**4. Discussion**

436 Cancer Prevention – From Mechanisms to Translational Benefits

mortality reduction. Also, the controversy with the potential increase in high grade cancers could not be overlooked. Their conclusion was based on the fact that the risks of high-grade cancer were potentially real and could not be explained entirely by volume grade bias, increased sensitivity of PSA and DRE or removal of low-grade cancers. Finally, since the both REDUCE and the PCPT trials utilized end-of-study biopsies, the trial results were not yet generalizable to the US population. ODAC voted against the new indication for dutasteride (yes = 2, no = 14, abstain = 2) and against the new labeling for finasteride (yes =

Due to ODAC's ruling, the FDA does not currently support the use of 5-ARIs for prostate cancer chemoprevention. After the decision made by ODAC, a publicly funded clinical trials cooperative group, SWOG (Southwest Oncology Group), released a statement disagreeing

Clearly, disagreement remains after the publication of the two trials. GlaxoSmithKline has subsequently announced that it is withdrawing applications for similar approval in other countries.36 More long term data is needed to help experts agree on a consensus although we doubt that any further trials will be done with these agents to prevent prostate cancer. And likely because the other trials mentioned above have been negative, future trials for

Current economic assessments for chemoprevention are based on varying assumptions that take into account data from the PCPT, treatment costs, and life expectancy. In addition, variations on the model include how the PCPT data is integrated into the model. For example, PCPT high grade disease can include projections based on the actual data set or

To be effective, chemoprevention for cancer should cost roughly \$100,000 or less per life year (LY) saved due to low adoption rates when cost is greater than \$100,000/yr and high when cost is less than \$20,000/yr .37 Svatek *et al* used SEER data to estimate real world incidence and analyzed the cost-effectiveness of finasteride. Their group concluded that

Subsequent studies supported that chemoprevention was too expensive and estimated the expense per LY saved at up to \$1.6 million.39 However, an analysis on quality adjusted lifeyears (QALYs) based on PCPT prevalence rates showed a lower cost per LY due to higher PCPT prevalence rates. This analysis demonstrated \$122,000 per QALY saved.40 If finasteride is assumed to not increase the incidence of high grade cancers, then the analysis demonstrated \$112,000 per QALY saved. Thus more patients benefit from chemoprevention. These analyses were based on the current price of finasteride at \$66/month. If finasteride becomes less expensive, then the cost per QALY has the potential to drop significantly. Similarly, one study evaluated dutasteride based on the REDUCE study data and concluded

Currently chemoprevention with either finasteride or dutasteride is not cost effective. The identification of a high risk subgroup would potentially decrease the cost to benefit ratio thus making chemoprevention feasible from an economic standpoint. In addition, decreasing the cost of either 5-ARI has the potential to make chemoprevention feasible.

finasteride was too expensive at \$578,000 to \$1,107,000 USD per LY saved.38

that it too was not cost effective as a general chemopreventative agent.41

with ODAC's decision to not use 5-ARIs for the prostate cancer prevention.35

chemoprevention of prostate cancer will be rare.

based on a data set adjusted for biases.

**3.5 Economic impact of prostate chemoprevention** 

0, no = 17, abstain = 1).

Currently the only proven chemopreventative agents for prostate cancer are finasteride and dutasteride with up to a ~24% reduction in prostate cancer (24% PCPT, 23% REDUCE). However, as discussed earlier, the perceived risk of high grade cancers and the unclear long term benefit for low grade cancers has caused the ruling against the use of 5-ARI's for chemoprevention. Reanalysis of the Prostate Cancer Prevention Trial (PCPT) does not support this ruling and suggests that high-grade cancer is not associated with finasteride therapy and that prostatectomy is the only definitive diagnosis for the evaluation for prostate cancer.42 In addition, the effects of PSA, DRE and prostate volume bias will continue to make interpretation of the data difficult.43

It is important to note that as many of 30% of clinically insignificant cancers on first biopsy are then upstaged on second biopsy to become significant cancers. Consequently, the long term benefits of preventing low grade disease are uncertain.44 Also, by reducing the incidence of low grade disease, the potential for decreasing the "burden of treatment" is uncertain. But in the US environment where greater than 90% of men diagnosed with prostate cancer seek treatment, it is clear that individuals who have low grade cancer prevented will benefit.45

Despite evidence from the PCPT and REDUCE trials, there does not appear to be a trend towards prescribing 5-ARIs for the prevention of prostate cancer. Approximately 64% of Urologists and 80% of primary care providers never prescribe finasteride for prostate cancer chemoprevention. Over half of Urologists reported concerns for inducing high grade tumors. In addition, half of the primary care physicians were not aware 5-ARIs could be used for chemoprevention.46 With the current ruling by ODAC, it is likely that physicians will trend away from prescribing 5-ARI medications for chemoprevention.

Further analyses are required to pinpoint the subgroup population that will benefit most and the timing that is required to be effective. The PCPT revealed a high prevalence of prostate cancer, but no reliable markers were available to determine who would benefit most from biopsy or treatment. REDUCE prospectively collected samples to retrospectively analyze potential biomarkers but has not yet identified a subgroup that would yet benefit from dutasteride prevention.47

In the current political environment, the adoption of 5-ARI medications is slim due to the uncertainty surrounding finasteride and dutasteride. Further analysis into subgroups of patients may reveal that 5-ARIs are clinically significant and economically available for at risk individuals. Maybe then, the benefits of 5-ARI medications will outweigh their uncertainty regarding high risk disease. In the meantime, investigations into new biomarkers, nutritional supplements and other pharmacologic agents may elicit a potential solution to the perplexing problem of primary prevention.
