Therapeutic Approaches to Prostate Cancer

From the University of California, San Francisco, School of Medicine’sInnovations in Prostate Cancer: What’s New, What’s Next

Educational Objectives

The goal of this program is to improve the treatment and prevention of prostate cancer. After hearing and assimilating this program, the clinician will be better able to:

1.   Discuss the long-term and short-term effects of radiation therapy.

2.   Reduce a patient’s exposure to radiation (and associated complications) without reducing treatment efficacy.

3.   Eliminate unnecessary or harmful nutritional supplements from a patient’s diet.

4.   Recommend agents shown to be effective in the chemoprevention of cancer.

5.   Prevent loss of bone mineral density in patients undergoing hormone therapy for prostate cancer.

Faculty Disclosure

In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty and members of the plan­ning committee 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. Oh has received research funding from sanofi-aventis and Genentech and is on the Speakers’ Bureau for sanofi-aventis. Drs. Roach and Meng and the planning committee reported nothing to disclose. In their lectures, Dr. Meng and Dr. Oh present informa­tion that is related to the off-label or investigational use of a therapy, product, or device.  

Acknowledgments

Drs. Roach, Meng, and Oh were recorded at Innovations in Prostate Cancer: What’s New, What’s Next, held February 13-14, 2009, in San Francisco, CA, and sponsored by the Department of Urology, University of California, San Francisco, School of Medicine. The Audio-Digest Foundation thanks the speakers and UCSF School of Medicine for their cooperation in the production of this program.

Long-term Risks of Radiation Therapy: Do They Exist?

Mack Roach III, MD, Professor and Chair of Radiation Oncology and Urology, University of California, San Francisco, School of Medicine

Background on radiation therapy (RT): MD Anderson Cancer Institute randomized trial  —  higher doses of radia­tion showed better control rates, but also increased complications (eg, rectal reactions and bleeding); 3-dimensional planning only used for boost portion of RT field; dose constraints not implemented (safe doses not yet established at time of study); intensity-modulated radiation therapy (IMRT) study  —  magnetic resonance imaging identified specific sections of prostate to receive 9000 rad (90 gy) via IMRT (entire prostate received 7560 rad concurrently); electronal portal imaging   —  position of prostate varies daily; gold seeds placed in prostate, then visualized in 3-di­mensional (3D) reconstruction (allows compensation for setup errors and organ movement on daily basis); facili­tates elegant and exact dose distributions (reduces complications by sparing rectum, bladder, and penis); changes in RT  —complications cited by older studies not always relevant, due to significant changes in methodology of RT; better planning yields superior results with fewer complications

Short-term complications: correlated with development of long-term complications (eg, bleeding); during treatment  —  urgency; frequency; nocturia; rectal bleeding; nausea and fatigue (rare); chronic irritation; urgency  —  most common signifi­cant genitourinary (GU) complication; irradiated patients do not often develop typical incontinence, but frequently report urge incontinence; strictures  —  significant occurrence after brachytherapy; not common after external beam radiation (XRT); dilation of strictures may lead to incontinence

Late effects: resolution of long-term constipation; fistulae (uncommon with XRT; associated with brachytherapy [particularly near “hot spot” between rectal wall and urethra]); secondary cancers; hip fractures (associated with excessive exposure to ra­diation); impotence (common late effect with most forms of RT); urinary complications (bladder injuries often appear sev­eral years after treatment); New England Journal of Medicine (NEJM) study  —  RT showed lower rates of incontinence and impotence when compared to surgery; patients in surgical arm younger by average of 10 yr and entered with higher levels of functioning; dose and volume  —  minimization reduces hot spots and complications; 3D conformal RT vs IMRT  —  IMRT provides better dose distributions (eg, delivers greater doses to prostate and lymph nodes, but less radiation to normal tissue); preventing rectal complications  —  IMRT allows effective doses 30% below thresholds associated with bleeding in published literature; majority of patients undergoing IMRT with lowered doses showed mild toxicity; secondary cancers  —  study com­pared rates in men spared prostate-directed RT and men given XRT; XRT showed increased odds ratio of 1.6 for secondary cancers of bladder and rectum; however, patients undergoing RT also showed increased rates of cancer in areas not exposed to radiation (eg, colon, brain); elevated risks not shown with brachytherapy; speaker contends factors influencing selection for RT biased study outcomes; morbidity rates typically higher among patients undergoing RT (ie, greater incidence of smoking, obesity, other factors increasing risk for secondary cancer); observation bias possibly introduced through increased follow-up of patients showing common side effects of RT (eg, rectal bleeding, hematuria); study of bladder and rectal can­cer after RT (2008)  —  243,000 men with history of prostatectomy or RT; when compared to prostatectomy, XRT increased relative risk (RR) for bladder cancer to 1.8 (1.5 for brachytherapy and 1.85 for combination of XRT and brachytherapy); no increased risk for rectal cancer found after comparing rates in study to incidence in general population of United States; speaker’s editorial on study of bladder and rectal cancer after RT  —  study showed RT increased bladder cancer by 1.4% at 10 yr; factoring in competing causes of death may cut apparent risk in half; assuming bladder cancer associated with 5-yr survival rate of 50%, actual risk for death 15 yr after RT may be estimated at 0.035% (in comparison, radical prostatectomy associated with 30-day mortality risk of 0.66% for average 70-yr-old man)

Risks associated with combined treatments: phase III data show postoperative RT increases survival after radical prostatectomy; androgen deprivation therapy (ADT)  —  utilized in combination with RT; misconceptions about car­diac risks associated with ADT  —  several epidemiologic studies show ADT induces metabolic syndrome and in­creases arterial stiffness; population-based studies show increased heart problems; however, studies also show ADT increases survival in patients with metastatic disease; studies showing cardiac risks not randomized; speaker points out that ADT more commonly given to men with severe illness (affects study outcomes); cardiac effects of ADT temporary and reversible; Cancer of the Prostate Strategic URologic Endeavor (CaPSURE) study  —  found in­creased risk for cardiac-related death in patients undergoing prostatectomy; ADT and survival  —  several studies show ADT does not increase risk for myocardial infarction (MI); speaker’s reconstruction of study data showed 50% fewer occurrences of MI in men receiving 3 mo or 8 mo of ADT (compared to men receiving no hormone therapy); recent study data show no increase in earlier cardiac events; 4 mo of ADT found to increase overall sur­vival at 15 yr by 25% (median of 1.4 yr); when looking at disease-specific mortality, incidence of death greater in men receiving RT without hormone therapy; study of time-to-metastatic disease  —40% of men with locally ad­vanced prostate cancer showed metastasis to bone within 5 yr; 4 mo of hormone therapy delayed metastasis by av­erage of additional 7 yr

Supplements: Implications of the SELECT Trial

Maxwell V. Meng, MD, Associate Professor, Department of Urology, University of California, San Francisco, School of Medicine

Prevention of prostate cancer: ideal target for preventive interventions due to high prevalence and significant effects of disease; prolonged latency and natural history indicate that early intervention (eg, dietary supplementation or di­etary modification) may change prognosis or eliminate need for treatment in patients with low-risk disease; patients derive significant benefit from prevention, due to significant morbidity associated with treatments; androgens  —  stimulate development of prostate cancer; high-grade prostatic intraepithelial neoplasia (PIN)  —  implicated in stepwise pathogenesis of prostate cancer; identification of hereditary components  —  allows preventive action in high-risk populations (instead of targeting all men)

Chemoprevention of cancer: colorectal cancer  —  strong evidence for role of nonsteroidal anti-inflammatory drugs (NSAIDs); other agents include calcium, vitamin D, and folate; cyclooxygenase (COX)-2 inhibitors (controver­sial due to adverse cardiovascular effects); breast cancer  —  selective estrogen receptor modulators (SERMs; eg, tamox­ifen, raloxifene) shown to prevent breast cancer; evidence  —  additional human trials required to prove efficacy of agents for preventing colorectal, breast, and prostate cancer; risks and benefits associated with giving agents to large popula­tions remain unknown; indicated in patients with higher risk for disease development (as opposed to general popula­tion); selenium and vitamin E for prostate cancer  —  show activity as antioxidants affecting cytochrome P450 pathway (cause cell cycle arrest, apoptosis, and modification of sphingolipid synthesis); apparently safe

Studies on Supplementation

Selenium: Nutritional Prevention of Cancer Study Group  —patients randomized to 200 µg selenium or placebo; sele­nium group showed significant reductions in incidence of prostate cancer (effect primarily confined to patients with lower prostate-specific antigen [PSA]); Physician’s Health Study (PHS)  —  in nearly 600 men in cohort who devel­oped prostate cancer, prediagnostic plasma levels of selenium inversely correlated with advanced disease; higher selenium levels also associated with lower risk for disease in men with elevated PSA

Alpha-tocopherol and b-carotene (ATBC): prostate cancer reduced by 32% in patients receiving vitamin E (with 41% re­duction in prostate cancer mortality); however, b-carotene increased lung cancer risk and mortality; beneficial and nega­tive effects disappeared during long-term follow-up

SELenium and Vitamin E Cancer Prevention Trial (SELECT) (2001): included >35,000 men from diverse popula­tion (20% nonwhite); patients received placebo, selenium, vitamin E, or vitamin E plus selenium; 1500 to 2000 cancers found during follow-up; demonstrated feasibility of large-scale cancer prevention trial; ended early by data safety and moni­toring board when preliminary data indicated that continued follow-up unlikely to show benefits; no reductions in prostate cancer found in patients receiving vitamin E and selenium; trend toward increased prostate cancer shown in vitamin E group; selenium group showed increase in diabetes (not seen in patients taking vitamin E plus selenium); no other differ­ences in secondary end points (eg, other cancers, cardiovascular events); no differences in rates of cancer-specific or overall death; possible explanations for results of SELECT trial  —  SELECT study chose selenomethionine for more consistent dos­ing (other studies utilized high-selenium yeast); doses of vitamin E higher than in ATBC trial (possibly associated with neg­ative effects); relatively few smokers included; most study participants selenium replete; many previous studies focused on men with low baseline plasma selenium (elevating levels past normal may not provide benefits; bringing men from selenium-depleted state to selenium repletion may still prevent cancer); corroborating evidence  —  Physician’s Health Study-II and Heart Outcomes Prevention Evaluation (HOPE) trial

Women’s Health Initiative: combination of 160,000 postmenopausal women from observational trials and trials of hormones, multivitamins, calcium plus vitamin D, and dietary changes; median follow-up, 8 yr; end points in­cluded cardiovascular disease, several cancers, and total and overall mortality; no changes in hazard ratios for any end points in nearly half of women

Hormones and prostate cancer: Prostate Cancer Prevention Trial (PCPT)  —  showed finasteride reduced total prostate cancer incidence by 25%; initial results indicating increases in high-grade cancers now dismissed; efficacy and cost-effectiveness in population-wide prevention remains uncertain; toremifene  —  promising in prevention of progres­sion from high-grade PIN to prostate cancer; may improve lipid profiles and bone mineral density in men undergoing ADT

Rationale for Multimodal Therapy in
Patients with High-Risk Disease

William K. Oh, MD, Associate Professor, Harvard Medical School, and Clinical Director, Lank Center for Genito­urinary Oncology, Dana-Farber Cancer Institute, Boston, MA

ADT toxicity: symptoms related to all biologic processes involving testosterone; hot flushes and loss of libido well recognized as symptoms (although impact on quality of life [QOL] poorly studied); other symptoms include weight gain, decreased muscle mass, accelerated osteoporosis, bone fractures, and decreased cognitive function; responses often heterogeneous

Bone mineral density (BMD): significantly decreased by luteinizing hormone-releasing hormone (LHRH) agonists; dual en­ergy x-ray absorptiometry (DEXA) of lumbar spine, and total hip show significant decreases at 12 mo (compared to con­trols); loss occurs at rate of 2% to 3% per year of ADT; progressive loss eventually causes exponential rise in vertebral fractures; NEJM fracture study (2005)  —  at 1 to 5 yr after diagnosis of prostate cancer, ADT increased risk of developing fractures by 7%; fractures associated with pain and significant rate of hospitalization; LHRH agonists showed dose-response curve (1-4 doses showed no significant toxicity); risk for fractures increased 15% to 20% after 5 yr of ADT (compared to risk at 2-3 yr); data on fractures in patients with prostate cancer show inferior survival associated with any fracture or history of fracture; fractures also increase mortality risk in healthy older patients with no significant comorbidities

Effects of bisphosphonates: study in NEJM  —  men given pamidronate before starting therapy with LHRH agonists main­tained BMD; zoledronic acid (Zometa) given every 3 mo increased BMD; alendronate study  —  results comparable to those with intravenous bisphosphonates (eg, pamidronate and zoledronic acid); associated risks  —  flu-like symptoms (typically with first or second dose); nausea; fatigue; renal toxicity (controversial; zoledronic acid label changed due to effects on creatinine clearance; speaker’s retrospective study associated zoledronic acid with »25% risk for renal insuffi­ciency); osteonecrosis of jaw (modest occurrence in prostate cancer; patients should avoid tooth extractions and consult specialist dentists for necessary procedures)

Estrogen: has secondary hormonal activity (eg, antitumor activity); severely deficient in castrated patients; critical hormone in building bone; SERMs targeting estrogen receptor (ER)-a (most important for bone building) assessed for efficacy in increasing BMD; toremifene study  —  no anticancer activity in hormone-resistant disease; older pa­tients and patients with low BMD undergoing ADT randomized to receive toremifene or placebo; toremifene ex­hibits mixed antiestrogenic and proestrogenic properties; toremifene showed improvements in BMD comparable to alendronate; however, toremifene also reduced RR for vertebral fractures by 50% during observation period; tore­mifene also increased risk for venous thromboembolism (VTE) (effect seen with all estrogenic compounds) toremi­fene and thromboembolism  —  increases in risk seen mostly during initial years of treatment; majority of occurrences predictable based on specific risk factors (eg, older age, recent surgery, history of VTE)

Speaker’s recommendations: assess risk factors for osteoporosis and osteopenia; ask about loss of height; screening not high priority with short-term ADT; monitoring  —consider BMD; all men should take calcium and vitamin D supplements; BMD increased with exercise and decreased with alcohol and smoking; bisphosphonate therapy rea­sonable in patients with osteoporosis or osteopenia; repeat monitoring every 1 to 2 yr

Cardiovascular effects of ADT: evidence suggests modest effects (if any); dependent on other factors affecting risk for death from MI; without comorbidities, 6 mo of hormone therapy clearly improves survival; however, with specific co­morbidities (eg, cardiovascular [CV] risk factors), hormones deceased survival; patients with CV risks should consult car­diologist for evaluation before undergoing ADT

Suggested Reading

Gaziano JM et al: Vitamins E and C in the prevention of prostate and total cancer in men: the Physicians' Health Study II random­ized controlled trial. JAMA 301:52, 2009; Li H et al: A prospective study of plasma selenium levels and prostate cancer risk. J Natl Cancer Inst 96:696, 2004; Lippman SM et al: Effect of selenium and vitamin E on risk of prostate cancer and other cancers. JAMA 301:39, 2009; Moon K et al: Cancer incidence after localized therapy for prostate cancer. Cancer 107:991, 2006; Nieder AM et al: Radiation therapy for prostate cancer increases subsequent risk of bladder and rectal cancer: a population based cohort study. J Urol 180:2005, 2008; Pollack A et al: Prostate cancer radiation dose response: results of the M. D. Anderson phase III randomized trial. Int J Radiat Oncol Biol Phys 53:1097, 2002; Sanda MG et al: Quality of life and satisfaction with outcome among prostate-cancer survivors. N Engl J Med 358:1250, 2008; Saylor PJ, Smith MR: Bone health and prostate cancer. Prostate Cancer Prostatic Dis 13:20, 2010; Shahinian VB et al: Risk of fracture after androgen deprivation for prostate cancer. N Engl J Med 352:154, 2005; Smith MR et al: Pamidronate to prevent bone loss during androgen-deprivation therapy for prostate cancer. N Engl J Med 345:948, 2001; Smith MR et al: Toremifene improves lipid profiles in men receiving androgen-deprivation therapy for prostate cancer. J Clin Oncol 26:1824; Virtamo J et al: Incidence of cancer and mortality following alpha-tocopherol and beta-carotene supplementation: a postintervention follow-up. JAMA 290:476, 2003.