Androgen suppression, primarily castration, has been the key objective of treatment of metastatic prostate cancer. Surgical castration, achieved by the use of bilateral orchiectomy, produces a short-term symptomatic and objective tumor response in 70% to 80% of patients.[1] Medical castration, by the use of leuteinizing hormone-releasing hormone (LHRH) agonists, produces an almost equivalent effect. However, use of medical or surgical castration eliminates only 90% to 95% of the daily testosterone production. The remainder is produced in the adrenal glands.
In the 1980s, Labrie hypothesized that counteracting adrenal androgens would further inhibit tumor growth.[2] In response to this hypothesis, a number of antiandrogen agents were identified and used in combination with medical or surgical castration to obtain maximum androgen blockade.
In a Southwest Oncology Group (SWOG) trial (INT 0036), Crawford and colleagues reported a 24% improvement in survival for patients receiving an antiandrogen (flutamide, Eulexin) and an LHRH agonist (leuprolide, Lupron), compared with medical castration with leuprolide alone.[3] This early observation initiated interest and further research into the efficacy of maximum androgen blockade in advanced prostate cancer.
Interestingly, the current Intergroup report (INT 0105), unlike the first, concludes that there is no clinically significant difference between surgical castration alone or with an antiandrogen (flutamide).[4] The relative risk point estimate of 0.91 in the current report favors orchiectomy plus flutamide(Drug information on flutamide), but the 90% confidence limit includes 1.0, ranging from 0.81 to 1.01. Further, in a parallel report on quality of life measures, orchiectomy plus flutamide was associated with several reduced quality scores.
Given these new results, it is important to review the strength of the evidence provided by the recently reported SWOG study and then interpret the results in conjunction with other trials addressing the same clinical questions.
The INT 0105 study was a well-designed, randomized, controlled trial with special precautions to ensure blinded allocation. In terms of baseline characteristics, the two arms of the trial differed only with respect to bone pain: A higher proportion of patients in the placebo group had bone pain. To the extent that bone pain reflects disease severity, control patients (orchiectomy only) would be expected to do more poorly.
The study was double blinded, and the ascertainment of outcomes was performed relatively equally. Follow-up was complete with the exception of three patients. Once disease progression occurred, however, patients were allowed to cross over to treatment with orchiectomy plus flutamide.
If delayed orchiectomy plus flutamide actually improves survival, then control patients would be expected to have a later survival advantage. This would possibly minimize differences between the treatment arms. The treatments administered after disease progression were not captured or reported, making it difficult to determine the magnitude of crossover exposure.
Even though the relative risk in this study is not significant, the wide confidence interval suggests that differences as large as 20% between the two groups, or as small as no difference at all, are possible. The median survival difference was 3.6 months, favoring the orchiectomy plus flutamide arm, although again this was not statistically significant.
Life Expectancy a Better Measure?
It is important to note that the measures of outcome in this study (median survival and relative risk) were taken at individual points on the survival curve. Some argue that life expectancy, which was not reported in this study, may provide a better measure of overall differences in survival.[5]
Using the Declining Exponential Approximation of Life Expectancy and the reported mean survival for each treatment arm, life expectancy for the orchiectomy plus flutamide arm is estimated to be 48.3 months and for the orchiectomy alone arm, 43.1 months.[6] Consequently, the point estimate for life expectancy gained could be in the range of 5.2 months.
This gain in life expectancy is within the same range of benefit achieved by performing a prostatectomy on a 65-year-old man with localized prostate cancer and is similar to the benefit with other anticancer therapies.[5]
Quality of Life
The second publication from the recent SWOG trial focused on quality of life differences between the two treatment arms at 1, 3, and 6 months.[7] For this separate report, only half of the patients were included. The sampling of patients was not clearly described.
The two arms in this subgroup of the study population differed at baseline with respect to severity of disease. For those assigned to receive orchiec-tomy plus flutamide, 82% had extensive disease vs 74% assigned to orchiectomy alone.
To the extent that both disease severity and early toxicity from treatment affect the patient’s reporting of quality of life, the measures are likely to be lower in the intervention group. This, in fact, was the case in this study.
Diarrhea and worse emotional functioning were statistically more likely in the orchiectomy plus flutamide arm. At 3 months, the absolute risk difference for diarrhea was 5.9% (8.6% vs 2.7%). Viewed in a different manner, for every 17 patients treated with flutamide, one will experience diarrhea. In practice, the diarrhea is easily reversed by reducing the dose or stopping the drug, but, in the trial, discontinuation of the drug was the only available option.
More important, to more fully assess the overall impact of a treatment on patients’ overall health-related quality of life, one should assess the short-term side effects as well as the potential long-term clinical benefits of a treatment. By limiting quality of life assessment to the first 6 months of treatment, this study focuses on short-term side effects and fails to account for the potential long-term clinical and quality of life benefits of flutamide.
In summary, the evidence from both the clinical trial and quality of life reports of the recently reported SWOG study (INT 0105) suggests that the survival differences between the orchiectomy plus flutamide and orchiectomy alone groups are small. Furthermore, the evidence suggests that quality of life may be worse in the first 6 months of treatment in those receiving orchiectomy plus flutamide. In addition, the overall clinical significance of the differences is unclear when compared to the potential of longer term quality of life benefits stemming from extended time to progression.
These results need to be considered alongside those reported in other studies of maximum androgen blockade. A recent systematic review with metaanalysis has integrated the SWOG trial into an overview summary.[8] This literature-based review by Bennett et al included only trials that used flutamide with medical or surgical castration in the maximum androgen blockade arm. Nine studies, involving 4,128 patients with advanced prostate cancer, were reviewed.
In this metaanalyis, overall survival was significantly better in those receiving maximum androgen blockade than in those undergoing castration alone. The relative risk was .90, an estimate that is similar to estimates included in previous metaanalyses based on smaller numbers of patients treated with flutamide as part of a maximum androgen blockade regimen as well as to the results of the recent SWOG report.[4,9,10] The 95% confidence interval was between 0.79 and 1.00.
If the relative risk point estimate of .90 in this overview is indeed correct, then one must determine if this difference is likely to be clinically significant. As stated previously, this point estimate is associated with expected improvements in survival that, on average, are comparable to other currently employed cancer interventions.
In 1999, fewer than one-fifth of metastatic prostate cancer patients are expected to undergo a surgical castration procedure. Thus, the role of flutamide in the treatment of advanced prostate cancer seems less clear as an adjunct therapy to surgical castration than to medical castration with an LHRH agonist, which is the more common castration therapy in the current era.
In addition, the most recent meta-analysis, as well as the preliminary results of the updated Prostate Cancer Trialists’ Collaborative Group, from Oxford University, in 1997, suggests that, overall, there appears to be a small survival difference that favors maximum androgen blockade. In any case, more trials (and even more metaanalyses) are unlikely to further refine the relative risk point estimate associated with maximum androgen blockade.
