New Guidelines for Salvage Radiation Dimensions

It has always been troubling that only about half of all salvage radiation treatments after prostatectomy failure are successful. Usually, only the prostate bed is treated. But sometimes recurrent patients (or those with persistently elevated PSA) receive salvage radiation to the pelvic lymph nodes as well, or subsequently. Radiation oncologists usually follow RTOG (now called NRG Oncology) guidelines on what constitutes the dimensions of the prostate bed and the pelvic lymph nodes.

Prostate Bed Coverage

Often, the cancer has only penetrated into the bed or fossa. This is especially suspected if there are significant positive surgical margins. The 2010 RTOG consensus guidelines were updated in 2020 by the Francophone Group of Urological Radiotherapy (GFRU) based on standard imaging (MRI and CT). (Update 5/12/23) Dal Pra et al. Harmon et al. reported on 45 patients within the LOCATE trial who received a positive Axumin PET/CT upon recurrence or persistent PSA after prostatectomy.

• 30 patients had cancer in the prostate fossa
• The 2010 RTOG guidelines completely or partially missed cancer in 33% of the patients
• The 2020 GFRU guidelines completely or partially missed cancer in 10% of the patients

The new GFRU guidelines are clearly superior in terms of oncological outcomes, but toxicity must be considered as well.

Pelvic Lymph Node Coverage

In 2020, NRG Oncology revised its previous 2009 RTOG pelvic lymph node coverage consensus guidelines based on MRI and PET scans. They recommended coverage as high as the aortic bifurcation or common iliac lymph nodes (whichever is higher, depending on patient anatomy), which is about the level of the L4-L5 vertebrae. The expanded coverage area extends down to the pre-sacral nodes at the bottom of vertebra S3. Harmon et al. also validated the expanded NRG Oncology guidelines based on Axumin PET/CT scans. They found:

• There were 43 sites of cancer in the pelvic lymph nodes
• The 2009 RTOG guidelines completely or partially missed 32% of the nodal cancers
• The 2020 NRG Oncology guidelines completely or partially missed none of the nodal cancers

The SPPORT trial found that treating pelvic lymph nodes prophylactically improved outcomes with no increase in late-term genitourinary or gastrointestinal toxicity, and only minor increases in the short-term. This study did not examine the toxicity of the expanded coverage.  Careful contouring of the pelvic lymph node area to exclude bowel, bone, bladder, and muscle seems to prevent excess toxicity at the doses usually used (45-50.4 Gy). In one recent study of high-risk patients, a pelvic lymph node dose as high as 56 Gy was used without extra toxicity. Also there have been no second pelvic malignancies due to the expanded coverage in this study.

 Boosted site doses can also be utilized where PET/CT  or MRI has identified specific tumors. However, treatment should not be delayed until such tumors become apparent on imaging.

Whole pelvic salvage radiation + short-term ADT improves oncological results

We didn't expect to see this for another two years, but they hit their recruitment goal early and were able to provide 5-year results. Alan Pollack, the lead investigator, presented the preliminary findings of NRG Oncology/RTOG 0534 (or SPPORT) trial at the ASTRO meeting, and in Medpage Today. It proved that salvage whole pelvic radiation (sWPRT) with short term ADT  (STADT) is superior to either prostate-bed only salvage radiation (PBRT) or prostate-bed only salvage radiation with short term ADT.

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. sWPRT+STADT
2. PBRT + STADT
3. PBRT

• 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 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. 

The oncological results were:

• 5-year freedom from progression (biochemical or clinical) was 89% for sWPRT+STADT, 83% for PBRT+STADT, and 72% for PBRT (all significantly different). They used a nadir+2 definition of biochemical progression because it correlated best with clinical progression.
• 8-year incidence of metastases was 25 for sWPRT+STADT (HR=0.52), 38 for PBRT+STADT (HR=0.64), and 45 for PBRT (sWPRT+STADT was significantly better than the other two)

The reported toxicity results were:

• GI grade 2 or higher: 7% for sWPRT+STADT vs. 2% for PBRT
• Bone marrow grade 2 or higher: 5% for sWPRT+STADT vs. 2% for PBRT
• Bone marrow grade 3: 2.6% for sWPRT+STADT vs. 0.5% for PBRT
• Late term bone marrow grade 2 or higher was 4% for sWPRT+STADT

There were some caveats. The researchers found that the benefit of salvage whole pelvic treatment and ADT was not maintained in men with very low PSA. There are further analyses expected based on patient risk characteristics and genomic biomarkers. We previously saw in a retrospective study that prostatectomy Gleason score had a significant influence. With better PET scans now, we can have more assurance that whole pelvic radiation is necessary. But at very low PSA (<0.2), even our best PET scans may not find the cancer. Also, it may be that long-term ADT may improve results even further, and that dose escalation may improve results. While this changes the standard of care for many men with persistent PSA and recurrences after prostatectomy, the patient and his radiation oncologist still must rely on judgment.