Salvage radiotherapy: a new standard of care

The consensus in the US appears to be moving to that of the Europeans: adjuvant therapy after RP may have no survival advantage over early salvage and leads to overtreatment and more severe toxicities. The results of the first studies specifically designed to answer this question are coming in. One of the main points is that improvement in BCR rates with adjuvant do not translate to overall survival or metastasis-free survival benefits. There is some question whether these findings hold for the very high risk group as well (high Gleason score with adverse RP findings). In the discussion sections of these and previous studies, mention is very often made that adjuvant therapy post RP has been underutilized (compared to guideline recommendations) in favor of waiting to see whether further treatment (salvage) is indeed needed. I'm sure we'll see more discussion and papers on this topic in the journals, and perhaps a revision of US treatment guidelines.

Salvage radiotherapy: a new standard of care (2020)

"Adjuvant radiotherapy following radical prostatectomy (RP) has been shown to reduce the risk of disease recurrence in men with high-risk prostate cancer. Nonetheless, this strategy represents overtreatment for some, who would not otherwise have disease recurrence after RP.

Paul Sargos, a lead investigator on the GETUG–AFU 17 study explains: 'Three randomized trials from the 1990s compared the efficacy of adjuvant radiotherapy, to that of observation after RP. These studies, which included patients with pathological high-risk features, indicated better long-term biochemical and/or clinical tumour control, albeit with higher rates of genitourinary, sexual and gastrointestinal toxicities,' adding that: 'Interestingly, despite the positivity of these data, and, despite only retrospective evidence favouring an observation policy, observation followed by salvage radiotherapy at biochemical failure has been widely adopted in daily practice, predominantly by urologists and by some radiation oncologists.'

Now, data from three randomized controlled trials indicate no evidence of an improvement in 5-year event-free survival (EFS) with the adjuvant approach over early salvage radiotherapy.

Investigators in Australia and New Zealand (TROG 08.03/ANZUP RAVES), France (GETUG–AFU 17) and Canada, Denmark, Ireland, and the UK (RADICALS-RT) randomly assigned men with Gleason grade ≥6 prostate cancer with at least one risk factor for disease progression undergoing RP (1:1) to receive either adjuvant radiotherapy or salvage radiotherapy upon detection of a rising serum PSA level (either ≥0.2 ng/ml or >0.1 ng/ml and rising on three consecutive occasions). Each trial had a different primary end point: biochemical progression-free survival (bPFS), EFS and freedom from distant metastases, respectively.

In TROG 08.03/ANZUP RAVES, involving 333 patients, both groups had similar 5-year rates of bPFS (86% in the adjuvant radiotherapy group versus 87% in the early salvage group (stratified HR 1.12; Pnon-inferiority = 0.15)). This observation was accompanied by a significant increase in grade ≥2 genitourinary toxicities in those receiving adjuvant radiotherapy (70% versus 54%, OR 0.34; P = 0.0022).

Similarly, GETUG–AFU 17, involving 424 patients, revealed no significant difference in 5-year EFS (92% in the adjuvant radiotherapy group versus 90% in the early salvage group, HR 0.81, log-rank P = 0.42) also with fewer acute grade ≥2 toxicities (59% versus 22%) and late grade ≥2 adverse events (27% versus 7%; P < 0.0001). Unlike in TROG 08.03/ANZUP RAVES, patients in this trial also received a short course of hormone therapy.

These data were further confirmed in RADICALS-RT, involving 1,396 patients, which revealed similar rates of 5-year bPFS (85% in the adjuvant group versus 88% in the salvage group, HR 1.10; P = 0.56). Significant reductions in all radiation-related toxicities (diarrhoea, proctitis, cystitis, haematuria and urethral stricture, all P ≤ 0.02) were observed in the salvage group, although patient-reported outcome measures revealed only short-term (<1 year of randomization) reductions in self-reported urinary or bowel function.

These data provide robust evidence that men undergoing RP can safely be spared adjuvant radiotherapy and the associated risk of adverse events. These conclusions are elegantly summarized in ARTISTIC, a prospectively planned, collaborative meta-analysis, which confirms a 1% difference in 5-year EFS between groups (89% with adjuvant, versus 88% with early salvage radiotherapy).

Sargos summarizes: 'These three studies, added to the ARTISTIC meta-analysis results, are an important step forward and support the use of early salvage as opposed to adjuvant radiotherapy after RP for many patients. This is a practice changing conclusion!'

When asked about future directions, Chris Parker, a lead investigator on RADICALS-RT highlights: 'Although the trial started 13 years ago, the results in terms of freedom from metastases and overall survival remain immature, with insufficient events currently accrued for analysis. We plan to continue follow-up monitoring in order to analyse these end points in due course.'

This article is modified from the original in Nat. Rev. Clin. Oncol. (https://doi.org/10.1038/s41571-020-00443-3)."

[Emphasis mine]
__________________________________________

Early salvage versus adjuvant therapy for treatment of prostate cancer following prostatectomy (2020)
__________________________________________

Early Salvage Radiotherapy Bests Adjuvant Treatment for Prostate Cancer (2020)
_______________________

One of the three studies discussed in the article above:

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 (2020, The Lancet Oncology)

Here is a statement by A. D'Amico on these findings. He discusses possible sources of bias. Dr. D'Amico has published on the advisability of offering adjuvant therapy especially to G9-10 men who have at least one of the four major local adverse RP findings: SVI, R1, N1, or EPE.

Adjuvant vs Early Salvage Radiation After Radical Prostatectomy: For All, for None, or for Some? (2020

"Previous randomized clinical trials have shown that adjuvant radiotherapy (RT) was associated with an approximate halving of recurrence risk in patients with positive surgical margins, and/or prostatectomy(p) T3 disease, but these trials were conducted at a time when postoperative PSA monitoring was not a standard, leading to delayed salvage RT and a possible overestimate of the impact of adjuvant RT on recurrence risk.

Three randomized controlled trials (RADICALS-RT, RAVES, and GETUG-AFU 17)1-3 along with a meta-analysis investigating the timing of RT after radical prostatectomy (RP) utilizing post-RP PSA monitoring have now been published and did not show superiority of adjuvant compared with salvage RT based on the early endpoint of progression-free survival (PFS). However, although entry criteria for men on RAVES and GETUG-AFU 172,3 were those that have been studied in the earlier trials (being men who had extraprostatic extension, seminal vesicle invasion [SVI], or positive surgical margins), the RADICALS trial1 enrolled these men as well as those whose only adverse-risk factor was a preoperative PSA over 10 ng/mL or pGleason score 7. This means a favorable-risk patient with pT2N0, pGleason 3 + 4 and a pre-RP PSA of 11 ng/mL was eligible for the RADICALS-RT study.

The authors conclude that salvage RT should be the preferred approach; yet, whether this conclusion applies to all men is unclear. First, men at high risk for progression (being those with pGleason score 8–10 and/or pT3a or higher disease) comprised at most 9% to 17% of men enrolled in the three randomized trials. As a result, any benefit for adjuvant RT in men with high-risk prostate cancer could have been missed given that the vast majority of men on the study had more favorable pathology at RP where a benefit for adjuvant RT would not be expected. Second, while not significant, the point estimate of the overall hazard ratio for PFS comparing adjuvant with salvage RT was >1.0 in the largest trial (RADICALS-RT)1 and in high-risk subsets including men with SVI and pGleason score 8 to 10 in the next largest study (RAVES),2 suggesting that early salvage RT may be superior to adjuvant RT with respect to PFS in these high-risk men, which is counterintuitive.

This unusual result may be explained by immortal time bias in that men on the salvage RT arm following the trigger PSA level of 0.1 ng/mL or 0.2 ng/mL needed time to have their salvage RT planned and delivered during which time PSA was not being assessed. Therefore, in men with adverse pathology such as SVI and pGleason score 9 disease who have short PSA doubling times or rapid PSA rises, the PSA level could have surpassed the threshold set for progression being 0.4 ng/mL while they were having their RT planned or delivered but not assessed, given that assessment for PSA failure could not be performed until the salvage RT was complete. This would lead to bias (ie, immortal time bias) by scoring PSA failure on the salvage RT arm at a later time than the true failure time observed on the adjuvant arm, which could make salvage RT “appear” superior to adjuvant RT.

As a result, the question of whether men with adverse pathology at RP (ie, pT3 and pGleason score 8–10) benefit from adjuvant compared with early salvage RT remains unanswered. Therefore, it would be advised to still offer adjuvant RT to men with adverse features at RP until more definitive evidence of absence of benefit in these men with high-risk pathology at RP is provided."

[Emphasis mine. References follow]

Post Edited (DjinTonic) : 12/31/2020 12:35:01 PM (GMT-7)

DjinTonic said...
The consensus in the US appears to be moving to that of the Europeans: adjuvant therapy after RP may have no survival advantage over early salvage and leads to overtreatment and more severe toxicities. The results of the first studies specifically designed to answer this question are coming in. One of the main points is that improvement in BCR rates with adjuvant do not translate to overall survival or metastasis-free survival benefits. There is some question whether these findings hold for the very high risk group as well (high Gleason score with adverse RP findings). In the discussion sections of these and previous studies, mention is very often made that adjuvant therapy post RP has been underutilized (compared to guideline recommendations) in favor of waiting to see whether further treatment (salvage) is indeed needed. I'm sure we'll see more discussion and papers on this topic in the journals, and perhaps a revision of US treatment guidelines.

Salvage radiotherapy: a new standard of care (2020)

"Adjuvant radiotherapy following radical prostatectomy (RP) has been shown to reduce the risk of disease recurrence in men with high-risk prostate cancer. Nonetheless, this strategy represents overtreatment for some, who would not otherwise have disease recurrence after RP.

Paul Sargos, a lead investigator on the GETUG–AFU 17 study explains: 'Three randomized trials from the 1990s compared the efficacy of adjuvant radiotherapy, to that of observation after RP. These studies, which included patients with pathological high-risk features, indicated better long-term biochemical and/or clinical tumour control, albeit with higher rates of genitourinary, sexual and gastrointestinal toxicities,' adding that: 'Interestingly, despite the positivity of these data, and, despite only retrospective evidence favouring an observation policy, observation followed by salvage radiotherapy at biochemical failure has been widely adopted in daily practice, predominantly by urologists and by some radiation oncologists.'

Now, data from three randomized controlled trials indicate no evidence of an improvement in 5-year event-free survival (EFS) with the adjuvant approach over early salvage radiotherapy.

Investigators in Australia and New Zealand (TROG 08.03/ANZUP RAVES), France (GETUG–AFU 17) and Canada, Denmark, Ireland, and the UK (RADICALS-RT) randomly assigned men with Gleason grade ≥6 prostate cancer with at least one risk factor for disease progression undergoing RP (1:1) to receive either adjuvant radiotherapy or salvage radiotherapy upon detection of a rising serum PSA level (either ≥0.2 ng/ml or >0.1 ng/ml and rising on three consecutive occasions). Each trial had a different primary end point: biochemical progression-free survival (bPFS), EFS and freedom from distant metastases, respectively.

In TROG 08.03/ANZUP RAVES, involving 333 patients, both groups had similar 5-year rates of bPFS (86% in the adjuvant radiotherapy group versus 87% in the early salvage group (stratified HR 1.12; Pnon-inferiority = 0.15)). This observation was accompanied by a significant increase in grade ≥2 genitourinary toxicities in those receiving adjuvant radiotherapy (70% versus 54%, OR 0.34; P = 0.0022).

Similarly, GETUG–AFU 17, involving 424 patients, revealed no significant difference in 5-year EFS (92% in the adjuvant radiotherapy group versus 90% in the early salvage group, HR 0.81, log-rank P = 0.42) also with fewer acute grade ≥2 toxicities (59% versus 22%) and late grade ≥2 adverse events (27% versus 7%; P < 0.0001). Unlike in TROG 08.03/ANZUP RAVES, patients in this trial also received a short course of hormone therapy.

These data were further confirmed in RADICALS-RT, involving 1,396 patients, which revealed similar rates of 5-year bPFS (85% in the adjuvant group versus 88% in the salvage group, HR 1.10; P = 0.56). Significant reductions in all radiation-related toxicities (diarrhoea, proctitis, cystitis, haematuria and urethral stricture, all P ≤ 0.02) were observed in the salvage group, although patient-reported outcome measures revealed only short-term (<1 year of randomization) reductions in self-reported urinary or bowel function.

These data provide robust evidence that men undergoing RP can safely be spared adjuvant radiotherapy and the associated risk of adverse events. These conclusions are elegantly summarized in ARTISTIC, a prospectively planned, collaborative meta-analysis, which confirms a 1% difference in 5-year EFS between groups (89% with adjuvant, versus 88% with early salvage radiotherapy).

Sargos summarizes: 'These three studies, added to the ARTISTIC meta-analysis results, are an important step forward and support the use of early salvage as opposed to adjuvant radiotherapy after RP for many patients. This is a practice changing conclusion!'

When asked about future directions, Chris Parker, a lead investigator on RADICALS-RT highlights: 'Although the trial started 13 years ago, the results in terms of freedom from metastases and overall survival remain immature, with insufficient events currently accrued for analysis. We plan to continue follow-up monitoring in order to analyse these end points in due course.'

This article is modified from the original in Nat. Rev. Clin. Oncol. (https://doi.org/10.1038/s41571-020-00443-3)."

[Emphasis mine]
__________________________________________

Early salvage versus adjuvant therapy for treatment of prostate cancer following prostatectomy (2020)
__________________________________________

Early Salvage Radiotherapy Bests Adjuvant Treatment for Prostate Cancer (2020)
_______________________

One of the three studies discussed in the article above:

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 (2020, The Lancet Oncology)

I agree with Prat. Even with the Dr. D'Amico reservations, it appears that guys like myself may have been better off waiting all along (or, at least not hurt). I"ve been waiting for this study Djin. It appears to me that studies are beginning to lean toward ART vs early SRT having little to no effect on life span. I think this will be the ultimate findings. (But, that's me) Thanks for posting it.

Before I read D'Amico’s comments, I came to the same conclusion. The listed studies are populated by lower risk men.

I am doing both...did adjuvant after surgery and am doing salvage now. So far so good.