FOIU 2018: Optimizing the Management of High Risk Prostate Cancer with Radiotherapy
Zelefsky next discussed how to reduce the potential toxicity of dose intensification therapy. First, tight margins around the prostate target need to be used. Second, careful attention needs to be paid to dose constraints for normal tissue. Third, image guidance and online tracking of the prostate is needed to ensure accuracy during the actual treatment. Lastly, the use of hydrogel spacer is recommended to minimize the dose to the rectum.
The role of combination therapy for higher risk disease was the next topic discussed by Zelefsky. Recognition is required that combined modality treatment is critical for improved outcomes in intermediate-risk disease. The greatest advantage of combined modality treatment is related to the dose intensification which cannot be achieved with any other radiation intervention. Standard practice at MSKCC for high-risk disease is to use ADT with low dose rate (LDR) or high dose rate (HDR) brachytherapy followed by EBRT/ stereotactic body radiation therapy (SBRT).
Zelefsky moved on to the topic of ADT combined with radiotherapy for high-risk PC. In a systematic review published in 20122 it was demonstrated that shorter courses of treatment demonstrated a 21% reduction in the risk of mortality (Hazard ratio of 0.79, 95% C.I. 069-0.9, p=0003). However, longer treatment durations provided an even greater magnitude of mortality risk reduction (HR 0.61, 95% C.I. 0.47-0.81, p=0.0005).
Another trial, the AASUR trial, is exploring SBRT combined with 2nd generation anti-androgens to improve outcome in very high-risk patients. This is a single-arm multicenter phase 2 trial, examining abiraterone, ARN-509, prednisone, leuprolide, stereotactic hypofractionated radiation therapy (40Gy in 5 fractions), involving 58 patients in 5 sites.
Zelefsky brought up the issue of using genomic profiling to predict radiotherapy responses for high-risk PC. It is known that a substantial proportion of patients with primary PC harbor somatic and/or germline genetic alterations in DNA repair. A small subset of patients with PC harbor germline defects in BRCA2. Recent advances in high-throughput genomic profiling have allowed the identification of deleterious genetic alterations in a more diverse set of DNA repair genes than previously recognized, including those involved in homologous recombination repair, Fanconi anemia repair, and DNA damage signaling.
The association of PARP inhibitors and radiotherapy was discussed next. Preclinical data suggest that inactivation of homologous DNA repair results in tumor-specific sensitivity to the combination of ionizing radiation and PARP inhibition. A phase 1 study attempting to analyze the effects of PARP inhibitors and radiotherapy in high-risk patients with DDR mutations will be initiated soon at MSKCC.
Zelefsky concluded his discussion stating that high-risk disease managed with radiotherapy requires dose intensification strategies in combination with ADT. Level 1 evidence suggests that combined modality approaches of brachytherapy + EBRT in conjunction with ADT for at least 12 months is associated with improved outcomes compared to EBRT and ADT. Using Novel anti-androgen therapy in conjunction with radiation being explored for the high-risk patients, to determine if outcomes can be further improved. Lastly, genetic profiling for high-risk patients to optimize therapy with targeted and biologic therapy holds much promise for the future.
References:
1. Morris et al. Int J Radiat Oncol Biol Phys 2017
2. Sasse et al. BC 2012
Presented by: Michael Zelefsky, MD, MSKCC, New York, NY, USA
Written by: Hanan Goldberg, MD, Urologic Oncology Fellow (SUO), University of Toronto, Princess Margaret Cancer Centre @GoldbergHanan at the 2018 FOIU 4th Friends of Israel Urological Symposium, July 3-5. 2018, Tel-Aviv, Israel