Do you account for prostate shrinkage during XRT if ADT is started concurrently?

This is a common question since we reported the study results, and a valid one for sure. Stay tuned for an even larger meta-analysis of many more RCTs that further dives into the oncologic superiority of adjuvant compared to neoadjuvant ADT. However, to your question, what about toxicity?

Here are my thoughts:

1. We showed in the JCO paper in question that there was no difference in late grade 3-5 toxicity between neoadjuvant vs adjuvant ADT (Ottawa trial was conc/adjuvant and RTOG 9413 was pure adjuvant). This provides likely the strongest evidence that there are not clinically measurable differences despite the hypothesized changes in prostate size.
2. The Ottawa trial has since reported from Dr. @Dr. First Last that patient-reported outcomes were similar between neo/concurrent and conc/adjuvant (Roy et al., PMID 33524545). This provides strong evidence that any theoretical differences in prostate size are not of clinical relevance.
3. RTOG 9910 compared prolonged neoadjuvant ADT vs just 2 months of neoadjuvant ADT, both receiving concurrent ADT. It is well established that there continues to be cytoreduction beyond 2 months, and the ~6 months of neoadjuvant ADT would result in greater cytoreduction. Again, there was no measurable difference in acute or late GI/GU toxicity between study arms (there were, of course, greater hormone side effects with the prolonged ADT).
4. We should not forget that for people who use neoadjuvant ADT with leuprolide alone, it takes ~3-4 weeks to reach castrate testosterone, and thus only ~1 month of true ADT has been delivered. Cytoreduction, as mentioned continues out to ~12 months so even with neoadjuvant ADT for 1 or 2 months there is expected continued prostate shrinkage. For example, a study from Lilleby et al., PMID 11054523 in 2000 showed that compared with the pre-treatment scan the prostate gland with ADT reduced in size by 18%, 35%, and 46% at 1, 6, and 12 months, respectively, and 2/3s of patients, there was continued prostate shrinkage beyond the 1st 3 months. So really there is likely a greater change in prostate size by using 1-2 months of neoadjuvant ADT during RT, then starting ADT at the time of prostate RT, especially given most RT now is 4 weeks or less in duration. Other studies by Pinault et al., PMID 1546420, model substantial changes in prostate size during 1 month, 2 months, and 3 months of ADT, so again using neoadjuvant ADT for ~2 months still is inducing continued prostate shrinkage during RT.
5. Standard and preferred treatment for most of localized prostate cancer is ~20 treatments, which is 4 weeks. There is minimal change in prostate size during 4 weeks, especially considering the added PTV margins we use. For those who use SBRT, this is essentially irrelevant over 1.5 weeks, and for brachy.
6. For most localized prostate cancer cases, we align to fiducial markers, prostate itself, and/or the prostate/rectal interface using CBCT. So even if there is some shrinkage most would on daily CBCT ensure the prostate/rectal interface is well aligned to avoid overdose to rectum.
7. For those using adaptive RT (vast minority) they can account for this, but this, as mentioned is likely to be non-clinically relevant in most cases. The intrafraction monitoring may be even of greater value shown in the recent MIRAGE trial.

In summary, the randomized evidence shows no difference in physician or patient-reported outcomes from using prolonged neoadjuvant ADT, 2 months neoadjuvant ADT, concurrent ADT, or adjuvant ADT when assessing GI/GU toxicity (early or late) when synthesizing the available evidence. This is likely due to our contours in general, and PTV margins, are generous, we align using IGRT, our RT duration is even shorter now than in the trials mentioned before, and 2 months of neoadjuvant ADT likely causes similar continued changes in prostate size as starting ADT at the same time as RT. One more reason to use either brachy mono or SBRT to not even worry about this theoretical dilemma.

Hope this helped. Great question.

Best,
Dan

Start ADT, wait 8 weeks or thereabouts, planning scans, and start RT.

My experience from years of pubic arch studies both before and after androgen deprivation is that in a majority of patients, most of the cytoreduction is done in 2 to 2.5 months from initiation of androgen deprivation. So I usually wait 3 months to plan. I am sure there are a few who continue to shrink after that but you will catch almost everybody at their smallest size if you wait to plan 3 months after 1st injection.