Prostate Cancer

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Evidence-Based Oncology, May, Volume 18, Issue SP3

Prostate cancer is the most prevalent non-cutaneous malignancy among men, accounting for over 240,000 new diagnoses each year in the United States.1 Because of its indolent nature and the excellent curative options for early-stage disease, prostate cancer deaths are more modest, occurring in fewer than 34,000 men each year.1 According to estimates from the American Cancer Society, the 5-year survival for patients with prostate cancer is almost 100%, and the 10-year survival is 91%.2

In a significant portion of patients, prostate cancer progresses very slowly or poses limited danger. Therefore, it is sometimes said that “more people die with prostate cancer than of prostate cancer.” Conservative approaches to treatment for patients with indolent prostate disease often include little more than periodic monitoring with prostate-specific antigen (PSA) testing.

Even patients with indolent prostate cancer often choose active treatment approaches, which can include surgery or radiation therapy followed by hormonal therapy, which essentially reduces testosterone to post-castration levels. In patients with active disease, this approach prolongs survival, but in a proportion of these patients, the disease will progress. Once patients reach this advanced stage, called metastatic castrate-resistant prostate cancer (CRPC), the disease is no longer indolent, having a median survival of only 16 to 20 months.3,4 For these patients and the healthcare system, the question of value is more of a consideration.

Nearly 2.36 million American men are estimated to have prostate cancer,5 and the total cost of caring for these patients has been estimated to be $9.86 billion.6 Approximately 10% to 20% of these men will develop CRPC within 5 years of diagnosis.7 In 1 health economic study of CRPC patients, the total per patient prostate cancer—related costs were $21,588 annually.8 In another study, performed in 2006 prior to the approval of the 4 most recent agents, the mean costs for the last year of life were $33,691.6 Current costs are almost certainly significantly greater.

Current Treatment Options

For patients who have metastatic CRPC, metastases are most often found in the bone, with 1 study reporting that 84% of all patients with CRPC have bone metastases upon diagnosis.9 These patients generally receive either the bisphosphonate zoledronic acid or the more recently approved targeted agent denosumab to prevent or delay skeletalrelated events (SREs) associated with bone metastases.10 Radiation therapy may also be used to control bone pain, and surgical intervention is sometimes necessary as well. In addition to these palliative treatments, the active treatments described below are prescribed, depending on whether these patients are currently experiencing symptoms or not.

For asymptomatic metastatic CRPC patients, the National Comprehensive Cancer Network recommends treatment with 1 course (3 doses) of sipuleucel- T (Provenge),10 the first therapeutic vaccine to be approved by the US Food and Drug Administration (FDA) and which has been shown to produce a survival advantage of 4.1 months.11 Asymptomatic patients are also often treated with secondary hormonal therapy, such as ketoconazole or an antiandrogen, although no survival benefit has ever been established for this approach.

Once patients develop symptomatic disease, they generally receive treatment with the chemotherapeutic agent docetaxel (Taxotere), which has demonstrated a survival advantage of 2.4 months.12 After failure of docetaxel, several options exist, including (1) the targeted hormonal agent abiraterone acetate (Zytiga), providing a survival benefit of 3.9 months,13 (2) another chemotherapy agent, cabazitaxel (Jevtana), providing a survival benefit of 2.4 months,14 (3) docetaxel rechallenge, and (4) secondary hormonal therapy.

Economics

All of the above-outlined, recently approved treatment options for CRPC patients come at a high price tag. Sipuleucel- T is the most expensive therapy, costing $93,000 for a full course, but only 1 course of therapy is given to each patient. The average wholesale price of cabazitaxel is $9600 for 1 course of treatment, with a median of 6 courses given in the pivotal trial, for a median total of $57,600 per patient.15 Abiraterone costs $5000 per month and the average duration of treatment in its pivotal trial was 8 months, for an average total of $40,000 per patient.13

Abiraterone has the additional challenge of being an oral drug, which is often covered (or not covered) under a patient’s pharmacy benefit rather than as a medical benefit. Because prescription drug coverage is typically less generous than medical coverage, patients prescribed oral targeted agents often find themselves responsible for paying thousands of dollars in coinsurance. Thus, the amount of patient out-ofpocket costs often becomes the deciding factor in treatment choice, with patients often forgoing life-prolonging therapy due to the high cost of the drug.

For the prevention of SREs, the cost of denosumab is $1650 per dose, compared with $844 for zoledronic acid,16,17 but the drug acquisition costs are not the only considerations when determining overall cost-effectiveness. Because denosumab is administered via subcutaneous injection rather than intravenous infusion, it saves both chair time and infusion costs relative to zoledronic acid. In addition, denosumab avoids 0.11 SREs per year in patients with CRPC.15 In 1 health economic study, when all costs were considered, including the cost of avoided SREs, denosumab was associated with a $51,319 incremental increase per SRE avoided over a 3-year period in this patient population.15 Based on a willingness-to-pay threshold of $70,000 per SRE avoided, denosumab was costeffective in nearly 50% of cases at 1 year and 79% of cases at 3 years.15

Additional Drivers of the Cost of Care

According to 1 analysis, costs incurred by patients with CRPC are greatest in the 6 months preceding death because of home-care services, hospitalization, and palliative-care costs.18 This analysis was conducted before the advent of the newer, more expensive drugs now available for the treatment of CRPC. In the current landscape, drug costs are certain to be a formidable driver of costs. However, unlike many therapies in the past, these drugs produce a survival advantage, making them potentially a good value despite their high cost.

In a recently published health economic study of patients with prostate cancer, ambulatory costs were determined to be the main driver of the cost of care, accounting for 57% of the total costs.8 Ambulatory costs were those incurred during physician office visits and visits at outpatient facilities, such as outpatient procedures and services (eg, laboratory work, radiology services). The next most costly driver of the cost of care for patients with CRPC was inpatient costs, absorbing 30% of the total costs. Pharmacy costs accounted for less than 10% of the total cost, and emergency department costs were negligible.

Payer PerspectiveInterview with Kenneth Schaecher, MD

EBO:

Prostate cancer is a bit unusual as a carcinoma because it is either aggressive or very slow growing and there are a number of options to treat it (eg, surgical resection, cryotherapy, radiologic therapy, chemotherapy, immunomodulatory treatment). How do health plan efforts to help patients make choices that are most appropriate for them provide value?

Dr Schaecher:

Helping patients make the choice that is right for them is a challenge because of the fragmented nature of the sites of care for prostate cancer. Urologists attempt to provide counseling but their bias is to do surgery, and patients may be unintentionally steered in that direction. Patients themselves let their own biases choose therapies. For example, they may decide on proton-beam therapy, based on marketing, rather than other forms of radiation therapy, which are equally efficacious but much less costly.

Our health plan is embarking on “shared decision-making” pilots around this area, in an effort to help patients objectively wade through the volume of information on the various treatment modalities in an objective and organized manner free of individual provider or marketing biases. These shared decision-making tools will be available at both specialty care sites and primary care offices for patients diagnosed with prostate cancer and working through the decision process as to how they wish to proceed with treatment.

EBO:

What is your view on prostate-specific antigen (PSA ) testing and its ability to stratify patients at risk for aggressive malignancy?

Dr Schaecher:

The role of PSA testing has become more controversial, given the recent recommendations of the US Preventive Services Task Force to discontinue use of this test as a means to screen for prostate cancer. This recommendation was based upon their review of a number of studies but especially 2 large studies that showed the harms from this testing likely outweighed the benefits.

This recommendation has not been universally supported by urologists and some other practitioners, as they feel PSA testing has some benefit when used in conjunction with a digital rectal exam of the prostate and when viewed serially over time rather than as a single value.

From a payer perspective, I believe there is increased skepticism regarding the value of PSA testing as it is primarily being performed by primary care physicians (PCPs) and they remain for the most part uninformed about the nuances of this testing. There is a great deal of evidence to support that PSA testing is not a sensitive tool for determining the aggressiveness of prostate cancer, but at the same time it is a readily available and accepted test by PCPs and thus is used.

EBO:

How strong a role does your organization’s medical technology assessment group play in policy making for prostate cancer treatments (versus a Pharmacy & Therapeutics [P&T] Committee)?

Dr Schaecher:

It depends on the treatment. Drugs are typically assessed by a P&T Committee whereas other treatments like surgical procedures, radiation, or cryotherapy are evaluated by the Technology Assessment Committee. There can be some overlap in committee function should there be a pharmaceutical treatment that is administered by some unique device. In that circumstance, the technology assessment committee would take the lead and present its final determination to P&T for notification and discussion.

EBO:

Does your health plan cover the Provenge vaccine?

Dr Schaecher:

We do cover Provenge, but we apply prior authorization that is specific to the FDA labeling.

EBO:

Do you believe that therapeutic vaccines like Provenge will provide an avenue to good value in prostate cancer treatment?

Dr Schaecher:

Therapeutic vaccines have the potential to offer an alternative treatment for patients who have failed alternative therapies and perhaps over time an earlier line of therapy. However, the word “value” is pejorative. Is this clinical “value” or financial “value”? At the current price points set for Provenge, it doesn’t seem to offer significant financial value, though it may offer limited clinical value. The failure of urologists and medical oncologists to embrace this therapy as evidenced by its slow update may also speak to residual questions regarding the clinical value of this particular therapy, but I don’t think it is a statement regarding therapeutic vaccinations in general.

From a health plan perspective, Provenge is not felt to be of value based on its current pricing and the fact that it offers limited clinical benefit based on current clinical studies.

EBO:

What do you believe is the most exciting area for pipeline research in prostate cancer?

Dr Schaecher:

Immune system modulation—whether it be through therapeutic vaccine or biologic therapy—is the area that has the greatest “mojo” at present. Given that for many patients, prostate cancer is an indolent disease that has characteristics which are more akin to a chronic immune state like lupus, rheumatoid arthritis, or multiple sclerosis, engaging a targeted approach that helps the immune system identify and eliminate aberrant cell lines shows significant promise in treating this condition.

Dr Schaecher is medical director, SelectHealth, based in Salt Lake City, Utah.

Additional Suggested Reading

Stokes ME, Ishak J, Proskorovsky I, Black LK, Huang Y. Lifetime economic burden of prostate cancer. BMC Health Serv Res. 2011;11(1):349.

A model was developed to estimate the lifetime costs of patients with prostate cancer; the authors found that this averaged $34,400.

Park S, Kim SC, Kim W, Song C, Ahn H. Impact of adjuvant androgen-deprivation therapy on disease progression in patients with node-positive prostate cancer [published online ahead of print November 17, 2011]. Korean J Urol. 2011;52(11):741-745.

Adjuvant androgen-deprivation therapy patients with metastatic prostate cancer did not reduce or delay disease progression or improve survival, according to this research from South Korea, raising doubts about the value of this therapeutic intervention.

Chou R, Dana T, Bougatsos C, et al. Treatments for Localized Prostate Cancer: Systematic Review to Update the 2002 U.S. Preventive Services Task Force Recommendation [Internet]. Rockville, MD: Agency for Healthcare Research and Quality (US); October 2011:Publication No. 12-05161-EF-1.

This comprehensive review of evidence-based data demonstrates that for patients with early, localized prostate cancer, virtually any active intervention has important adverse effects. Based primarily on cohort studies, treating approximately 3 men with prostatectomy, 7 men with radiation therapy, or 2 to 3 men with androgen deprivation therapy instead of watchful waiting would each result in 1 additional case of erectile dysfunction, and treating approximately 5 men with prostatectomy would result in 1 additional case of urinary incontinence (in addition to perioperative mortality or other complications).

Lin K, Croswell JM, Koenig H, Lam C, Maltz A. Prostate-Specific Antigen-Based Screening for Prostate Cancer: An Evidence Update for the U.S. Preventive Services Task Force [Internet]. Rockville, MD: Agency for Healthcare Research and Quality (US); October 2011:Publication No. 12-05160-EF-1.

In this updated review, the reviewers find that after about 10 years, PSA-based screening results in the detection of more cases of prostate cancer, but small to no reduction in prostate cancer—specific mortality.

Allan GM, Chetner MP, Donnelly BJ, et al. Furthering the prostate cancer screening debate (prostate cancer specific mortality and associated risks). Can Urol Assoc J. 2011;5(6):416-421.

In high-quality studies of prostate cancer screening (particularly prostate-specific antigen), there is good evidence that prostate cancer mortality is reduced. However, the risks associated with prostate cancer screening (including a 70% false-positive rate and adverse events associated with biopsy) are considerable and must be weighed against the advantage of reduced cancerspecific mortality.

Godbole AM, Njar VC. New insights into the androgen-targeted therapies and epigenetic therapies in prostate cancer [published online ahead of print October 12, 2011]. Prostate Cancer. 2011;2011:918707.

A review of the findings about the antiandrogens and the epigenetic factors that modulate the action of androgen receptors in patients with prostate cancer.

Swanson GP, Quinn D. Using molecular markers to help predict who will fail after radical prostatectomy [published online ahead of print April 14, 2011]. Prostate Cancer. 2011;2011:290160.

Recent phase III trial data clearly demonstrate that adjuvant therapy can reduce recurrence and increase survival after prostatectomy for prostate cancer. There is great interest in being able to accurately predict who is at risk of failure, to avoid treating those who may not benefit. This is a comprehensive review of the current status of molecular markers in predicting patient outcome after radical prostatectomy.

Bitting RL, Armstrong AJ, George DJ. Management options in advanced prostate cancer: what is the role for sipuleucel-T [published online ahead of print October 20, 2011]? Clin Med Insights Oncol. 2011;5:325-332.

Authors from the Duke Cancer Institute provide a review of the clinical trial data leading to the approval of sipuleucel-T and the implications for optimal management and sequencing of treatment in this patient population.

Engel-Nitz NM, Alemayehu B, Parry D, Nathan F. Differences in treatment patterns among patients with castration-resistant prostate cancer treated by oncologists versus urologists in a US managed care population [published online ahead of print July 4, 2011]. Cancer Manag Res. 2011;3:233-245.

Patients with castration-resistant prostate cancer who were treated by oncologists had greater use of hormones, chemotherapy, and radiation; higher percentages of patients with inpatient stays, emergency department, and ambulatory visits; and higher healthcare costs, than patients treated by urologists.

Prostate cancer trends. Centers for Disease Prevention and Control website. http://www.cdc.gov/cancer/prostate/ statistics/trends.htm. Accessed January 5, 2012.

The CDC offers state-by-state prevalence, ethnic, and age-related risk information on prostate cancer.

Comparative Effectiveness of Therapies for Clinically Localized Prostate Cancer. Agency for Healthcare Research and Quality. http://www.effectivehealthcare.ahrq.go/ehc/pr oducts/9/79/2008_0204ProstateCancerExecSum.pdf. Accessed January 5, 2011.

Part of AHRQ’s Effective Health Care Program on comparativeeffectiveness research, this monograph spells out the evidence on watchful waiting, cryoablation, prostatectomy, radiotherapy, high-intensity ultrasound, and brachytherapy for the management of localized prostate cancer.Funding Source: None.

Author Disclosures: Mr Mehr reports receiving payment for involvement in the preparation of this article. Dr Klemm reports no relationship or financial interest with any entity that would pose a conflict of interest with the subject matter of this article.

Authorship Information: Concept and design (JK); acquisition of data (SRM); analysis and interpretation of data (SRM); drafting of the manuscript (JK, SRM); and critical revision of the manuscript for important intellectual content (JK, SRM).1. American Cancer Society. Cancer Facts & Figures 2011. Atlanta: American Cancer Society; 2011.

2. American Cancer Society. What are the key statistics about prostate cancer? http://www.cancer.org/Cancer/ProstateCancer/DetailedGuide/prostate-cancer-survival-rates?docSelected=prostate-cancer-key-statistics.Accessed January 5, 2012.

3. James ND, Caty A, Payne H, et al. Final safety and efficacy analysis of the specific endothelin A receptor antagonist zibotentan (ZD4054) in patients with metastatic castration-resistant prostate cancer and bone metastases who were pain-free or mildly symptomatic for pain: a double-blind, placebo-controlled, randomized Phase II trial. BJU Int. 2010;106(7):966-973.

4. Kantoff PW, Schuetz TJ, Blumenstein BA, et al. Overall survival analysis of a phase II randomized controlled trial of a Poxviral-based PSA-targeted immunotherapy in metastatic castration-resistant prostate cancer. J Clin Oncol. 2010;28(7):1099-1105.

5. Cancer prevalence: how many people havec ancer? American Cancer Society website.http://www.cancer.org/cancer/cancerbasics/ cancer-prevalence. Accessed January 2, 2012.

6. Roehrborn CG, Black LK. The economic burden of prostate cancer. BJU Int. 2011;108:806-813.

7. Kirby M, Hirst C, Crawford ED. Characterising the castration-resistant prostate cancer population: a systematic review. Int J Clin Pract. 2011;65(11):1180- 1192.

8. Alemayehu B, Buysman E, Parry D, Becker L, Nathan F. Economic burden and healthcare utilization associated with castration-resistant prostate cancer in a commercial and Medicare Advantage US patient population. J Med Econ. 2010;13(2):351-361.

9. Inoue T, Segawa T, Kamba T, et al. Prevalence of skeletal complications and their impact on survival of hormone refractory prostate cancer patients in Japan. Urology. 2009;73(5):1104-1109.

10. NCCN Clinical Practice Guidelines in Oncology. Prostate cancer. V4.2011. National Comprehensive Cancer Network website. http://www.nccn.org/professionals/physician_gls/pdf/prostate.pdf. Accessed January 2, 2012.

11. Kantoff PW, Higano CS, Shore ND, et al. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med. 2010;363(5):411-422.

12. Tannock IF, de WR, Berry WR, et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med. 2004;351(15):1502-1512.

13. de Bono JS, Logothetis CJ, Molina A, et al. Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med. 2011;364(21):1995- 2005.

14. de Bono JS, Oudard S, Ozguroglu M, et al. Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomised open-label trial. Lancet. 2010;376(9747):1147-1154.

15. Xie J, Namjoshi M, Wu EQ, et al. Economic evaluation of denosumab compared with zoledronic acid in hormone-refractory prostate cancer patients with bone metastases. J Manag Care Pharm. 2011;17(8):621-643.

16. FDA approves Amgen’s XGEVA(TM) (denosumab) for the prevention of skeletal-related events in patients with bone metastases from solid tumors [press release]. Amgen website. http://www.amgen.com/media/media_pr_ detail.jsp?releaseID=1498709. Accessed January 5, 2012.

17. Amgen’s Xgeva hits resistance over costbenefit debate. Wall Street Journal. April 5, 2011.

18. Krahn MD, Zagorski B, Laporte A, et al. Healthcare costs associated with prostate cancer: estimates from a population-based study. BJU Int. 2010;105(3):338-346.