Lower salvage radiation dose - are outcomes the same?

A large randomized clinical trial, SAKK 09/10, found that a salvage radiation dose of 64 Gy over 32 treatments had equivalent biochemical outcomes compared to 70 Gy over 35 treatments.

They treated 350 patients from 2011 to 2014 at 28 hospitals in Germany, Switzerland, and Belgium. They were treated with either 3D-CRT (44%) or more modern radiation techniques. None had positive lymph nodes. Key patient characteristics were as follows:

• Biochemically recurrent after prostatectomy (median PSA= 0.3 ng/ml)
• Positive margins in 45%
• Gleason score ≥ 8 in 18%
• No detectable tumors

After 6.2 years of follow-up, outcomes were as follows:

• Freedom from biochemical progression (FFBP) was enjoyed by 65% of those who got 64 Gy vs 73% of the 70 Gy group. This difference is not statistically different (p=0.11).
• Local recurrences (only) occurred in 9% of the 64 Gy group vs 2% of the 70 Gy group. This difference is statistically significant (p= 0.005)
• Regional recurrences (only) occurred in 11% of the 64 Gy group vs 17% of the 70 Gy group. This difference is not statistically significant (p= 0.11)
• Distant recurrences (any) occurred in 15% of the 64 Gy group vs 15% of the 70 Gy group.
• In an earlier report, acute urinary toxicity of Grade 2 or greater occurred in 14% of the 64 Gy group vs 18% of the 70 Gy group (not different)
• In an earlier report, acute rectal toxicity of Grade 2 or greater occurred in 17% of the 64 Gy group vs 18% of the 70 Gy group (not different)
• Late urinary toxicity of Grade 2 or greater occurred in 29% of the 64 Gy group vs 30% of the 70 Gy group (not different)
• Late rectal toxicity of Grade 2 or greater occurred in 12% of the 64 Gy group vs 22% of the 70 Gy group (different)
• Patient-reported outcomes were not different between the two dose regimens.

Oncological Outcomes

The stated purpose of SAKK 09/10 was to detect a difference in 6-year FFBP, and they detected no difference. But is that enough to change practice? The ICECAP working group cautions  that 5-year metastasis-free survival, but not biochemical recurrence-free survival, is a good surrogate endpoint when overall survival would take too long to obtain in trials of primary therapy for localized prostate cancer. For trials of salvage therapy of recurrent prostate cancer after prostatectomy, some early analysis suggests that the 5-year occurence of distant metastases may be a good surrogate endpoint. 6-year FFBP used in this trial is probably not a good surrogate endpoint.

Focusing our attention on the actual cancer progression instead of just PSA progression, we see that the higher dose did significantly better at preventing local progression of the cancer. If the trial were to run 15 years, we might see a very meaningful difference between the curative powers of the two dose regimens. Furthermore, as shown in the SPPORT trial, salvage treatment of pelvic lymph nodes, even when none is detectable, may slow progression or possibly cure some patients with regional micrometastatic progression. 

There may be other ways to improve outcomes:

• Using the expanded prostate bed delineation guidelines may improve local control.
• As PSMA PET/CT becomes more widely available, it will be possible to detect more loco-regional cancer for boost doses, and eliminate salvage treatment from patients who already have small distant metastases (see this link). 
• The use of genomic tests, like Decipher Genomic Classifier (GC), may aid in selecting patients in whom higher doses are needed. In a subset analysis, among Decipher "high GC-risk" patients, FFBF was 51% for 70 Gy vs 39% for 64 Gy patients; among Decipher "low GC-risk" patients, FFBF was 75% for 70 Gy vs 69% for 64 Gy patients (update) FFBF was 45% for GC-high patients vs 71% for GC-low patients. 
• There is a clinical trial at UCLA that will determine whether raising the biologically effective dose (BED) using SBRT (34 Gy/ 5 fractions) gives good outcomes compared to historical controls. The BED is equivalent to 85 Gy if given in fractions of 1.8 Gy.
• There is a clinical trial in France that will determine whether adjuvant hormone therapy intensification with Erleada improves results.
• Keeping in mind that very few patients in this trial had Gleason scores of 8-10, and none had detectable gross tumors at or near the prostate, those patients may still be good candidates for dose intensification (as well as adjuvant ADT).

Toxicity Outcomes

If there is no cost to the patient in terms of increased toxicity, there is no reason not to increase the dose. The patients were unable to detect a difference in urinary, rectal, or sexual outcomes. There was a difference in physician-reported late-term rectal toxicity that deserves further attention.

Compared to acute urinary toxicity, late-term urinary toxicity is about twice as bad in both dosing regimens, although the ratings are not different between regimens. Compared to acute rectal toxicity, late-term rectal toxicity was 29% lower for the 64 Gy dose group, but marginally higher for the 70 Gy dose group. The authors believe that rectal dose constraints could be tightened with IMRT.

For comparison, MSK reported that using 70 Gy as a salvage dose, late-term urinary toxicity (Grade≥2) was 17% (vs 30% in this trial) and late-term rectal toxicity (Grade≥2) was 5% (vs 22% in this trial). They also reported that IMRT improved rectal toxicity over 3D-CRT, while no difference was observed in this trial.

The reason for these atypical results is mysterious, although physician-reported toxicities are notoriously unreliable.

So, lacking more reliable endpoints and considering that patients did not notice any difference in their quality of life based on dose intensification, the decision on what dose to use is best based on a discussion with the radiation oncologist.

(update 04/22/2022) Beck et al. report that adherence to treatment guidelines was poor in the SAKK 09/10 trial. This may explain the mysterious toxicity results as well as being responsible for worse freedom from biochemical progression.