Wednesday, January 3, 2018

When can ADT be safely avoided with salvage radiation therapy?

Two randomized clinical trials (GETUG-AFU-16 and RTOG 9601) proved that adding at least some ADT to salvage radiation (SRT) improved outcomes. "Some ADT" was 6 months of goserelin in the GETUG-AFU-16 trial, and two years of bicalutamide in the RTOG 9601 trial. Retrospective studies suggest improved outcomes as well (see this link and this one). On the whole, adjuvant ADT improves SRT outcomes. But is there a subgroup of patients, especially those treated early enough, in whom adjuvant ADT can be safely avoided?

This was the subject of a retrospective analysis by Gandaglia et al. They examined the records of 525 post-prostatectomy patients treated with SRT at six international institutions between 1996 and 2009. Inclusion criteria were:
  • Undetectable PSA (<0.1 ng/ml) after prostatectomy
  • Biochemical recurrence - two consecutive PSA rises above 0.1 ng/ml
  • PSA mostly ranged from 0.2 to 0.9 ng/ml (median 0.4) at the time of SRT
  • No detected lymph node metastases
There were 178 patients who received adjuvant ADT (median 15 months) and 347 who had SRT without ADT. Compared to those who received no ADT, those that did were:
  • Similar in age, initial (pre-op) PSA, and Gleason score
  • More likely to be stage T3b/4
  • Less likely to have positive margins
  • Received higher SRT dose (70 Gy vs 66 Gy)
There were 8 years median follow-up for those who had no ADT, and 12 years median follow-up for those who had adjuvant ADT. The authors compared the actual 10-yr metastasis rate to the predicted 10-yr metastasis rate based on PSA at SRT, Gleason score, stage, positive margins, SRT dose, and whether lymph nodes were treated. They found that:
  • Only those with a 10-year probability of distant metastases greater than 1 in 3 benefited from the addition of ADT
  • The benefit grew exponentially with increasing risk
  • Adjuvant ADT only benefited those with higher PSA (≥0.4 ng/ml), Gleason score 8-10, stage T3b/4. 
  • Higher SRT dose and whole pelvic SRT improved outcomes independently of whether adjuvant ADT was used.
It should be noted that high-dose SRT and whole pelvic treatment were used in a minority of cases, and there is a significant risk of selection bias in this study.

The authors conclude that a higher radiation dose alone may be sufficient to treat many patients with a recurrence detected early enough, but for those with aggressive tumor characteristics, adjuvant ADT will improve outcomes measurably. While this was not proved with a randomized trial, it does suggest that adjuvant ADT will not be necessary in all cases of SRT. Patients who are undecided may wish to have a Decipher genomic classifier done on their prostate tissue to determine their 10-year risk of metastases.

1 comment:

  1. The study by Gandaglia et al is another study where the questions asked beg the real underlying issue: "Can we identify local vs regional vs distant prostate cancer accurately?" Given the results of Gandaglia et al study, it is not surprising that all the instances where ADT shows some value relate to situations where the PC recurrence is NOT in the RT field. Higher PSA, higher Gleason score, higher probability of metastases all would favor the ADT + RT arm. Whole pelvic RT and higher salvage radiation therapy (SRT) doses would negate most of the benefits in using ADT.
    Scholz et al showed that the response of ADT insofar as leading to an undetectable PSA (≤ 0.05) related significantly to the metastatic-free survival of patients. The hazard ratios of those with PSA nadirs > 0.05 were 17.8x greater for time to progression and 14.2x greater for mortality. At ten years follow-up 90% of patients with ADT induced nadirs ≤ 0.05 were alive versus 10% for those with PSA nadirs > 0.05.

    I would surmise that any study involving SRT should involve at least 6 months of ADT and optimally use multi-agent ADT rather than monotherapy with either anti-androgen or LHRH-agonist agents. Those patients not having a nadir ≤ 0.05 would or should be considered high-risk patients that require systemic therapy and not have their focus on RT. If they are to receive SRT, then they should do so after an adequate trial of ADT and the use of sensitive imaging modalities such as 68Ga-PSMA-11 PET/CT and/or Combidex-Enhanced MRI (CEM). Both of these advanced imaging techniques are not FDA approved despite compelling literature and first-hand clinical experience.