Adjuvant Radiotherapy For Pathologically Advanced Prostate Cancer: A Randomized Clinical Trial

UroToday.com- Extraprostatic prostate cancer (CaP) is detected in up to 50% of men at radical prostatectomy (RP). But as urologists, do we decide to initiate adjuvant radiotherapy (XRT) or wait for a biochemical recurrence and then start salvage XRT? Adjuvant therapy may improve outcomes by treating with a minimal residual disease burden, but some patients are potentially being treated without really having residual cancer and may do equally well with salvage therapy. This longstanding question was addressed in a prospective multi-institutional trial that began in 1988. The results appear in the November 15, 2006 issue of JAMA and are authored by Dr. Ian Thompson and colleagues.

Beginning in 1988, patients who had undergone RP and met 1 or more of 3 criteria for extraprostatic disease were eligible. The criteria were extracapsular tumor extension, positive surgical margins, or seminal vesicle invasion. A pelvic lymphadenectomy with no evidence of nodal metastases was required for inclusion.

Starting in 1995 patients who were at pre-defined low clinical risk for lymph node metastases did not require a lymphadenectomy. An undetectable PSA at enrollment was not required. Radiotherapy was delivered at a dose of 60-64 Gy. Follow-up included PSA and clinical scans. The primary study endpoint was metastasis-free survival. The assumption was that the primary endpoint, median metastasis-free survival would be 6 years and that adjuvant XRT would decrease this by one-third.

A total of 425 men were eligible for analysis and had been enrolled between 1988 and 1997 with follow-up through September 2005. Mean follow-up was 10.9 years. The actual median metastasis-free survival for the observation group in this study was 13.2 years, with 5- and 10-year metastasis-free survival of 84% and 63%, respectively. A total of 91 of the 211 patients (43%) in the observation group were diagnosed with metastatic disease or died (median metastasis-free estimate, 13.2 years) vs. 76 of 214 patients (35.5%) (median metastasis-free estimate, 14.7 years). The hazard ratio for metastasis-free survival with adjuvant XRT was 0.75 and not statistically significant. Among the 167 men total who were diagnosed with metastatic disease or who died, 115 (69%) died without documented metastatic disease. There were 35 cases of metastatic disease found in the observation group and 17 in the XRT group.

Regarding PSA relapse (defined as a PSA >0.4ng/ml), 112 of 175 (64%) in the observation group had PSA relapse compared with 60 of 172 (35%) in the adjuvant XRT group. Adjuvant XRT was associated with a significant reduction of PSA relapse (median PSA relapse-free survival 10.3 years for XRT vs. 3.1 years for observation). A total of 111 of 211 (53%) of patients in the observation group experienced a recurrence of disease of death, compared with 84 of 214 (39%) in the adjuvant XRT group. Adjuvant XRT was associated with a significant reduction in disease recurrence. A total of 83 of 211 (39%) of patients in the observation group died during follow-up (median survival 13.8 years) compared with 71 of 214 (33%) in the XRT group. The hazard ratio was 0.80, which was not statistically significant. Among patients in the observation group, 21% received hormonal therapy by 5 years, compared with 10% of the XRT patients.

Patients with disease beyond the prostate capsule or with positive margins had a 6.1 year median time to PSA relapse, compared with a 2.1 years median time to relapse in those with seminal vesicle invasion and 3.1 years for those with both pathologic findings. Complications in the XRT group were consistent with usual reports and higher than the observation group.

This study did not demonstrate its primary endpoint that adjuvant radiotherapy results in a significant reduction in metastatic disease. Despite prolonged follow-up, the rate of metastatic disease was significantly less than anticipated.

Ian M. Thompson Jr; Catherine M. Tangen; Jorge Paradelo; M. Scott Lucia; Gary Miller; Dean Troyer; Edward Messing; Jeffrey Forman; Joseph Chin; Gregory Swanson; Edith Canby-Hagino; E. David Crawford


JAMA. 2006;296:2329-2335.

Reviewed by UroToday.com Contributing Editor Christopher P. Evans, MD

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