Adjuvant radiotherapy (ART) after prostatectomy yielded significantly better outcomes than surveillance followed by early-salvage radiotherapy (ESRT) in a large retrospective analysis of patients with pathologically unfavorable disease, researchers reported in JAMA Oncology (2018: doi:10.1001/jamaoncol.2017.5230).
The study of outcomes in 1,566 consecutive patients treated at 10 U.S. cancer treatment centers found that those given ART had appreciably lower rates of post-irradiation biochemical failure and distant metastases, as well as better overall survival, than their counterparts who received ESRT. High-risk patients were those with T3 disease and/or positive margins.
"To our knowledge, this is the largest multi-institutional study to date comparing ART to ESRT," said senior author Jason A. Efstathiou, MD, DPhil, Director of the Genitourinary Division, Department of Radiation Oncology, Massachusetts General Hospital, Boston. "Pending prospective validation, our findings suggest that there may be a benefit to adjuvant post-prostatectomy radiotherapy (RT) in prostate cancer patients with adverse pathological features."
It is estimated that approximately half of patients with adverse pathological features will recur following prostatectomy. Many of these men are initially treated with surveillance followed by ESRT. However, the optimal timing of postoperative RT is a topic of considerable debate.
Efstathiou said national practice patterns suggest that the use of ART is declining in patients with adverse pathologic features.
"Since 2005, the rate has fallen from 9 percent to 7 percent largely because of concerns that these patients are being overtreated and may have been cured by surgery alone."
Methods, Results
The researchers conducted a retrospective observation of outcomes in patients who underwent postprostatectomy ART or ESRT between 1987 and 2013. To reduce the risk of confounding or bias due to different variables, the investigators used 1-to-1 propensity score matching to compare freedom from post-irradiation biochemical failure, freedom from distant metastases, and overall survival, with all outcomes measured from surgery date.
Among the patients, 1,195 with prostate-specific antigen (PSA) levels of 0.1-0.5 ng/mL received ESRT, while 371 with levels lower than 0.1 ng/mL received ART. The median age was 60 years. After propensity score matching, the median follow-up after surgery was similar between the two groups (73.3 months ESRT, 65.8 months ART).
Compared to the ART group, ESRT patients had an earlier median year of surgery, lower pathological T stage (T3: 52.7% vs. 73.6%), lower Gleason scores (8-10: 18.8% vs. 28.8%), lower rate of positive margins (60.3% vs. 84.9%), less use of intensity modulated RT (36.5% vs. 46.9%), and greater use of postoperative androgen deprivation therapy (11.3% vs. 6.2%). The median pre-ESRT PSA level was 0.3 ng/mL.
ART was associated with 26 percent greater freedom from biochemical failure, with a 12-year rate of 69 percent compared to 43 percent in ESRT patients, while freedom from distant metastases was 10 percent higher with ART (95% vs. 85%) and overall survival was 91 percent with ART compared to 79 percent among patients treated with ESRT.
Adjuvant RT, lower Gleason score and T stage, nodal irradiation, and postoperative androgen deprivation therapy use were favorable prognostic features on multivariate analysis for biochemical failure.
Sensitivity analysis demonstrated that the decreased risk of biochemical failure associated with ART remained significant unless more than 56 percent of patients in the ART group were cured by surgery alone. This threshold is greater than the estimated 12-year freedom from biochemical failure rate of 46 percent after radical prostatectomy alone, Efstathiou noted.
"If these results are validated, we need to reevaluate current practice patterns and further define potential economic and quality-of-life impact," he told Oncology Times.
He noted that several prospective randomized clinical trials are currently underway that include comparison of the two approaches, with data expected to become available within the next few years. At the same time, advances in diagnostics may help better stratify patients, he said.
"Emerging genomic biomarkers and advanced imaging may also help with risk stratification and patient/treatment selection for ART and ESRT." Risk stratification may be enabled using genomic biomarkers such as the Decipher score, while molecular imaging techniques, such as fluciclovine (18F) PET, may be useful for optimizing target coverage in the salvage setting.
"Ultimately, the onus is on the uro-oncology team to discuss postoperative radiation therapy with the patient, address its optimal timing when it is used, and provide justification when it is not," Efstathiou stated.
Commentary
Timothy N. Showalter, MD, Associate Professor of Radiation Oncology at the University of Virginia's Emily Couric Clinical Cancer Center, Charlottesville, said that, while the study provides important information to help guide treatment decisions, the debate over which option to use for these patients is likely to continue.
"Since all members of the salvage radiation therapy group already had a biochemical recurrence, while many members of the adjuvant radiation therapy group were likely already cured by surgery, conclusions from comparative analyses are inherently limited," he noted.
The sensitivity analysis of the results showed that the observed benefit of adjuvant radiation therapy would remain significant unless more than 56 percent of patients in the ART group were cured by surgery alone.
"This is interesting to me as a clinician, since it is possible that nearly half of these patients in the adjuvant group could have already been cured by prostatectomy, which would reduce the benefit of adjuvant therapy," he told Oncology Times.
"Although the study showed a general trend toward improved outcomes with adjuvant radiation therapy, when one considers the sensitivity analysis and the differences between the two treatment groups, it seems that there is no single correct answer for the adjuvant versus salvage therapy debate," Showalter stated. "This supports the need for shared decision-making for each individual patient, as well as more tools to guide tailored decision-making."
Kurt Samson is a contributing writer.