
breast conservation—current option for treating primary lesion includes partial breast irradiation after
lumpectomy
|
| Systemic management: primary treatment; adjuvant hormone therapy—often incorporated into systemic management;
tamoxifen (Nolvadex) remains critical agent in managing many women; Early Breast Cancer Trialists Collaborative
Group (EBCTCG) data show 5 yr of adjuvant therapy reduced recurrence by 47% and mortality by
26% in receptor-positive patients; adjuvant chemotherapy — standard therapy for selected patients; traditionally
started immediately after initial surgery; sequencing of radiation and adjuvants—chemotherapy (radiation can
be administered before or after chemotherapy; chemotherapy should be administered early after initial treatment);
hormonal therapy (no difference in outcomes noted among patients who received concomitant administration
of tamoxifen and radiation)
|
| Conclusions about management: early hormone therapy superior to hormone therapy given at time of relapse; long-
term hormone therapy superior to short-term hormone therapy; early chemotherapy better than chemotherapy
given at time of relapse; immediate salvage therapy considered standard of care for women who relapse
|
| Prostate cancer: status quo—early hormone therapy indicated for select patients managed by irradiation; no established
role for chemotherapy; controversy over when to initiate hormone therapy in setting of recurrence or salvage;
chemotherapy often delayed until advanced disease develops; in patients receiving irradiation — early
hormonal therapy alters mortality rate among men with high-risk disease; in patients with positive nodal
disease—early hormone intervention beneficial; delayed hormone therapy associated with poorer disease-free
and overall survival rates
|
| Conclusions derived from meta-analysis of study data: early hormone therapy (adjuvant and neoadjuvant) proven
beneficial for men with—intermediate- and high-risk disease who are undergoing irradiation; node-positive disease
undergoing surgery; long-term hormone therapy—superior for patients at greatest risk for cancer death, including
men with Gleason scores of 8 to 10, and those with bulky T3 and T4 disease; early intervention indicated
at time of relapse; chemotherapy—worth considering and studying in adjuvant setting
|
| Problem patient population: benefits from adjuvant hormone therapy and irradiation; ultimately does poorly, with
marked risk for biochemical failure and death even after receiving optimum therapy; Radiation Therapy Oncology
Group (RTOG) study—important ongoing study; designed to improve care of problem patients; investigating use
of reasonable radiation doses and long-term androgen deprivation in high-risk patients with Gleason scores ≥7 and
PSA levels ≤150 ng/mL; patients receive 72 to 76 Gy of radiation and undergo long-term androgen deprivation; 28
days after completion of irradiation, patients (who seem to be doing well) randomized to 6 cycles of docetaxel and
prednisone; breast cancer model—basis for approach; showed efficacy of adjuvant therapy using drugs known to
work in advanced disease
|
| Bottom line: data show trend toward improvement at 10 yr after early hormonal intervention; management of prostate
cancer should include paradigms proven effective in breast cancer management
|
| ROBOTIC SURGERY —Donald L. Lamm, MD, Clinical Professor, University of Arizona College of Medicine,
Scottsdale, and Director, BCG Oncology, Phoenix, AZ
|
| Consider disease risk when selecting treatment: Gleason score ≤4—mortality rate 7%; patients require either no
treatment or nontoxic treatment; Gleason score 5 — mortality rate 10% at 5 yr; Gleason score ≥6 — potential for
long life; can be treated (minimize morbidity of approach)
|
| Management options: modern cryotherapy nontoxic and proven beneficial in certain cases, eg, management of
obese patients; radical retropubic prostatectomy—gold standard; operating time, <3 hr; duration of hospitalization,
<3 days; length of catheterization, 1 to 2 wk; transfusion rate, 5%; mortality rate, 0.2%; biochemical disease-free
survival, ≈70%
|
| Laparoscopic prostatectomy: advantages—overall decreased morbidity; significantly less postoperative pain and
blood loss; patients able to leave hospital and return to full activity sooner; fewer complications; superior cosmesis;
economically competitive with open radical prostatectomy
|
| Robotic approach to radical prostatectomy: patient demand markedly increased use of robotic prostatectomies;
comparison to laparoscopic procedure—shorter learning curve; shorter operative time (but similar outcomes);
more expensive; comparison to open radical prostatectomy—reduced blood loss; increased hematocrit at discharge
|
| Conclusions: individualize treatment approach based on—life expectancy; PSA level; numbers of positive biopsies;
robotic surgery—popularity will increase with demand for less morbid surgery; competitive with radical
prostatectomy
|
Suggested Reading
Ferdowsian HR, Barnard ND: The role of diet in breast and prostate cancer survival. Ethn Dis 17:S2, 2007; Friedman
AE: Can a single model explain both breast cancer and prostate cancer? Theor Biol Med Model 4:28, 2007;
Kipp RT, McNeel DG: Immunotherapy for prostate cancer—recent progress in clinical trials. Clin Adv Hematol
Oncol 5:465, 2007; McKeage MJ: Satraplatin in hormone-refractory prostate cancer and other tumour types: pharmacological
properties and clinical evaluation. Drugs 67:859, 2007; Moyad MA: What happened to the Provenge
(Sipuleucel-T) vaccine for hormone refractory prostate cancer? Urol Nurs 27:256, 2007; Murphy G: Atrasentan for
metastatic hormone refractory prostate cancer. Issues Emerg Health Technol 77:1, 2005; Pilepich MV et al: Androgen
suppression adjuvant to definitive radiotherapy in prostate carcinoma-long-term results of phase III RTOG 85-
31. Int J Radiat Oncol Biol Phys 61;1285, 2005; Raman JD et al: Robotic radical prostatectomy: operative technique,
outcomes, and learning curve. JSLS 11:17, 2007.
Educational Objectives
| The goal of this program is to improve management of prostate cancer through a greater acquaintance with new technologies.
After hearing and assimilating this program, the clinician will be better able to:
|
| 1. Discuss the role of targeted therapy in the management of hormone refractory prostate cancer.
|
| 2. Describe concepts underlying active cellular immunotherapy with sipuleucel-T and targeted small molecule
therapy using atrasentan.
|
| 3. Explore correlations in demographic and clinical data between prostate cancer and breast cancer.
|
| 4. Assess the clinical merits of early hormonal therapy in the management of prostate cancer
|
| 5. Determine the present and future role of robotic surgery in prostate cancer management.
|
Faculty Disclosure
In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty members to disclose
relevant financial relationships within the past 12 months that might create any personal conflicts of interest. Any
identified conflicts were resolved to ensure that this educational activity promotes quality in health care and not a proprietary
business or commercial interest. For this program, the following has been disclosed: Dr. Crawford is affiliated
with Auxilium Pharmaceuticals, Celgene, Endocare, Merck & Co, Oncura, Praecis Pharmaceuticals, Sanofi-
Aventis, and Watson Pharmaceuticals (division formerly known as Andrx); Dr. Lamm is affiliated with Organon and
Sanofi Pasteur.
Acknowledgments
Drs. Beyer, Crawford, and Lamm gave their scientific presentations at Perspectives in Urology: Point/Counterpoint, presented
November 9-11, 2006, in Scottsdale, AZ, by US Micron (now known as Grant Downing Education, www.grantdowning.com).
The Audio-Digest Foundation thanks the speakers and the sponsor for their cooperation in the production
of this program.
|
