Adjuvant radiation and ADT following prostatectomy for high-risk prostate cancer:
RTOG Trial 9601, Shipley et al., JCO, 2017 Jan.
The findings from this randomized Phase III trial supported the current standard of care for this situation. It compared two treatments initiated after a PSA rise to between 0.2 – 4.0 ng/mL after a prostatectomy and lymphadenectomy. The study involved 761 men with localized cancer having a high risk for recurrence, i.e., extra capsular extension or seminal vesicle involvement, or nodular disease with positive surgical margins. Salvage radiation to the prostate region was given to all.
Randomization specified 2 years of ADT with adjuvant bicalutamide (‘Casodex’ – 150 mg daily) for one arm and a placebo for the other. The researchers chose androgen suppression with this anti-androgen as opposed to Lupron, conventionally used in the US.
An important stratification allowed analysis of one group (85%) that began ‘salvage’ radiation (RT) at PSA values of <1.6 ng/mL and a second cohort which received RT at PSA between 1.6 and 4. (The current standard for commencing savage radiation in this situation is at PSA < 0.5 ng/mL, and often well below that value.)
Findings: Actuarial overall 10-year survival was 82% for RT + ADT vs. 78% RT alone. At 12 years death occurred in 2.3% in the RT/ADT arm vs. 7.5% for RT alone.
In Conclusion: In this high-risk group RT + 24 months of ADT after prostatectomy improved
Of Special Note: The difference in death rate, i.e. 2.3% with ADT vs 7.5% without would appear to be strong support for the superiority of the addition of ADT. But these are overall death rate data between treatment arms.
The text of the abstract concluded with the statement, “Subgroup analysis of the relative benefits of the addition of AAT [i.e. ADT] are planned and will be presented.”
The following is the promised subgroup analysis.
Upon secondary subgroup analysis of RTOG 9601 a clinically important observation emerged: presented in “Long-term Hormone Therapy May Increase Other-Cause Mortality in Men with Prostate Cancer Receiving Early Salvage Radiotherapy.”
The study was presented in abstract form at ASTRO 2019 by Dr. Dan Spratt, Associate Professor, Radiation Oncology, University of Michigan. Dr. Spratt, along with 19 colleagues, focused on two groups stratified by pre-salvage RT PSA values, i.e. PSA 0.2 – 1.5 vs >1.5 to 4.0 ng/mL. Some in each group had been randomized to receive ADT and others not. Of the 760 men, 85% had
pre-RT PSA values of < 1.5 ng/mL. In recognition that androgen suppression increases cardiac adverse events, the authors focused on the rate of ‘other-cause mortality’ as an important additional observation.
1) The men in the low PSA group gained no overall survival benefit with the addition of bicalutamide. This was in contrast to the more the 50% increase in overall survival associated with ADT in the >1.5 PSA cohort.
2) Men taking ADT whose pre-RT PSA was < 0.6 ng/mL experienced nearly 2X other-cause mortality compared to those taking no ADT. Those men taking ADT who started radiation at PSA values of 0.2 – 0.3 ng/mL experienced a 4X increase in other-cause mortality compared to those men not under hormone suppression. “There was also increased grade 3- 5 cardiac events in those on the bicalutamide arm (p=0.04).”
1) Co-morbidity, especially cardiac co-morbidity, needs to be considered in any treatment employing androgen suppression. The rationale underlying this concern is that for most men with low-risk prostate cancer, and to a lesser degree, for men with higher-risk cancer (as in this RTOG study), mortality after primary treatment is largely due to cardiac complications.
2) Spratt concluded: “Pre-salvage radiotherapy PSA is both a prognostic and true predictive biomarker for benefit of hormone therapy combined with salvage radiation.” Rationale: The PSA value following primary treatment is a surrogate for the residual burden of disease. In instances of low PSA/low tumor burden the toxicity of ADT can outweigh its benefit.