Adjuvant Radiation Therapy in the Modern Management of High-Risk Prostate Cancer: Too Much Too Soon?
By: Kathryn A. Marchetti, MD; Colton H. Walker, MD; Todd M. Morgan, MD | Posted on: 01 Apr 2022
The debate regarding the decision to treat men at high risk for local recurrence of prostate cancer following radical prostatectomy (ie men with positive surgical margins, extraprostatic extension [pT3a], and/or seminal vesicle invasion [pT3b]) with immediate adjuvant radiation therapy or early salvage radiation therapy seems to be coming to a close. Three recent randomized control trials–RADICALS-RT,1 RAVES2 and GETUG-AFU 173–show that early salvage radiation therapy is not inferior to adjuvant radiation therapy in terms of 5-year biochemical progression-free survival. A meta-analysis of these 3 trials reports a 5-year event-free survival of 89% for adjuvant therapy and 88% for early salvage therapy.4 Yet, even before these data were published, adjuvant therapy was rarely utilized with many urologists opting to use early prostate specific antigen (PSA) recurrence to selectively guide the use of postoperative radiation instead. Now that the desire to avoid overtreatment and reduce toxicity for postprostatectomy patients at high risk for local recurrence is supported by randomized control trial data, is it time to remove adjuvant radiation therapy from prostate cancer guidelines all together?5
In short, not yet.
While the above trials do offer important data comparing outcomes for adjuvant and early salvage therapy, there are limitations that restrict their generalizability and may have biased the initial findings in favor of early salvage radiation therapy. First, patients in these studies tended to have disease that was more intermediate-risk, rather than high-risk, in nature. For example, of all the included study participants, only 8%–17% had Gleason ≥8 disease, and the maximum preoperative PSA was 11.6 ng/ml.1–3 Additionally, only about a third of patients were categorized as CAPRA-S high-risk in RADICALS-RT.1 With the patient cohort weighted toward the lower end of the risk spectrum, one would expect a decreased event rate and, as a result, an attenuated benefit of adjuvant radiation therapy.
Secondly, in the RADICALS-RT1 and GETUG-AFU 173 trials, participants received androgen deprivation therapy shortly after randomization in the adjuvant therapy arm, compared to 2–3 years after randomization in the early salvage therapy arm at the time of salvage radiation therapy. Based on this timeline, participants who underwent early salvage therapy would be virtually guaranteed to not experience biochemical recurrence until their testosterone started to recover at a later timepoint, potentially biasing the results toward early salvage radiation therapy.
It is also important to recall that prior randomized control trials comparing adjuvant radiation therapy to observation (and often late salvage radiation therapy) showed that adjuvant radiation therapy reduced the risk of biochemical recurrence by 50%,6–8 improved locoregional cancer control6,7 and contributed to an overall survival benefit.6 From the patient perspective, while the rates of late side-effects of adjuvant therapy were significantly higher than those of observation, there was no significant difference in grade 3 or higher toxicity.7 Furthermore, patient-reported global health-related quality of life following adjuvant therapy was actually improved compared to observation at 5 years,9 reflecting the timing of recovery from the side effects of adjuvant therapy as well as the decreased likelihood of biochemical recurrence and need for additional treatment.
While the latest randomized control trials suggest that observation with early salvage radiation therapy is an appropriate approach for many men at high risk of local recurrence following radical prostatectomy,1–3 it is also important to acknowledge that, in practice, the utilization of early salvage radiation therapy more closely resembles late salvage radiation therapy or even observation.5,10 In a study of over 1,000 patients in Michigan with a detectable PSA following radical prostatectomy, only 29.5% underwent salvage radiation therapy.5 Critically, over 30% of patients reached a PSA of 0.5 ng/ml or greater without receiving salvage radiation therapy.
Two key conditions should be met before we move on entirely from adjuvant radiation therapy. First, hard oncologic end points, such as metastasis-free and disease-specific survival, need to be reported in the 3 recent trials to provide confidence that adjuvant radiation does not offer an oncologic benefit over early salvage radiation. Second, practice patterns need to change such that early salvage radiation therapy is utilized in at least the majority of men with biochemical recurrence following radical prostatectomy.
In the meantime, adjuvant radiation therapy for men who are at very high risk of recurrence should at a minimum be discussed and potentially be recommended. A 60-year-old man with a PSA of 15 ng/ml and Grade Group 4 pT3bN0 prostate cancer with a positive margin has only a 12% recurrence-free probability at 5 years and a 6% recurrence-free probability at 10 years.11 Extrapolating the latest data to recommend against adjuvant radiation therapy in such a patient is likely an overreaction based on our current understanding of the disease. A patient who is nearly guaranteed to experience biochemical recurrence in the short-term may be better served by moving forward with adjuvant therapy once he has fully recovered from surgery. Ultimately, whether adjuvant or early salvage, appropriate postoperative radiation therapy is utilized far too infrequently given how well tolerated these treatments are and the high-level evidence supporting their oncologic benefit.12 Ensuring that we as urologists are working closely with radiation oncologists as part of a multidisciplinary team is an integral component of optimizing outcomes for men at the highest risk of dying from prostate cancer.
- Parker CC, Clarke NW, Cook AD et al: Timing of radiotherapy after radical prostatectomy (RADICALS-RT): a randomised, controlled phase 3 trial. Lancet 2020; 396: 1413.
- Pearse M, Fraser-Browne C, Davis ID et al: A phase III trial to investigate the timing of radiotherapy for prostate cancer with high-risk features: background and rationale of the Radiotherapy–Adjuvant Versus Early Salvage (RAVES) trial. BJU Int 2014; 113: 7.
- Sargos P, Chabaud S, Latorzeff I et al: Adjuvant radiotherapy versus early salvage radiotherapy plus short-term androgen deprivation therapy in men with localised prostate cancer after radical prostatectomy (GETUG-AFU 17): a randomised, phase 3 trial. Lancet Oncol 2020; 21: 1341.
- Vale CL, Fisher D, Kneebone A et al: Adjuvant or early salvage radiotherapy for the treatment of localised and locally advanced prostate cancer: a prospectively planned systematic review and meta-analysis of aggregate data. Lancet 2020; 396: 1422.
- Hawken SR, Spratt DE, Qi J et al: Utilization of salvage radiation therapy for biochemical recurrence after radical prostatectomy. Int J Radiat Oncol Biol Phys 2019; 104: 1030.
- Swanson GP, Hussey MA, Tangen CM et al: Predominant treatment failure in postprostatectomy patients is local : analysis of patterns of treatment failure in SWOG 8794. J Clin Oncol 2007; 25: 2225.
- Bolla M, Van Poppel H, Collette L et al: Postoperative radiotherapy after radical prostatectomy: a randomised controlled trial (EORTC trial 22911). Lancet 2005; 366: 572.
- Wiegel T, Bartkowiak D, Bottke D et al: Adjuvant radiotherapy versus wait-and-see after radical prostatectomy : 10-year follow-up of the ARO 96-02/AUO AP 09/95 trial. Eur Urol 2014; 66: 243.
- Moinpour CM, Hayden KA, Unger JM et al: Health-related quality of life results in pathologic stage C prostate cancer from a Southwest Oncology Group trial comparing radical prostatectomy alone with radical prostatectomy plus radiation therapy. J Clin Oncol 2008; 26: 112.
- Chen BRC and Choudhury A: Adjuvant versus early salvage radiation therapy after radical prostatectomy for men with adverse pathologic features–the debate continues. Int J Radiat Oncol Biol Phys 2021; 109: 839.
- Stephenson AJ, Peter T, Eastham JA et al: Preoperative nomogram predicting the 10-year probability of prostate cancer recurrence after radical prostatectomy. J Natl Cancer Inst 2006; 98: 715.
- Akthar AS, Liao C, Eggener SE et al: Patient-reported outcomes and late toxicity after postprostatectomy intensity-modulated radiation therapy. Eur Urol 2019; 76: 686.