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Adjuvant radiotherapy after radical prostatectomy significantly reduced biochemical progression for men with pT3 prostate cancer in a multicenter phase III trial conducted in Germany
The 385-patient study showed progression-free survival of 55% for men randomized to adjuvant radiotherapy versus 44% for those who were assigned to "watchful waiting" after surgery.
This gap widened when 78 patients dropped out of the study in a planned exclusion because they did not reach undetectable prostate-specific antigen (PSA) levels. An intent-to-treat analysis of the remaining 307 men showed biochemical control reached 72% with adjuvant radiotherapy versus 54% with watchful waiting. The difference was highly significant (P = .0015), lead author Dr. Thomas Wiegel reported.
The benefit would have been even more dramatic had all patients in the radiotherapy arm actually received radiotherapy, said Dr. Wiegel, a radiation oncologist at the University of Ulm (Germany) Hospital. Community-based urologists did not send 32 of 148 patients (22%) for adjuvant treatment despite their enrollment in the study. Nonetheless, these patients were included in the intent-to-treat comparison of 148 undetectable-PSA patients randomized to radiotherapy versus 159 comparable patients assigned to watchful waiting.
It remains in dispute whether all patients should receive adjuvant radiotherapy, or whether radiotherapy should be delivered only in the presence of a rising PSA, Dr. Wiegel said. When interviewed, he was not optimistic that his findings would end the controversy over the role of adjuvant radiotherapy in pT3 prostate cancer. Adding to the debate, he said, is the emergence of ultrasensitive PSA testing capable of detecting PSA levels that were undetectable when the study was conducted.
"We can't say it [adjuvant radiotherapy] is the standard of care, but with these studies it is now really allowed," he said, emphasizing that the trial confirms three previous studies that found adjuvant radiotherapy confers a 20% advantage in biochemical control. He noted that subgroup analyses showed patients with preoperative PSA scores greater than 10 ng/mL, all Gleason scores, and pT3 A/B tumors benefited from adjuvant radiotherapy, as did those with positive surgical margins.
The trial randomized patients from April 1997 to September 2004. Outcomes were reported at a median follow-up of 55 months (range 2-109 months).
The average radiation dose for trial completers was 60 Gy delivered in single 2-Gy doses five times per week. Patients excluded because of detectable PSA received 66 Gy of radiation.
The only grade 3 toxicities reported were acute and late side effects (3% and 2%, respectively) in the bladder. Late grade 1 or grade 2 bladder events occurred in 16% of patients, acute grade 2 rectal side effects in 12% of patients, and late grade 1 or grade 2 rectal events in 10%. "There were no major problems," Dr. Wiegel said.
Wiegel T. et al. Phase III results of adjuvant radiotherapy (RT) versus wait-and-see (WS) in patients with pT3 prostate cancer following radical prostatectomy (RP)(ARO 96-02/AUO AP 09/95). Abstract 5060.
Commentary |
Radiotherapy is common following surgery for patients with high-risk features in a number of solid tumors, including breast, lung, cervix, endometrial, rectal, musculoskeletal, and head and neck neoplasms. In all these sites adjuvant radiotherapy reduces the risk of local or regional recurrence. It improves disease-free and overall survival in patients with breast cancer. Adjuvant radiotherapy after prostatectomy is less accepted, however. The randomized trial by Wiegel et al. demonstrates that local radiotherapy (to modest doses) can alter the natural history of prostate cancer. The results are consistent with two larger randomized trials that reported radiotherapy for high-risk features following prostatectomy reduces biochemical recurrence by approximately 50%. The radiotherapy techniques used in the German study were more sophisticated than those in the two previous studies and may explain the low rates of moderate to severe toxicity. Biochemical recurrence may not be the best end point, but the Southwest Oncology Group trial with the longest follow-up indicates early radiotherapy after prostatectomy can reduce the risk of distant metastases by 25% at 10 years. The controversy will continue until a trial demonstrates a survival advantage to early radiotherapy. — W. Robert Lee, M.D., and Judd W. Moul, M.D.
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