Chemoprevention in Prostate Cancer: Identifying Patients at Greatest Risk May Provide Greatest Value

May 7, 2013
Marj P. Zimmerman, MS, BS Pharm

Stanton R. Mehr

Volume 19, Issue SP3

Prostate cancer is a common cancer in men that, once it progresses to the later stages, has serious morbidity and mortality consequences as well as burdensome financial issues for patients, the healthcare system, and society. Prostate cancer, second only to skin cancer, is responsible for about 10% of the deaths attributed to all of the cancers.1 As a result, several strategies have been developed to reduce the morbidity, mortality, and costs associated with prostate cancer, inclusing the identification of patients at risk, chemoprevention regimens that prevent the development of the disease in those at risk, and the early diagnosis of patients with confirmed disease.

By the Numbers

According to the American Cancer Society, prostate cancer will be diagnosed in about 240,000 men in 2013, and it will be listed as the cause of death in 30,000.1 African Americans have a higher incidence of prostate cancer than Caucasians and are also more likely to die from the disease. Race, age, and family history are risk factors. Around 2.5 million men currently are prostate cancer patients.2

The majority of cases (approximately 60%) are diagnosed in men 65 years and older, and 97% of cases are diagnosed in men at least 50 years of age. The average age at diagnosis is approximately 67 years.1 Known genetic factors are linked to the disease in about 5% to 10% of patients.2

The disease usually has no symptoms and if diagnosed in the early stages, defined as being in the local or regional stages, it has an excellent 5-year survival (nearly 100%) and survival after 15 years is also very high (93%).2 Ironically, since patients with early-stage prostate cancer experience few or no symptoms, the cancer may not be diagnosed until it has spread to distant areas of the body, including lymph nodes, bones, and other organs. The 5-year survival for patients with metastatic disease is only 28%.2

Since the disease is usually diagnosed in older patients, men with slow-growing tumors are frequently monitored using a strategy termed “active surveillance,” monitoring the disease and delaying therapy until the disease demonstrates signs of being progressive.3

As would be expected, costs associated with the treatment of prostate cancer are greatest (approximately $34,000) in the last year of life. In 2006, the total estimated cost for all prostate cancer care was $9.86 billion.4 Newer treatments, such as sipuleucel-T, costing more than $93,000 for a full course of therapy, will undoubtedly increase these estimates.5

Screening for Prostate Cancer

During the years from 2005 to 2009, the incidence of prostate cancer and number of deaths attributed to it decreased each year. Policy makers speculated that screening with the prostate-specific antigen (PSA) blood test was responsible for the decline.1 Interestingly, the US Preventive Services Task Force (USPSTF) issued a statement on PSA screening in May 2012 that recommended against PSA-based screening for prostate cancer in the general population. However, it did not apply this recommendation to men who had already been diagnosed with or were being treated for prostate cancer.6 This recommendation was based on the potential harms of screening, which included:

• High false-positive rate—approximately 100 to 120 of every 1000 men screened may receive an incorrect diagnosis based on the PSA test result, subjecting them to unnecessary biopsies, which could result in undesirable side effects and unneeded worry or anxiety.

• Overdiagnosis—most cancers of the prostate do not grow or cause symptoms. If the tumor does grow, it does so at a slow rate and usually does not cause health problems in the duration of the man’s life (based on the older age at diagnosis). The potential for overdiagnosis exists, as current technology cannot differentiate slow-growing tumors from aggressive tumors (a small minority of cases, but life threatening when they do occur).

• Overtreatment—if more men are diagnosed, it is likely that some proportion of them will undergo active treatment, with potentially deleterious effects.

The Task Force suggested that physicians should not offer PSA testing unless the patient raises the issue, and then the physician discusses with the patient the benefits and potential harms of PSA testing, as well as risks involved with the diagnostic testing and treatment.7

Recently, a computer model was used to assess alternative PSA screening strategies. The model evaluated 35 screening strategies that varied by the starting and ending age for screening, screening intervals, and thresholds for recommending a biopsy. Raising the PSA threshold in men aged 50 to 74 years being screened yearly was found to reduce the risk of prostate cancer and the risk for overdiagnosis. In even older men, the risk for prostate cancer was similar to that observed in the men aged between 50 and 74 years, but the risk for overdiagnosis was further reduced. Screening done every other year in men at low risk reduced the risk for prostate cancer and overdiagnosis; moreover, this strategy reduced the number of total tests by 59% and false-positive tests by 50%.8 This study suggests that screening may not be needed in men older than 70 years, and thresholds for recommending biopsies could be raised in older men. Overall, men with normal PSA levels at baseline may need less frequent monitoring.9

The Chemoprevention Controversy

Table 1

Chemoprevention is the use of drugs, vitamins, or other agents () to try to reduce the risk of, or delay the development or recurrence of, cancer as defined by the National Cancer Institute.10 It is further classified as primary, secondary, and tertiary prevention. Primary prevention refers to preventing the development of cancer, usually in men who have an average or high risk for its occurrence. This includes men with a family history of cancer. Secondary prevention is aimed at individuals with known precancerous lesions. In this case, chemoprevention is used to deter the progression of these lesions to the cancerous state. Tertiary prevention is used in patients with diagnosed prostate cancer to prevent new cancers or metastasis.11-14 The precancerous state is usually typified by the presence of intra-epithelial neoplasia, which is identified most commonly through biopsy or pathologic samples taken at surgery.15

In 2008, the American Society of Clinical Oncology (ASCO) and the American Urological Association (AUA) issued a clinical practice guideline for the use of 5-α-reductase inhibitors (eg, finasteride and dutasteride) for the chemoprevention of prostate cancer (primary prevention only). This guideline was developed based on the results of 15 randomized clinical trials, of which 9 included the prevalence of prostate cancer studies over 1 to 7 years (clinical trial data do not extend beyond 7 years). Only 1 completed trial, the Prostate Cancer Prevention Trial (PCPT), was randomized and was designed to show in a reduction in period-prevalence of prostate cancer. This trial, using finasteride as the intervention, had a very large study population of men who were being actively screened for prostate cancer. The clinical trial REDUCE (Reduction by Dutasteride of Prostate Cancer Events), in which men with a PSA >3 ng/mL were enrolled, was not yet completed at the time of review by the guideline development panel. Thus, the panel knew that additional information would be forthcoming from the REDUCE trial, and that the PCPT trial results would be further analyzed. Neither of these 2 trials was designed to assess the risk of death resulting from prostate cancer. The primary objective of both of these clinical trials was to study the safety and efficacy of drugs indicated for the treatment of benign prostatic hyperplasia (BPH).

The panel concluded that therapy with a 5-α-reductase inhibitor during a 7-year period would lead to a 25% relative risk reduction (but only a 1.4% absolute risk reduction) for a prostate cancer diagnosis. The panel noted an increase in high-grade cancers, but they believed it was doubtful that this could occur while there was also a decrease in low-grade tumors. However, since men are prescribed 5-α-reductase inhibitors for BPH and male pattern baldness, they recommended that this potential finding should be discussed with these respective patients. Additionally, they knew that data from the REDUCE trial would support or dispute the findings of the presence of increased high-grade prostate cancer in men receiving a 5-α-reductase inhibitor.

The suggestion from the panel was that men with a PSA level below 3.0 ng/mL who agreed to annual PSA screening might benefit from 5-α-reductase inhibitor therapy for a period of 7 years. Men should also be made aware of the potential benefits and risks of such therapy by their physicians.11

Table 2

The results of the REDUCE trial were similar to those seen in the PCPT trial (). There was a decrease in relative risk and absolute risk for developing prostate cancer when using 5-α-reductase inhibitor therapy, but there was in increase in the absolute risk for the development of high-grade prostate cancer. The original publication of the trial did not show an increased risk for high-grade prostate cancer, but the FDA mandated a reanalysis of the data using a modified scoring scale which resulted in an increase in high-grade prostate cancer.16

In December 2010, the Oncologic Drugs Advisory Committee voted against approving dutasteride and finasteride for the prevention of prostate cancer based on the findings of the REDUCE and PCPT trials. The FDA followed the committee’s recommendation in January 2011.17 Since the FDA did not approve the drugs for the prevention of prostate cancer, ASCO and AUA subsequently archived the 2008 clinical guideline on the use of 5-α reductase inhibitors for prostate cancer chemoprevention. However, the guideline is available in the “Archived Guides” section of the AAU website.18

The AUA communicated that it believes some urologists and urologistoncologists would continue to prescribe these medications for men at potentially high risk for prostate cancer and that these agents should be used with caution. It believed the decision was controversial and still debatable.18

The Southwestern Oncology Group (SWOG) disagreed with the FDA’s decision, saying that it believed the PCPT reanalysis demonstrated that the use of 5-α-reductase inhibitors could significantly reduce the risk of prostate cancer.19 Even the USPSTF concluded that additional studies were needed to determine the impact of 5α-reductase inhibitors on the mortality of men with prostate cancer.20 Furthermore, a reanalysis of the data from the PCPT and REDUCE trials for mortality suggested there may have been a small increase in deaths due to therapy, but that there could have also been a modest decrease. 21

Coupled with the clinical analysis of the use of 5-α-reductase inhibitors for the chemoprevention of prostate cancer, several investigators examined the cost-effectiveness and cost utility of using these drugs specifically for chemoprevention. A study in the mid-2000s utilizing a Markov decision analysis model concluded that prescribing finasteride in a lower-risk population ≥50 years would not be cost-effective; however, if it were used in men with a high risk for prostate cancer (defined as at least 50 years of age with a probability of at least 30% for developing prostate cancer), the chemoprevention strategy could be cost-effective. If the lifetime prevalence were to be increased, the costs per life-year saved would be reduced; moreover, the cost of the chemoprevention strategy would also affect the costs.22 Another study utilizing a Markov decision analysis model also concluded that finasteride would not be likely to be cost-effective for use in the general population, but that it would be cost-effective to prescribe it in high-risk men (defined as ≥50 y and a ≥30% chance of developing prostate cancer), especially if quality-of-life issues (erectile dysfunction, loss of libido, and incontinence) were considered. The sensitivity analysis showed a cost-effectiveness ratio of <$50,000 per QALY with a 25% risk reduction in the men at high risk.23 There appears to be a level of agreement that utilizing these medications in low-risk populations would not be cost-effective, but that there is a cost benefit to their use in high-risk men.24-27

Age alone (ie, men older than 50 years) does not appear to be the only criterion for initiating chemoprevention. Assuming that finasteride use resulted in a constant risk reduction for all tumor grades, the drug was found not cost-effective because of the costs associated with side effects (urinary and bowel incontinence, impotence, and erectile dysfunction).28 A Markov model has been developed that shows high-risk men, defined as those having a positive family history and the presence of genetic markers for prostate cancer, would benefit from chemoprevention.29

What Exactly Is the Focus of the Debate?

There is little question that PSA testing at present is a useful tool, but has been an overused one, in our limited arsenal to screen for prostate cancer. And when it is used appropriately, there is little consensus (except in cases of extreme readings) on how to interpret the results. Many even argue that the logic in favor of screening is faulty, owing to the relatively slow growth of earlystage prostate tumors. However, few would not want to prevent late-stage prostate cancer and seek to improve its poor 5-year survival.

Therefore, the real debate seems not to address the value of preventing prostate cancer but whether our technologies for prevention (both screening and treatment) are efficient enough to yield cost-effective outcomes. If 5-α-reductase inhibitors are not sufficiently effective in preventing the development of prostate cancer, or if the side effects of the medications are such that the costs to treat (or in terms of reduced quality of life) result in inadequate cost-effectiveness, are there specific patients where the drugs may be useful and are there more effective chemoprevention strategies available or on the horizon?

The debate about the use of 5-α-reductase inhibitors as chemoprevention for prostate cancer continues, as does the utilization of PSA testing to screen men for the disease. Based on the sheer numbers of men who develop prostate cancer and the cost burden of the disease, it seems that the need exists for both a useful screening tool and a chemoprevention strategy. Appropriate application of this strategy will be the key to success. Evolving and improved technology will be paramount in making this happen.

Funding Source: None.

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

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Authorship Information: Concept and design (SRM); acquisition of data (MPZ, SRM); analysis and interpretation of data (MPZ, SRM); drafting of the manuscript (MPZ, SRM); critical revision of the manuscript for important intellectual content (MPZ, SRM); and supervision (SRM).