SPPORT trial: whole pelvic salvage radiation + short-term ADT after failed surgery can be a curative option

 In 2018, we saw the early results of the SPPORT randomized clinical trial (see this link). Now Pollack et al. has published the full results. To review:

They randomly assigned 1,792 men with a recurrence after prostatectomy in 2008-2015 at 460 locations in the US, Canada, and Israel to one of 3 therapies:

1. PBRT (prostate-bed radiation only)
2. PBRT + STADT (prostate-bed radiation + short-term ADT)
3. sWPRT + STADT (salvage whole pelvic radiation + short-term ADT)

• ADT consisted of 4-6 months of a combination of an anti-androgen and an LHRH agonist starting 2 months before salvage radiation.
• Radiation dose to the prostate bed was 64.8-70.2 Gy at 1.8 Gy per fraction.
• Radiation dose to the pelvic lymph nodes was 45 Gy at 1.8 Gy per fraction.
• The treated pelvic lymph node area was per RTOG guidelines and did not include the recently recommended expansion. (There is also an expansion of the prostate bed, as discussed here)
• The sample size was powered to detect progression-free survival, but not metastases, prostate cancer mortality, or overall survival. 8 years of follow-up is insufficient for those other endpoints.

The oncological results were:

• 8-year freedom from progression (biochemical or clinical) was 77% for sWPRT+STADT, 72% for PBRT+STADT, and 61% for PBRT (all significantly different, regardless of initial ADT, Gleason score, or stage). They used a nadir+2 definition of biochemical progression because it correlated best with clinical progression.
• At lower PSA (≤ 0.35), Group 3 did no better than Group 2, so widening the treatment area had no effect. Both groups did better than Group1, so ADT had a significant effect.
• At higher PSA (> 0.35), Group 3 was better than Group 2, but the difference was not statistically significant. Both groups did better than Group 1, indicating ADT effectiveness.
• 4 vs 6 months of ADT did not matter. It reduced the occurrence of local and regional metastases.
• Widening the treatment area reduced the long-term rate of local and regional metastases.
• 8-year incidence of metastases was 69 (12%) for PBRT (HR=0.71), 56 (10%) for PBRT+STADT (HR=0.74), and 41 (7%) for sWPRT+STADT (HR=0.52). sWPRT+STADT was significantly better than the other two.

The physician-reported acute toxicity results show some small early adverse effects of ADT and the wider treatment area:

• GI grade 2 or higher: 7% for sWPRT+STADT vs. 4% for PBRT+STADT vs. 2% for PBRT
• GU grade 2 or higher: 12% for sWPRT+STADT vs. 12% for PBRT+STADT vs. 9% for PBRT
• Bone marrow grade 2 or higher: 5% for sWPRT+STADT vs. 2% for PBRT+STADT vs. 2% for PBRT
• Bone marrow grade 3: 2.6% for sWPRT+STADT vs. <1% for PBRT+STADT vs. 1% for PBRT

The physician-reported late toxicity results show that late toxicity was not influenced by ADT or whole pelvic RT:

• GI grade 2 or higher: 9% for sWPRT+STADT vs. 10% for PBRT+STADT vs. 10% for PBRT
• GU grade 2 or higher: 40% for sWPRT+STADT vs. 35% for PBRT+STADT vs. 37% for PBRT
• Bone marrow grade 2 or higher: 4% for sWPRT+STADT vs. 2% for PBRT+STADT vs. 4% for PBRT

This RCT proved that whole pelvic salvage radiation with 4-6 months of ADT is the preferred salvage treatment.

In contrast to a previous trial (RTOG 9601) that told us that ADT can be safely avoided if PSA<0.7, this trial suggests at least 4 months of ADT and whole pelvic treatment. The reason for the difference in recommendations is due to the choice of endpoint. SPPORT is telling us that if we are willing to put up with 4 months of ADT and some extra short-term toxicity from the wider field of radiation, a cure is likely. RTOG 9601 tells us that if your PSA<0.7, you aren't likely to die if you don't get the extra short-term hormone therapy, but you may have to have lifelong ADT eventually. It will always be a managed disease. Patients should acknowledge these trade-offs and discuss with their doctors.

Results may possibly be improved further with:

• Better patient selection using PET scans (PSMA, Axumin, or NaF)
• Extra radiation to the prostate bed
• Boost doses to cancer detected with a PSMA PET scan (if PSA> 0.5 - but do not wait!)
• Selection of patients who would benefit from treatment intensification using a Decipher test
• Hormone therapy intensification in select patients (as in this clinical trial)