When is whole pelvic radiation needed for salvage post-prostatectomy?

Patients who elect to have post-prostatectomy radiation therapy 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. In the meantime, the best we can do is look at how patients have done in the past.

Ramey et al. conducted a retrospective analysis of 1,861 patients treated at 10 academic institutions between 1987 and 2013. The treatments and patient characteristics were as follows:

  • All had post-prostatectomy PSA levels > 0.01 ng/ml (median was 0.5 ng/ml)
  • All had post-prostatectomy Gleason scores ≥ 7
  • None had detected positive lymph nodes
  • 1,616 were treated with PBRT
    • 1,366 without ADT
    • 250 with ADT
  • 245 were treated with WPRT
    • 176 without ADT
    • 69 with ADT
  • Median salvage radiation dose was 66 Gy
  • More than half of patiensts with Gleason scores of 8 to 10 got ADT, whereas most patients with Gleason scores of 7 did not
  • 60 percent had extraprostatic extension
  • 21 percent had seminal vesicle invasion
  • 60 percent 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:

WPRT + 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 Gleason scores of 8 to 10. There was significant improvement even in men with GS 7; however, they did not have the data to ascertain whether they were Gleason 3 + 4 = 7 or 4 + 3 = 7. 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, clinical 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 + 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 data set of them all, 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 to 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 to 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 co-morbidities, 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, Gleason 3 + 4 = 7) that would not benefit from the additional treatment?

Editorial note: This commentary was written by Allen Edel for The “New” Prostate Cancer InfoLink.

6 Responses

  1. Well only 50% of the patients were cured by salvage radiotherapy + ADT. Other studies showed a better outcome if salvage EBRT was started at very low PSA values. So this is an important issue, more important than how to perform the salvage EBRT.

    As PSA at biochemical recurrence is low, the likelihood of a local recurrence is high. When PSA at biochemical recurrence is above 5 ng/ml, the likelihood of distant metastases increases. So there is a good explanation for the decline in outcome with increasing PSA at start of salvage EBRT. Unfortunately academia has never carried out a trial of the only major issue: should salvage EBRT be made blindly or should treatment be guided by multiparametric MRI and PSMA PET/CT for re-staging at immediately prior to salvage EBRT.

    Taking the broad perspective, recurrent prostate cancer after radical prostatectomy remains one of the few applications of radiotherapy where standard treatment is not currently guided by adequate imaging.

    For the patient with biochemical recurrence today, you might believe the radiation oncologist have supervsuality power and go with standard salvage EBRT and have 50 percent risk of in fact the oncologit just had normal visuality power, or you pay for yourself to get the modern imagings that will help decision making as to where to apply the radiotherapy (or perhaps something else).

    Of course other questions are good and relevant. I believe we need to set priorities. We have hundreds of randomized trials for treatment of breast cancer but only a few randomized trials for prostate cancer. We will never have randomized trials for eight different questions. Currently, patients with biochemical recurrence (and believe me, that’s many patients) have to decide for themselves what to go for in the absence of appropriate randomized trials and evidence-based medicine.

  2. WPRT + ADT is shown in several studies to be superior when used in either adjuvant or BCF salvage settings. The problem is with added side effects that raise the question of when is a patient being over-treated. A rising PSA can be controlled by PBRT, WPRT, ADT for 6 tp 24 months or by any in combination. I know many men like myself that did RP + aWPRT + aADT24. When it worked there were still issues with side effects in all cases. The problem with adjuvant is that you’ll never know if it was needed at all if the PSA never rises after RP. The problem with salvage is well-documented. WPRT + ADT has the best results. But is that something that is reasonable in all cases? The answer is, of course, “No”.

    Nicely written, Allen. I agree with your summaries and questions. I think most patients are going to go with what the radiation oncologist recommends unless they have a medical oncologist as well. At least on the ADT part. Unfortunately, there may be some guesswork on doing WPRT versus PBRT in a lot of cases.

  3. Finn:

    Unfortunately, the goal of treating a recurrence at the lowest possible PSA and the goal of detecting metastases are mutually exclusive. Yes, the salvage RT outcomes would certainly be better if we were able to definitively rule out distant metastases prior to salvage RT. But even our best PSMA PET scans are very poor at detection when PSA is below 0.5 ng/ml or is not rapidly rising, and the detection limit is about 4 mm. Nor are they good at detecting metastasis to the regional pelvic lymph nodes. The best methods for detection of metastasis to the regional lymph nodes seems to be the Combidex MRI, which is only available at Radboud University in Holland, as far as I know. Even that imaging method only detects down to a limit of 2 mm. So, until technology improves, we are forced to make the salvage RT decision with incomplete information.

  4. Are we to understand that the same RT dose was used for the entire field? My impression is that it is common to use a higher dose for the prostate bed, and a lower dose (e.g. 45 Gy) for the remaining pelvis area. I am surprised to find no such distinction made here.

  5. Really great post and summary! Thank you.

  6. TomT:

    I’m sure the dose to the whole pelvic field was lower. They did not provide that detail, if they had it. This was a multi-institutional study among patients treated over 26 years using a variety of technologies. It probably varied widely. Retrospective, multi-institutional studies often have incomplete details.

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