Whole pelvic salvage radiation may be better than precisely targeted lymph node salvage radiation

Last week, I looked at a retrospective study of metastasis-directed therapy (MDT) at the Mayo Clinic among oligorecurrent patients (see this link). Oligorecurrent means that they had already received primary therapy (mostly prostatectomy) and some had received salvage radiation as well, but there were only 1-5 metastases detected. They found there was no benefit if there were any bone metastases, but there may have been a benefit if the metastases were in the lymph nodes only. Lymph nodes were treated with either surgery (called pelvic lymph node dissection - PLND) or radiation to a small area around the detected (by C-11 Choline PET/CT) cancerous lymph nodes. I ended the analysis with this statement:

Another open question is whether whole pelvic salvage radiation might have been more effective than the limited margins they used at Mayo. With the more accurate PSMA PET scans, ROs are able to treat the entire PLN area with radiation boosts given to the detected ones. The RTOG-consensus treatment area has recently been expanded (see this link). It's important that patients understand the detection limits of even the best PSMA PET scan: metastases smaller than 4 mm, and those that put out only small amounts of PSA remain invisible.

De Bleser et al. reported the results of a retrospective study to examine precisely this question among 506 oligorecurrent patients conducted at 15 different institutions throughout Europe. Patients were selected and treated as follows:

• Detection of cancerous lymph nodes (LNs) was primarily (85%) with C-11 Choline PET/CT (a few with PSMA, FDG, or conventional imaging)
• 309 patients were treated with SBRT (at least 5 Gy per fraction, up to 10 fractions), A margin of 2-6 mm was treated also.
• 197 patients were treated with "Elective Nodal Radiation Therapy" (ENRT) of at least 45 Gy in 25 fractions to the entire pelvic lymph node area. Boost doses to detected lymph nodes were allowed. A margin of 5-7 mm was treated. 60 patients also had their prostate bed simultaneously treated.
• About half had already had salvage radiation to the prostate bed.
• About half had already had PLND at the time of prostatectomy. The SBRT group had a median of 1 positive LN at pathology, the ENRT group had 2.
• Patients with adjuvant ADT for more than a year were excluded. 77% of the SBRT had no ADT; 40% of the ENRT group had no ADT. Those who had ADT, had it for 6 months (median).
• 72% had pelvic LNs only; 28% had extrapelvic LNs (retroperitoneal) at imaging.
• 72% of the SBRT group had only one LN at imaging; 50% of the ENRT group had 2-5 LNs at imaging.
• Patients with bone or visceral metastases at relapse were excluded, as were patients already using ADT, and those with detected metastases before primary therapy.

After a median follow-up of 3 years:

•  3-year Metastasis-Free Survival (MFS) was 68%. (only distant metastases (M1) were counted)
• Among patients who were detected with only one positive LN at baseline, MFS was twice as long with ENRT compared to SBRT
• There was no difference among patients with more than one positive node at baseline.
• 57% of patients were detected with metastases (N1 and M1) in the SBRT group- 55% in pelvic LNs, 19% in extrapelvic LNs only, 20% in bone, and 6% in visceral organs.
• 38% of patients were detected with metastases (N1 and M1) in the ENRT group - 11% in pelvic LNs, 43% in extrapelvic LNs only, 35% in bone, and 8% in visceral organs.
• ENRT provided longer-lasting N1 control, but did not delay M1 control any more than SBRT.
• Castration-free survival did not differ between the two types of treatments.
• There was no acute toxicity reported for 99% of men receiving SBRT  and 94% of men receiving ENRT. Grade 3 (serious) toxicity was reported for 5 men receiving ENRT and none receiving SBRT.
• Similarly, there was no serious late-term toxicity reported for SBRT, and 2.5% for ENRT.

We conclude that ENRT provided better local (pelvic lymph node) control than SBRT, but neither seemed to delay distant metastases better. MFS was only improved by ENRT if there was just one LN metastasis detected at baseline. Reported toxicity, acute and late-term was low, but was lower with SBRT.

Of course, this retrospective study leaves many questions unanswered:

• Does either treatment improve MFS over ADT alone?
• What would have happened if long-term ADT were allowed rather than just 6 months? (see this link) 
• What if all patients received the same radiation dose, the same treatment margins, and a standard treatment area (up through the aortic bifurcation) were used?
• What would have happened if LN metastases were detected with PSMA PET/CTs rather than C-11 Choline PET/CT?
• What were the patient-reported quality of life outcomes?

These questions will be addressed in two randomized clinical trials:

• OLIGOPELVIS2 (FRANCE) is randomizing oligorecurrent patients to intermittent ADT with or without whole-pelvic IG/IMRT with a boost to PSMA-identified LNs. (Completion mid-2026)
• PEACE V (STORM) in Europe and Australia is randomizing oligorecurrent patients to MDT by either SBRT/salvage PLND or ENRT. C-11 Choline, PSMA or Axumin PET scans will be used for detection. (Completion end of 2023)