When is whole pelvic radiation needed for salvage?

Patients who elect to have post-prostatectomy radiation for recurrent prostate cancer face a couple of important decisions:

(1) Should the radiation be limited to the prostate bed (PBRT)? OR
(2) Should one treat all the pelvic lymph nodes at the same time (whole pelvic radiation - WPRT)? And if so, is the oncological outcome likely to be better if one has androgen deprivation therapy (ADT) along with it?

There is an ongoing prospective randomized clinical trial (RTOG 0534) to help answer these questions. But results are not expected until the end of 2020. Meanwhile, the best we can do is look at how patients have done in the past. Ramey et al. conducted a retrospective analysis of 1861 patients treated at 10 academic institutions between 1987 and 2013. The treatments and patient characteristics were as follows:

• All had post-prostatectomy PSA> 0.01 ng/ml (Median was 0.5 ng/ml)
• All had post-prostatectomy Gleason scores ≥ 7
• None had detected positive lymph nodes
• 1366 had PBRT without ADT,  250 with ADT
• 176 had WPRT without ADT, 69 with ADT
• Median salvage radiation dose was 66 Gy
• More than half of GS 8-10 patients got ADT, whereas most GS 7 patients did not
• 60% had extraprostatic extension
• 21% had seminal vesicle invasion
• 60% had positive surgical margins

After a median follow-up of 51 months, the 5-year freedom from biochemical failure outcomes are shown in the following table.

             5-Year Freedom from Biochemical Failure

	PBRT	WPRT	TOTAL
With ADT	51%	66%	55%
Without ADT	48%	60%	50%
TOTAL	49%	62%	51%
Among GS 7:
With ADT	56%	70%	59%
Without ADT	52%	66%	54%
TOTAL	53%	67%	56%
Among GS 8-10:
With ADT	45%	64%	49%
Without ADT	34%	44%	35%
TOTAL	37%	53%	44%

WPRT with ADT had the best outcomes in total and in each Gleason score category. Two-thirds of salvage patients had 5-year cancer control with the combination, whereas only about half had oncological control without them. The differences were especially marked among those with GS 8-10. There was significant improvement even in men with GS 7; however, they did not have the data to ascertain whether they were GS 3+4 or GS 4+3. Adjuvant ADT improved outcomes whether it was used in conjunction with WPRT or PBRT. On multivariate analysis, both WPRT and ADT independently increased freedom from biochemical failure. Higher radiation dose, lower PSA, lower Gleason score, Stage T2, and positive surgical margins decreased the risk of failure.

Neither WPRT nor ADT made any difference in the rate of metastases, which were low at 5 years post-prostatectomy.

Toxicity and quality of life, which would be the only reasons not to give WPRT and ADT to all salvage radiation patients, were not evaluated in this study. Also lacking were data on duration and type of adjuvant ADT

This study is congruent with a couple of retrospective studies (see this link and this one), but incongruent with a couple of other retrospective studies (see this link and this one). The present study is the largest and most recent dataset of them, and corrects for the effects of other variables in a way that the two opposing studies did not.

We saw previously that adjuvant ADT has been proven in a randomized clinical trial to improve oncological outcomes of salvage radiation after prostatectomy (see this link).

While we await the more definitive data from RTOG 0534, this builds the case that both WPRT and ADT should be included in the salvage radiation treatment of men with prostatectomy-diagnosed Gleason scores of 8-10, and at least some of those with Gleason score of 7. There are several open questions:

• Is there a benefit for GS 3+4, or only for GS 4+3 or higher?
• Is there a benefit when higher salvage radiation doses (70-72 Gy) are used, or with hypofractionated protocols that raise the biologically effective dose?
• What is the optimal duration of adjuvant ADT?
• Would any of the newer hormonal therapies (e.g., Zytiga or Xtandi) or other systemic therapies improve outcomes?
• What are the trade-offs with toxicity and quality of life?
• What is the optimal treatment field for WPRT, and should it vary with individual anatomy and comorbidities, given its potential toxicity?
• Can we use the newer PET scans or USPIO MRI to help decide if WPRT is necessary?
• Can we identify any subsets (e.g., low PSA, stage T2, GS 3+4) that would not benefit from the additional treatment?