The Timing of Radiation after Prostatectomy: Is There Still a Role for Adjuvant Radiotherapy?
By: Christopher L. Amling, MD | Posted on: 01 Feb 2022
With the increasing use of active surveillance, a greater proportion of men undergoing radical prostatectomy (RP) have high-risk disease, and as many as 50% of these men will develop biochemical recurrence (BCR) within 10 years.1 Thus, an increasing number of men are being considered for postoperative radiotherapy (RT). Three randomized trials have demonstrated improved oncologic outcomes with adjuvant RT when adverse pathological findings are found at prostatectomy, specifically extracapsular extension, seminal vesical involvement and/or positive surgical margins (table 1).2–4 However, the use of adjuvant RT has remained limited, at 10% to 15% at best.5 This low utilization is in large part due to the concern about overtreatment. About half of the patients in the control arms of these trials had no evidence of recurrence at 5 years. Thus, early salvage RT (given at the time of BCR) may be a preferable approach.
Table 1. Three randomized trials of adjuvant radiotherapy after prostatectomy versus initial observation for men with adverse pathological findings
|EORTC 22911||SWOG 8794||ARO 96-02|
EPE, SVI or +SM
EPE, SVI or +SM
EPE, SVI, ± SM
|Preop PSA (median)||12 ng/ml||∼10 ng/ml||9–10 ng/ml|
|Postop PSA||≤0.2 ng/ml in 70%||<0.2 ng/ml in 66%||≤0.2 ng/ml in 100%|
|Radiation||60 Gy conventional within 4 mos||60–64 Gy conventional within 4 mos||60 Gy 3-dimensional conformal within 3 mos|
|Median followup||10.6 yrs||12.6 yrs||9.3 yrs|
|End points (adjuvant vs wait-and-see)||BCR-free survival: 61.8 vs 39.4% (HR 0.49), NNT 5; no overall survival difference||Metastasis-free survival: 43% vs 54% (HR 0.71), NNT 10; overall survival: 52% vs 41% (HR 0.72), NNT 10||BCR-free survival (10-yr): 56% vs 35% (HR 0.51), NNT 5; overall survival: not powered to detect difference|
|Adapted from Rodriquez et al.16
EPE, extraprostatic extension; NNT, number needed to treat; SM, surgical margins; SVI, seminal vesical invasion.
Three randomized trials comparing adjuvant RT to early salvage RT have recently been published (table 2).6–8 RADICALS-RT recruited 1,396 patients in the United Kingdom, Denmark, Canada and Ireland (2007 to 2016); GETUG-AFU 17 recruited 424 patients in France (2008 to 2016); and RAVES recruited 333 patients in Australia and New Zealand (2009 to 2015). While the GETUG-AFU 17 and RADICALS-RT trials were designed to assess whether adjuvant RT was superior to salvage RT, the RAVES trial assessed whether salvage RT was noninferior to adjuvant RT. For all trials, patients randomized to receive adjuvant RT received it within 6 months after surgery. Salvage RT was triggered at low prostate specific antigen (PSA) level recurrences that differed slightly between the trials. The results of all 3 trials and a meta-analysis of the aggregate data (ARTISTIC)9 showed that the oncologic outcomes of early salvage RT were not inferior to adjuvant RT. In addition, all 3 trials reported increased side effects with adjuvant RT.
Table 2. Randomized trials comparing adjuvant to early salvage radiotherapy after prostatectomy
|Enrollment||1,396 pts; Canada, UK, Denmark, Ireland||333 pts; Australia, New Zealand||424 pts; France|
|Eligibility criteria||One or more of: pos margins, pT3a/pT3b/pT4, Gleason 7–10||pT2/pT3a/pT3b and either pos margins or ECE||pT3a/pT3b/pT4 and pos margins and ECE|
|Randomization and timing of RT||Immediate (within 6 mos of RP)
early salvage RT (within 2 mos of trigger PSA)
|Immediate (within 6 mos of RP)
early salvage RT (within 4 mos of trigger PSA)
|Immediate (within 6 mos of RP)
early salvage RT (as soon as possible after PSA relapse and before PSA=1 ng/ml)
|Use of ADT||Could be randomized to receive (none, short- or long-term) or receive off protocol||None||All received ADT, both adjuvant and salvage RT|
|Trigger for early salvage RT||PSA ≥0.1 ng/ml and rising or 3 consecutive rising PSA levels||PSA ≥0.2 ng/ml||PSA ≥0.2 ng/ml and rising|
|Primary outcome||Freedom from distant metastases||Freedom from biochemical recurrence||Event-free survival|
|Adapted from Vale et al.9
ECE, extracapsular extension.
While these results support early salvage RT as the preferred approach, it is noteworthy that these trials included only a small proportion of patients with high-risk disease. Men with pathological Gleason score 8–10 and/or pT3a or higher disease comprised only 9% to 17% of those enrolled.6–8 Since the majority had relatively favorable pathology, the potential benefit of adjuvant RT in high-risk patients may have been missed. In addition, fewer men underwent salvage RT than adjuvant RT in these trials. Since androgen deprivation therapy (ADT) was used concurrently with adjuvant RT in 2 of the trials, progression-free survival in the adjuvant RT group may have been favorably affected since ADT can delay time to progression. Immortal time bias, a well-recognized bias in observational studies, is another potential confounding factor. In the salvage RT arms of these trials, there was a period of time (salvage RT treatment planning and delivery) during which the outcome event (recurrence) could not occur. By scoring PSA failure on the salvage arm at a later time than the adjuvant arm, salvage RT could falsely appear superior to adjuvant RT.
If these trials were underpowered to address the adjuvant versus early salvage question in high-risk patients, could there still be a role for adjuvant RT? A recently published large retrospective analysis suggests a benefit to adjuvant RT in some cases. This analysis of 26,118 men from Germany and the United States, using propensity score matching to minimize treatment selection bias, found that in men with pN1, pathological Gleason score 8–10 and pT3a or higher disease, adjuvant RT was superior to early salvage RT with regard to all-cause mortality.10 In the salvage RT setting, multiple studies show better outcomes when radiation is administered at the lowest possible PSA level. Since PSA is proportional to the volume of residual disease, adjuvant RT would be delivered when there is the lowest microscopic disease burden (ie when PSA is undetectable).
The results of these trials establish early salvage RT as the standard of care in most cases, but adjuvant RT may still be preferable for some very high-risk patients. Prognostic nomograms such as the CAPRA-S scoring system (Cancer of the Prostate Risk Assessment–postsurgical) and/or the Stephenson nomogram can be used to accurately predict the probability of BCR.11,12 If these nomograms predict a near certain chance of recurrence, adjuvant RT could be considered. Postoperative PSA nadir has also been shown to be an indicator of recurrence. In one study, BCR was unlikely in those with postoperative PSA nadir ≤0.02 ng/ml, but almost all cases with PSA nadir above this level eventually recurred, especially those with PSA ≥0.05 ng/ml.13 Prognostic nomograms and nadir postoperative PSA levels could be used together to select men for adjuvant RT.
New tissue-based biomarkers will undoubtedly be developed to assist in identifying the best candidates for adjuvant RT. There is some evidence from retrospective studies that a tissue-based genomic classifier score (Decipher Prostate Cancer Classifier), based on the expression of 22 genes, may help predict who might be best suited for adjuvant versus salvage RT.14 Dalela et al developed a risk-stratification tool incorporating the Decipher score and pathological features to identify patients who would benefit most from adjuvant RT.15 In patients with 2 or more high risk factors, adjuvant RT was associated with a 10.1% 10-year clinical recurrence rate compared to a rate of 42.1% in those managed with initial observation. While positron emission tomography/computerized tomography imaging has improved detection of residual disease after RP, the sensitivity is limited at the very low PSA levels at which adjuvant RT would be given. Thus, although we now have good evidence from randomized trials that an early salvage RT approach is preferable in most cases, the role of adjuvant RT after RP will likely evolve and continue to be debated.
- Epstein JI, Zelefsky MJ, Sjoberg DD et al: A contemporary prostate cancer grading system: a validated alternative to the Gleason score. Eur Urol 2016; 69: 428.
- Bolla M, van Poppel H, Tombal B et al: Postoperative radiotherapy after radical prostatectomy for high-risk prostate cancer: long-term results of a randomised controlled trial (EORTC trial 22911). Lancet 2012; 380: 2018.
- Thompson IM, Tangen CM, Paradelo J et al: Adjuvant radiotherapy for pathological T3N0M0 prostate cancer significantly reduces risk of metastases and improves survival: long-term followup of a randomized clinical trial. J Urol 2009; 181: 956.
- 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.
- Sineshaw HM, Gray PJ, Efstathiou JA et al: Declining use of radiotherapy for adverse features after radical prostatectomy: results from the National Cancer Data Base. Eur Urol 2015; 68: 768.
- 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.
- Kneebone A, Fraser-Browne C, Duchesne GM et al: Adjuvant radiotherapy versus early salvage radiotherapy following radical prostatectomy (TROG 08.03/ANZUP RAVES): a randomised, controlled, phase 3, non-inferiority trial. Lancet Oncol 2020; 21: 1331.
- 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.
- Tilki D, Chen Ming-Hui, Wu J et al: Adjuvant versus early salvage radiation therapy for men at high risk for recurrence following radical prostatectomy for prostate cancer and the risk of death. J Clin Oncol 2021; 39: 2284.
- Cooperberg MR, Hilton JF and Carroll PR: The CAPRA-S score. Cancer 2011; 117: 5039.
- Stephenson AJ, Scardino PT, Eastham JA et al: Postoperative nomogram predicting the 10-year probability of prostate cancer recurrence after radical prostatectomy. J Clin Oncol 2005; 23: 7005.
- Hong SK, Park HZ, Lee WK et al: Prognostic significance of undetecfffff ultrasensitive prostate-specific antigen nadir after radical prostatectomy. Urology 2010; 76: 723.
- Den RB, Yousefi K, Trabulsi EJ et al: Genomic classifier identifies men with adverse pathology after radical prostatectomy who benefit from adjuvant radiation therapy. J Clin Oncol 2015; 33: 944.
- Dalela D, Santiago-Jiménez M, Yousefi K et al: Genomic classifier augments the role of pathological features in identifying optimal candidates for adjuvant radiation therapy in patients with prostate cancer: development and internal validation of a multivariable prognostic model. J Clin Oncol 2017; 35: 1982.
- Rodriquez JF, Liauw SL, Eggener SE et al: Managing cancer relapse after radical prostatectomy: adjuvant versus salvage radiation therapy. Urol Clin North Am 2017; 44: 597.