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Prostate Cancer Management Under Scrutiny: One Man's Meta-Analysis Is Another Man's Poisson

Division of Medical Oncology, University of Southern California–Norris Comprehensive Cancer Center, Los Angeles, CA

IT IS CLEAR THAT fewer patients with prostate cancer have been entered onto clinical trials compared with patients with breast cancer.¹ However, this is a changing trend, and investigators in the field of prostate cancer are now beginning to try to answer some of the fundamental conundrums of clinical management of this complex disease. The early attempts by the Veterans Administration Cooperative Urological Research Group² and the National Prostatic Cancer Project were important, and creative, but suffered from the inadequate statistical concepts of the time, in some cases with flawed assessment of outcome and often with insufficient case numbers.^3,4 More recently, clinical trial groups have tested important concepts, such as the true role of combined androgen blockade, using much larger trial accrual numbers and yet have still produced data that have left remaining clinical questions when the trials have produced conflicting results.^5-7 In an attempt to resolve these issues, the tool of meta-analysis has been more widely applied.^8,9 This statistical ploy, in which data from randomized trials are pooled to compare observed-versus-expected ratios, is intended to allow more accurate interpretation of data from smaller studies. However, for the clinician in practice, the use of meta-analysis is often confounded by inappropriate trial selection or exclusion, so that different assessments of the same database are often conflicting.^8,9

Against this complex background, several issues are currently under close scrutiny, including the topic of the review by Oh and Kantoff¹⁰ in this month's issue of the Journal of Clinical Oncology, ie, the definition, diagnosis, and optimal management of locally extensive prostate cancer (stage C/T3) with spread of the tumor beyond the capsule and into the surrounding tissues. In this quite thorough overview of the literature, the authors draw the following conclusions: (1) single-modality treatment for locally extensive prostate cancer is associated with a high failure rate; (2) the use of adjunctive hormonal therapy with definitive radiotherapy is associated with improved progression-free and overall survival; (3) adjunctive hormonal therapy has not been shown to improve outcomes from surgery; (4) innovations in chemotherapy have increased the objective response rate to 50%, depending on the criteria of assessment; and (5) systemic chemotherapy may have a role in the management of locally extensive prostate cancer, depending on the results of ongoing clinical trials. At present, a multidisciplinary expert panel of the American Society of Clinical Oncology is assessing this issue, and their report will be submitted later this year.

Three of the cited studies in the Oh and Kantoff review are of critical importance to the assessment of the correct approach to the treatment of stage C/T3 prostate cancer and thus bear more detailed assessment. Two seminal studies^11,12 have shown benefit from the combination of hormones and radiotherapy for stage C prostate cancer. Bolla et al¹¹ randomized 415 patients between 1987 and 1995 to receive radiation alone or goserelin plus identical radiotherapy in a European Organization for Research and Treatment of Cancer (EORTC) trial. Problems with the study included a relatively short median follow-up of less than 4 years and an unusually long period of adjuvant hormonal therapy, which could have masked the true impact of the combination. Furthermore, no comparison was made to hormonal therapy alone. Notwithstanding the problems of stage migration and limited case numbers, it should not be forgotten that Fellows et al,¹³ in the important randomized study of the British Medical Research Council (MRC), reported a median survival of 4.5 years for orchiectomy alone, versus 5.2 years for orchiectomy plus radiotherapy for patients with stages T2 to T4 (B, C) prostate cancer. It is important to note that, in this study, about 30% of patients had low Gleason scores and a similar proportion had T2 tumors, so that the data are not truly relevant to the discussion of all locally extensive disease. Although the EORTC study has been criticized for a purportedly low survival rate from radiotherapy alone, the results from the MRC and other trials suggest that the EORTC survival figures are quite comparable to those of other series, and the apparent survival benefit from combined treatment in this series withstands criticism.

The investigators of the Radiation Therapy Oncology Group (RTOG) have also studied the use of combined hormones and radiotherapy in detail, assessing the utility of both neoadjuvant/concurrent approaches¹² and classical adjuvant strategies.¹⁴ In their assessment of neoadjuvant hormonal therapy, they identified a disease-free survival benefit without an accompanying increase in overall survival.¹² Why do these results differ from those of the EORTC with respect to overall survival? Possible explanations include case selection and the duration of hormonal therapy, especially in the context that the RTOG trial used only 4 months of hormonal suppression. The adjuvant hormonal therapy trial (RTOG 85-31), which did show a survival benefit, used hormonal therapy indefinitely.

Oh and Kantoff cite the recent MRC trial of timing of hormonal therapy for advanced disease¹⁵ as evidence to support early introduction of systemic treatment. However, one important flaw in the MRC trial limits its utility as a general model. This study, which compared immediate hormonal treatment to delayed therapy at the time of symptomatic relapse of advanced prostate cancer, was well executed, with thoroughfollow-up and attention to detail. However, the follow-up schedules for patients in each arm were not identical. Patients were followed as necessary, based on the preference of the individual investigator, and this could easily have contributed to a bias in favor of the group who received early hormonal therapy. In a health system with significant fiscal limitations, wherein some participants did not even have routine access to radionuclide bone scanning for the staging workup, it could be argued that the pragmatism of the trial design seriously restricted the potential for widespread application to clinical practice in other countries.

One other issue is whether cytotoxic chemotherapy will offer any benefit in this context. Oh and Kantoff cite the real progress that has recently been made in the management of hormone-refractory disease through the application of modern cytotoxic regimens. Improvements have been documented in quality of life, prostate-specific antigen (PSA) response, cost-effectiveness, and symptomatic state.^16,17 However, one must be careful not to confuse real and imagined progress. Over the past decade, with the increasing emphasis on PSA response, quality of life, and assessment of patients with only soft-tissue involvement or rising PSA levels, the apparent increase in response rate in prostate cancer may actually be an illusion, predicated on stage migration.¹⁸ The demonstration of real progress will require the completion of randomized trials comparing novel regimens with supportive care (or novel regimens with old cytotoxic approaches), with overall survival as the primary end point. In the setting of locally extensive prostate cancer, it should not be forgotten that the Southwest Oncology Group showed no major difference in overall survival when patients with metastatic prostate cancer were randomized to treatment via hormonal manipulation or combined chemotherapy (doxorubicin-cyclophosphamide) plus hormonal manipulation.¹⁹ Although this does not disprove the potential usefulness of adjuvant chemotherapy, it does emphasize the importance of assessing this approach with well-designed randomized studies, rather than simply publishing single-arm novel trials marred by heavy selection bias and stage migration.

There are still important unresolved questions in the management of prostate cancer, despite all the rhetoric in the medical and lay press. The true benefit to the general population from screening of asymptomatic males for prostate cancer remains highly controversial in the absence of the completed results of any well-structured randomized trial. The plethora of case experience from nonrandomized series, confounded by issues of case selection and stage migration, has done nothing to clarify the situation. The true long-term benefits of radical surgery as compared with definitive radiotherapy are also hotly debated, based on large series of nonrandomized cases. However, the process of randomization is no magical solution to the resolution of genuine equipoise. Despite compelling data from a series of randomized trials that suggest that combined androgen blockade yields only a small (if any) survival benefit, there are still proponents of this expensive management approach. Longer follow-up of the completed trials may finally resolve this issue. Today, for the patient faced with stage C (T3) prostate cancer, it seems that there is a trend toward improved outcomes through the use of combined-modality treatment that incorporates hormones and definitive local treatment. It is clear that the benefits are more dramatic in association with definitive radiotherapy, but is not yet clear whether this is due to differences in the biology of the treatments or case selection or merely reflects the duration of hormonal therapy associated with combined-modality surgical regimens. If I were diagnosed with stage C prostate cancer today, I believe that I would have treatment with hormones and radiotherapy and would be prepared to participate in a randomized trial testing the role of added cytotoxic chemotherapy (provided that the toxicity was tolerable). I hope my opinion is not self-tested. By the time that I get to the usual age group for the presentation of prostate cancer, I hope that the medical profession will have overcome national barriers and the territorial imperative to produce definitive trial data, based on the large case numbers available through well-structured international randomized trials.

REFERENCES

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17. Tannock IF, Osoba D, Stockler MR, et al: Chemotherapy with mitoxantrone plus prednisone or prednisone alone for symptomatic hormone-resistant prostate cancer: A Canadian randomized trial with palliative endpoints. J Clin Oncol14:1756-1764, 1996[Abstract/Free Full Text]

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19. Osborne CK, Blumenstein B, Crawford ED, et al: Combined versus sequential chemo-endocrine therapy in advanced prostate cancer: Final results of a randomized Southwest Oncology Group study. J Clin Oncol8:1675-1682, 1990[Abstract]

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