Adjuvant Radiotherapy for Pathologically Advanced Prostate Cancer . A Randomized Clinical Trial

Ian M. Thompson, Jr, MD;  JAMA. 2006;296:2329-2335.  see graphs here and here
Despite a stage-shift to earlier cancer stages and lower tumor volumes for prostate cancer, pathologically advanced disease is detected at radical prostatectomy in 38% to 52% of patients. However, the optimal management of these patients after radical prostatectomy is unknown. Objective  To determine whether adjuvant radiotherapy improves metastasis-free survival in patients with stage pT3 N0 M0 prostate cancer.

Patients were 425 men with pathologically advanced prostate cancer who had undergone radical prostatectomy. Men were randomly assigned to receive 60 to 64 Gy of external beam radiotherapy delivered to the prostatic fossa (n = 214) or usual care plus observation (n = 211).

 
Results  Among the 425 men, median follow-up was 10.6 years (interquartile range, 9.2-12.7 years). For metastasis-free survival, 76 (35.5%) of 214 men in the adjuvant radiotherapy group were diagnosed with metastatic disease or died (median metastasis-free estimate, 14.7 years), compared with 91 (43.1%) of 211 (median metastasis-free estimate, 13.2 years) of those in the observation group (hazard ratio [HR], 0.75; 95% CI, 0.55-1.02; P = .06). There were no significant between-group differences for overall survival (71 deaths, median survival of 14.7 years for radiotherapy vs 83 deaths, median survival of 13.8 years for observation; HR, 0.80; 95% CI, 0.58-1.09; P = .16). PSA relapse (median PSA relapse–free survival, 10.3 years for radiotherapy vs 3.1 years for observation; HR, 0.43; 95% CI, 0.31-0.58; P<.001) and disease recurrence (median recurrence-free survival, 13.8 years for radiotherapy vs 9.9 years for observation; HR, 0.62; 95% CI, 0.46-0.82; P = .001) were both significantly reduced with radiotherapy. Adverse effects were more common with radiotherapy vs observation (23.8% vs 11.9%), including rectal complications (3.3% vs 0%), urethral strictures (17.8% vs 9.5%), and total urinary incontinence (6.5% vs 2.8%).

Conclusions  In men who had undergone radical prostatectomy for pathologically advanced prostate cancer, adjuvant radiotherapy resulted in significantly reduced risk of PSA relapse and disease recurrence, although the improvements in metastasis-free survival and overall survival were not statistically significant.


Radical prostatectomy is selected for treatment of localized prostate cancer by approximately one third of the 230 000 patients newly diagnosed each year in the United States. It is commonly accepted that this treatment has optimal results in patients with cancer confined to the prostate. Despite a stage-shift to earlier stages and lower tumor volumes, extraprostatic disease is detected at radical prostatectomy in 38% to 52% of patients. Each stratum of extraprostatic disease—ie, pathologic extension beyond the prostate, positive surgical margins, or invasion of the seminal vesicle—is associated with a risk of disease recurrence, progression, and death.

The optimal treatment for patients with extraprostatic disease noted after radical prostatectomy is unknown. Adjuvant radiotherapy has been used for more than 4 decades to reduce the risk of disease recurrence. A randomized controlled clinical trial of adjuvant radiotherapy has demonstrated a reduction in prostate-specific antigen (PSA) relapse and local progression, but due to short follow-up, it is unknown if radiation reduces risk of metastases or improves survival.  Here, we report the results of a randomized, prospective clinical trial comparing ajuvant radiation therapy with usual care and observation alone for patients with extraprostatic disease after radical prostatectomy and examining metastasis-free survival and overall survival as end points.

The study was a randomized multi-institutional clinical trial of adjuvant radiation therapy for locally advanced prostate cancer following radical prostatectomy. At the time of study activation on August 15, 1988, to be eligible, patients must have undergone a radical prostatectomy within 16 weeks prior to randomization, had a negative bone scan result, and met 1 or more of 3 criteria for extraprostatic disease: extracapsular tumor extension, positive surgical margins, or seminal vesicle invasion, confirmed by the institutional pathology report. A pelvic lymphadenectomy was required; patients with involved pelvic lymph nodes were ineligible for enrollment. Beginning in June 1995, 4 groups of patients at very low risk for involved pelvic lymph nodes were not required to undergo lymphadenectomy: (1) clinical stage T1a or T2a, Gleason score 2 through 6, and PSA level less than 10 ng/mL; (2) stage T1b-c, Gleason 2 through 5, and PSA level less than 10 ng/mL; (3) stage T2b, Gleason 2 through 6, and PSA level less than 6 ng/mL; and (4) stage T2c, Gleason 2 through 6, and PSA level less than 4 ng/mL.

An undetectable PSA level at enrollment was not required. Radiation therapy at a dose of 60 to 64 Gy delivered to the pelvic fossa in 30 to 32 fractions was initiated within 10 working days after randomization. Ports included the prostatic fossa and paraprostatic tissues. Patients must have had evidence of adequate bone marrow and liver function and a performance status of 0 through 2. Patients must not have had total urinary incontinence, intraoperative rectal injury, persistent urinary extravasation, or pelvic infection. Previous radiotherapy or chemotherapy for prostate cancer was not allowed. Toxicity was monitored weekly during radiotherapy.

The treatment of men with pathologically advanced prostate cancer after radical prostatectomy has remained a subject of intense interest for decades. The Southwest Oncology Group 8794 trial was developed at the outset of the "PSA era," as PSA testing swept across the United States. While it was hoped that through early detection, pathologically advanced prostate cancer (ie, tumors that had extended beyond the prostate, had extended to the surgical margins, or had invaded the seminal vesicles) would diminish substantially, contemporary series continue to report high rates of extraprostatic disease.

The results of this study provide guidance for clinicians and patients in weighing options for adjuvant radiotherapy for pathologically advanced disease. Arguments in favor of radiotherapy include the approximately 50% reduction in risk of PSA relapse or disease recurrence, and perhaps the nonsignificant reduction (P=.06) in risk of metastasis-free survival, the primary study end point. PSA relapse and disease recurrence are associated with several adverse consequences, including patient anxiety and use of adjuvant therapies with potential adverse effects. Such treatments can include radiotherapy and hormonal therapy, which is associated with risks of osteoporosis, sexual dysfunction, hot flashes, sarcopenia, and reduced quality of life. In our study, adjuvant radiotherapy significantly reduced the risk of receiving adjuvant hormonal therapy. The ability of this study to detect a significant improvement in metastasis-free and overall survival may have been attenuated by the one third of patients who were initially randomized to observation but who ultimately received pelvic radiotherapy.

Arguments against adjuvant radiotherapy must include that the study had negative findings, ie, a significant reduction in metastatic disease was not demonstrated. Despite prolonged follow-up of these patients, the rate of metastatic disease was significantly less than anticipated. Based on the data in this series, censoring death without metastatic disease, we estimate that at 13.2 years, the metastasis-free survival estimate would be 78%. To detect an HR of 1.25 and assuming 10 years of accrual (approximately 290 patients per year), 10 years of follow-up, a 2-sided {alpha} of .05, and 80% power, the study sample size would require 2900 patients. With 6 years of accrual, 10 years of follow-up, and a very large HR of 1.50, the sample size would be 1100. These estimates demonstrate the need for improved accrual of men with prostate cancer to clinical trials or inclusion of higher-risk patients, such as those with Gleason scores of 7 or greater. However, such a severe limitation in eligibility would limit the generalizability of results.

Currently, there is debate as to whether a PSA response to treatment can serve as a surrogate for disease-related outcomes; thus, the implications of a reduced risk of PSA relapse after radiotherapy are unknown.   This study demonstrates the potential inconsistency of PSA relapse and the primary end point, with a significant reduction in the former but no significant relation in the risk of metastatic disease. In addition to the lack of significant improvements in metastasis-free and overall survival, patients receiving radiotherapy more commonly had urinary or bowel complications.

In lieu of immediate adjuvant radiotherapy for patients with pathologically advanced prostate cancer, it has been advocated that patients receive surveillance of PSA levels during follow-up, with delayed radiotherapy if a detectable value is noted. Ultimately, this was the approach in the observation group of this study, because approximately one third of this group eventually received radiation. With a lack of a statistically significant improvement in metastasis-free and overall survival in the 2 study groups, this approach may be a reasonable alternative. Arguing against this approach was the fact that 8 (12.7%) of 63 of these patients ultimately developed metastatic disease.

Other studies of adjuvant therapies are currently under way, including a National Cancer Institute study comparing androgen deprivation for 2 years with androgen deprivation plus adjuvant mitoxantrone.18 With the recognition that 35 (16.6%) of 211 men in the observation group of our study ultimately developed metastatic disease within 10 to 15 years of follow-up, the need for completion of long-term studies with appropriately selected disease end points is clear.