Evidence for Dose Escalation in Adjuvant/Salvage Radiation

It is well known that prostate cancer is relatively radio-resistant compared to other kinds of cancer. While dose escalation (most recently by increasing the biologically effective dose using hypofractionated dose (more that 2.0 Gy per session) delivery or brachytherapy boost therapy) has become the mainstay in primary radiation therapy, doses delivered for adjuvant or salvage radiation has stayed about 10 Gy lower. Recently, Dr. King's analysis of the dose responsiveness of salvage radiation questioned this supposition (see this link). While his mathematical arguments provide us with intriguing plausibility, only clinical evidence from a randomized clinical trial can change practice.

We now have Level 1 evidence that expanding the adjuvant/salvage treatment field to include the pelvic lymph nodes improves the oncological outcomes in men with higher PSA at the time of salvage radiation.

Link et al. conducted a small, retrospective study among 120 locally advanced (stage T3/4) post-prostatectomy patients at the University of Heidelberg between 2009 and 2017. All were lymph node negative.

• 43 received whole pelvic radiation therapy (WPRT)- 62% received 79.3 Gy to the prostate
• 77 received radiation to the prostate bed only (PBO)- 70% received 79.3 Gy to the prostate
• Biologically equivalent dose (2 Gy) to the prostate was 79.3 Gy ("high dose") if they had positive margins or PET/CT/MRI imaging-detectable prostate bed tumors (62% of patients), 71.4 Gy ("low dose") if they had negative margins (38% of patients).

Median freedom from biochemical failure was:

• longer among those who got the higher dose: 76 months vs 21 months
• longer among those who received WPRT vs PBO: 68 months vs 32 months

There is a lot of overlap in treatments, so it is impossible to tease out the effect that each had on the oncological outcomes. Almost all of those who received the escalated dose also had positive margins - a known factor for predicting success of adjuvant/salvage radiation. Also, almost all men who had adjuvant radiation had positive margins and dose escalation - adjuvant radiation has proven to be more successful than "wait-and-see" in 3 major randomized clinical trials.

Toxicity increased with both dose and size of the treatment field. Grade ≥ 2 toxicity was reported by:

• 3.4% among those who received low dose and PBO
• 12.5% among those who received high dose and PBO
• 15.4% among those who received low dose and WPRT
• 36.7% among those who received high dose and WPRT
• No reports of Grade 3 gastrointestinal toxicity
• 13% Grade 3 urinary toxicity among high dose patients, none among low-dose patients

This is a far cry from the randomized clinical trial we need for practice-changing dose escalation for adjuvant/salvage radiation. However, we can't rule out that there is no oncological benefit to dose escalation. It remains unknown what proportion of these high-risk patients would have done just as well with lower doses and smaller treatment fields. The increase in toxicity with dose and treatment field means that patients ought not jump into this without understanding the risks and discussing them with their radiation oncologists.