The current state of adjuvant radiotherapy post prostatectomy: 3 take-home messages

Four randomized trials have established that adjuvant radiotherapy (ART) post radical prostatectomy (RP) for men with a positive margin and/or pathologic stage T3 (pT3) disease reduces biochemical recurrence compared with men managed with observation post RP.1-4 One of these 4 trials demonstrated improvements in metastasis rates and in overall survival (OS).2 These results led to most guidelines recommending the use, or at least discussion of the benefits, of ART for men with adverse pathology post RP.

However, ART did result in a small increase in grade 3 toxicity by 1% to 3% in most trials, and more than 30% of men in all trials never recurred post RP without ART. Thus, despite guideline recommendations, use of ART has decreased, with only 5% to 10% of men with adverse pathology receiving ART in the United States given the fear of overtreatment and unnecessary toxicity. Although this may seem troubling, it is not necessarily a problem given that salvage radiotherapy (SRT) can be used in the subset of patients who do develop a recurrence post RP. This will avoid unnecessary radiotherapy in men who may be cured by RP alone, and potentially reduce toxicity by treating men months to years after RP when more complete functional recovery has occurred. Thus, the real question is, does ART improve outcomes over SRT?

The first 3 trials of ART versus observation used very low rates of SRT in the observation arm. Often only approximately 30% of men who recurred received SRT. Additionally, when SRT was used, it was near uniformly at prostate-specific antigen (PSA) levels higher than 1.0 ng/mL. It is now well established that late SRT at PSAs higher than 0.5 ng/mL have far lower rates of success compared with early SRT when given at time of recurrence, closer to 0.2 ng/mL. Thus, the overall survival benefit observed in the SWOG 8794 randomized trial of adding ART may not be that hard to believe if only 30% of men received SRT, and when they did it was too late.

Three randomized trials reported early results in October 2020 that compared ART with early SRT: GETUG-AFU-17 (NCT00667069), RAVES (NCT00860652), and RADICALS (NCT00541047).5-7 Overall, there was no improvement seen with use of ART compared with early SRT in biochemical- or progression-free survival. As expected, there were lower rates of toxicity with SRT, and more than 40% of men in all trials randomized to early SRT have not required SRT because they have not recurred to date.

What this means is that for patients with favorable to moderately aggressive disease post RP, use of early SRT is preferred over ART and, I believe, is now the standard of care. However, there are 3 important take-home points and caveats that must be considered before applying this statement to all prostate cancer post RP.

1. ART = SRT only when early SRT is used. We know from the Finnish randomized trial of RP with or without ART that approximately 85% of men in the trial in the observation arm who recurred received SRT. However, it was late SRT at PSAs higher than 0.5 ng/mL. Despite this high rate of SRT in the observation arm, there was still a profound reduction in recurrence in the ART arm. Thus, if your practice does not closely monitor patients and send them for early SRT when their PSA is 0.1 or 0.2 ng/mL, it is likely that ART is superior. A study from MUSIC (Michigan Urological Surgery Improvement Collaborative) showed that only 1 in 6 men who recurred post RP received early SRT. Thus, in the real world, it may be that ART is superior if early SRT is not rapidly adopted.

2. ART = SRT only when all patients who recur post RP receive SRT. As stated, in most of the ART randomized trials, the minority of men who recurred post RP ever received SRT. In SWOG 8794 trial, the trial that demonstrated an overall survival benefit, only 30% of men received SRT who recurred post RP. However, in the Finnish trial, 85% of men who recurred post RP received SRT, and there was no metastasis or survival benefit noted. Despite SRT being the only potential curative treatment option for men who recur post RP, in that same analysis from MUSIC it was shown that only approximately 30% of men who recur post RP in the real world ever receive any SRT (early or late). Thus, if in the real world, only 30% of men who recur post RP ever get SRT, and of those men approximately half are given late SRT, it is highly likely that ART is superior to current real-world use of SRT.

3. ART = SRT only when patients have favorable to moderately aggressive prostate cancer. Although it is possible that ART has similar outcomes to early SRT regardless of tumor aggressiveness, this has not yet been shown. All 3 trials that compared ART with early SRT enrolled predominantly patients with Gleason 6 or 7 with either a positive margin or pT3a disease. Only 5% of men on the RADICALS trial, for example, had high-grade disease with seminal vesicle invasion. Thus, there were almost none of these more aggressive patients enrolled in the ART vs early SRT trials. Additionally, almost no men with lymph node-positive disease were enrolled in these trials. Therefore, I would continue to recommend ADT plus delayed ART for men with multiple, very high-risk features or node-positive disease, given that more than 90% of these men are predicted to recur post RP with commonly used nomograms.

It cannot be emphasized enough that SRT is equivalent to ART, but only when SRT is used at time of biochemical recurrence at low PSAs (approximately 0.2 ng/mL), SRT is uniformly used for men who recur post RP, and used for men with node-negative disease without multiple high-risk factors (eg, Gleason 8-10 and pT3b). Thus, urology practices must implement methods to closely monitor patients to ensure timely referral for early SRT if they are going to avoid the use of ART. If this is not done, ART should remain the standard of care, because low rates of SRT and late SRT at high PSAs will result in suboptimal outcomes for patients.

Spratt is a professor of radiation oncology at the University of Michigan, Ann Arbor.

References

1. Bolla M, van Poppel H, Tombal B, et al; European Organisation for Research and Treatment of Cancer, Radiation Oncology and Genito-Urinary Groups. Postoperative radiotherapy after radical prostatectomy for high-risk prostate cancer: long-term results of a randomised controlled trial (EORTC trial 22911). Lancet. 2012;380(9858):2018-2027. doi:10.1016/S0140-6736(12)61253-7

2. Swanson G, Thompson I, Tangen C, et al. Update of SWOG 8794: adjuvant radiotherapy for pT3 prostate cancer improves metastasis-free survival. Int J Radiat Oncol Biol Phys. 2008;72(1):S31. doi:10.1016/j.ijrobp.2008.06.835

3. Hackman G, Taari K, Tammela TL, et al; FinnProstate Group. Randomised trial of adjuvant radiotherapy following radical prostatectomy versus radical prostatectomy alone in prostate cancer patients with positive margins or extracapsular extension. Eur Urol. 2019;76(5):586-595. doi:10.1016/j.eururo.2019.07.001

4. Wiegel T, Bottke D, Steiner U, et al. Phase III postoperative adjuvant radiotherapy after radical prostatectomy compared with radical prostatectomy alone in pT3 prostate cancer with postoperative undetectable prostate-specific antigen: ARO 96-02/AUO AP 09/95. J Clin Oncol. 2009;27(18):2924-2930. doi:10.1200/JCO.2008.18.9563

5. 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(10):1341-1352. doi:10.1016/S1470-2045(20)30454-X

6. Kneebone A, Fraser-Browne C, Delprado W, et al. A Phase III multi-centre randomised trial comparing adjuvant versus early salvage radiotherapy following a radical prostatectomy: results of the TROG 08.03 and ANZUP “RAVES” trial. Int J Radiat Oncol Biol Phys. 2019;105(1):S37-S38. doi:10.1016/j.ijrobp.2019.06.456

7. Parker CC, Clarke NW, Cook AD, et al. Timing of radiotherapy after radical prostatectomy (RADICALS-RT): a randomised, controlled phase 3 trial. Lancet. 2020;S0140-6736(20)31553-1. doi:10.1016/S0140-6736(20)31553-1