The CHHiP trial recently reported the 5-year outcomes of a randomized, non-inferiority, Phase 3 study that aimed to determine if a discernable difference exists in efficacy and toxicity between conventional fractionation and hypofractionation in men with prostate cancer. To note, 73% of this population had intermediate-risk disease. The important arms in this study were the hypofractionated 60 Gy arm to the conventional 74 Gy arm. The results showed that there was no difference in efficacy endpoints at 5 years. In terms of adverse outcomes, there were more acute bowel toxicities, at least Grade 2, in the hypofractionation arm, though there was no difference in the amount of bladder toxicity reported.
Two other hypofractionation trials were conducted that add to our evolving understanding. RTOG 0415 was a noninferiority trial comparing 70 Gy hypo to 73.8 Gy, mainly in low-risk patients. This trial found an increase in late GI toxicity with hypofractionation, but again demonstrated the noninferiority of hypofractionation. Lastly, the HYPRO trial, which was comprised of mainly high-risk patients (74%) was a superiority trial that failed to demonstrate the superiority of 64.6 Gy hypo fractions to 78 Gy. Each of the trials had different populations, different hormonal treatment regimens, and relied on physician-reported toxicities. In CHHiP and RTOG, Dr. Den commends the authors for publishing patient-reported outcomes. Interestingly, there were no differences in patient-reported outcomes in those two studies.
In summary, hypofractionation is proving to have equivalent efficacy and toxicity with lower cost and treatment duration. Surely, this is good news for patients who chose RT as their prostate cancer therapy.
Dr. Den then highlighted results from the STAMPEDE trial reported in JAMA Oncology. In the N+M0 patient subcohort, patients who received local RT actually had a longer failure-free survival than patients who did not receive RT. And despite using larger radiation fields in the N+M0 cohort, there was no significant increase in late GI or GU toxicities compared to the N0M0 cohort.
Taking this “extended treatment effect” paradigm even further, new evidence appears to demonstrate efficacy of radiation therapy in stage IV prostate cancer. Rusthoven et al. published a trial in JCO demonstrating improvement in overall survival in patients with newly diagnosed metastatic prostate cancer who received RT + ADT compared to those who received ADT alone, with a HR of ~0.6. There are several trials currently underway studying the role of RT in N1 and M1 disease, and this is sure to lead to an improved understanding of how aggressive local therapy can beneficially impact survival in metastatic patients.
Lastly, as more patients are obtaining tumor genomic sequencing, researchers have been able to develop gene signatures that predict disease characteristics and response to therapy. Accordingly, investigators used a multi-institutional cohort to develop a 24-gene expression profile “PORTOS” that predicts response to post-prostatectomy RT. This test adds to a growing number of biomarkers that are predictive of patient and disease outcomes. PORTOS predicts radiation response, while DECIPHER might help with the decision of timing of postoperative radiation, and GARD can help define the appropriate radiation dose to be used.
Looking forward into 2017, it is likely that the use of hypofractionation will continue to increase. Hopefully, more data will also mature that helps us understand the role of RT in metastatic patients. Aggressive local treatment via radiation or surgery in M1 patients appears to be an exciting new way of managing disease kinetics in metastatic patients. To guide all of these decisions, predictive biomarker development will be paramount.
Speaker: Robert B. Den, MD; Radiation Oncology; Sidney Kimmel Medical College at Thomas Jefferson University
Written By: Shreyas Joshi, MD, Fox Chase Cancer Center
at the 2017 Genitourinary Cancers Symposium - February 16 - 18, 2017 – Orlando, Florida USA