Chemotherapy Offers Survival Benefit in Androgen-Independent Prostate Cancer

Abstract & Commentary

Synopsis: In a trial that included androgen-independent prostate cancer (AIPC) patients treated at M.D. Anderson and several of its community oncology affiliates, 2 drug regimens were shown by randomized phase II analysis to be comparable. These regimens were ketoconazole/doxorubicin alternating with vinblastine/estramustine (KA/VE) or paclitaxel, estramustine, and oral etoposide (TEE). Both produced survival advantage when compared to prior series, including those in which mitoxantrone and prednisone were used. However, there was significant observed toxicity, particularly in the community-enrolled patients. Thus, although it is encouraging to see that chemotherapy can influence the natural history of this disease, more effective and tolerable regimens are sought.

Source: Millikan R, et al. J Clin Oncol. 2003;21:878-883.

Androgen-independent prostate cancer (AIPC) is recognized as a highly aggressive disease associated with significant morbidity and a median survival of less than 1 year.1 Currently, the only FDA-approved regimen for AIPC is mitoxantrone and prednisone, but reports suggest overall survival is no better with this approach.1 However, a number of single-agent phase II trials2 and a smaller number of combination chemotherapy reports3 have suggested that the natural history of AIPC may be altered.

In the current report, Millikan and colleagues from M.D. Anderson with active collaboration from affiliated community oncology programs, report on a randomized phase II study of 2 different chemotherapy regimens for AIPC. The first was ketoconazole adriamycin alternating with vinblastine/estramustine (KA/VE) and the second was paclitaxel, estramustine, and oral etoposide (TEE). Patients were prospectively stratified on the basis of disease volume. The primary end points were response and overall survival time.

Of the 75 registered patients, 71 were eligible for analysis. Using criteria of an 80% prostate-specific antigen (PSA) reduction maintained for at least 8 weeks, 11 (30%) of 37 patients in the TEE arm responded, whereas 11 (32%) of 34 assigned to KA/VE responded. Median survival was 16.9 months (95% confidence interval [CI], 10.5-21.2 months) in the TEE arm and 23.4 months (95%CI, 12.9-30.6 months) for patients treated with KA/VE. Many patients (24%), particularly those treated at community sites rather than at the tertiary referral center, were unable to complete the initial 6 weeks of chemotherapy (either regimen). There were 5 (8%) treatment-related early deaths.

Millikan et al concluded that both regimens produced significant response rates but with moderate toxicity, particularly for those treated at community sites. They suggested that the improved overall survival (18.9 months for all 71 patients) when compared to prior series is an indication of the potential for combined chemotherapy to influence the course of AIPC but that newer, more tolerable regimens be developed before a large-scale, phase III study be undertaken.

Comment by William B. Ershler, MD

In the community setting, particularly among urological surgeons, there remains a sense that once prostate cancer becomes refractory to hormonal intervention, there is little useful therapy other than analgesics. Although the mitoxantrone/prednisone combination has been widely used, its approval by the FDA was based on an improved quality of life without demonstrated survival benefit. The current report hopefully will diminish this sense of therapeutic nihilism inasmuch as median survival for the treated AIPC patients (18.9 months) exceeded that from previous reports (eg, 7.9 months for mitoxantrone/prednisone).

In the design of this protocol, it is of particular interest to notethe effort made to recruit and retain community patients on study. Recruitment of patients in the community turned out to be more difficult than anticipated. Milliken et al speculated that this may reflect a sense the drug combinations were either too complex or toxic. Also, both arms included oral chemotherapy (estramustine, etoposide), which might have presented financial obstacles, particularly for those who rely on Medicare without supplemental prescription coverage.

Thus, the entire treatment group included those treated at M.D. Anderson and those treated in community practice affiliates. There was more toxicity, more withdrawals from study, and greater mortality observed in the community-treated patients. This observation is important to consider and requires explanation. Millikan et al speculate that it has more to do with patient selection (with younger patients with better performance status more likely to be treated at the cancer center) than other management issues. However, it is difficult to become too enthusiastic about selecting either of these comparable regimens for use in the community, in light of the burden of the schedule and the not insignificant treatment-related morbidities and mortality in this setting. Yet, it is apparent that combination chemotherapy will offer survival benefit to those with AIPC. However, we clearly need more community-based research protocols or more academic center protocols that include patients who better reflect what is seen in the community before community oncologists will be observing treatment advances for this disease.

Dr. Ershler, INOVA Fairfax Hospital Cancer Center, Fairfax, VA is Editor of Clinical Oncology Alert and Director, Institute for Advanced Studies in Aging, Washington, DC.

References

1. Dowling AJ, et al. J Urol. 2000;163:1481-1485.

2. Yagoda A, et al. Cancer. 1993;71(3 Suppl):1098-1099.

3. Kelly WK, et al. Curr Oncol Rep. 2000;2:394-401.