What is the optimal time to wait prior to surgery following radiation therapy for rectal cancer to maximize the pathologic complete response rate?

Great question- and this is an even more interesting question in the era of TNT, with variables of SC vs LC RT and sequencing of induction vs consolidation chemotherapy. Especially with the question of—how do we best maximize the chance of a pathCR? I think starting with that question is the first step. We know that the pCR rate in the German Rectal was only ~8% and with TNT this can be upwards of 25%-35%. Thus, the biggest bang for the buck in maximizing pCR would be TNT > standard CRT/RT. The recent RAPIDO (PMID: 33301740) and PRODIGE-23 (PMID: 33862000) trials had remarkably similar improvements in pCR with TNT, both reporting pCR rates of 28% (vs 12% for standard CRT in PRODIGE23 and 14% for upfront SC-RT in RAPIDO). Begging the next question of—well, how should we sequence the RT? And getting to your initial question of optimal time to surgery. Well, we know that there was a numeric improvement in pCR in the German CAO/ARO/AIO-12 Phase II study with consolidation chemo (e.g. starting with chemoRT) vs induction of 25% vs 17%, and initial OPRA results randomizing induction vs consolidation chemo with LC-CRT (in the setting of non-operative management) have shown improved organ preservation rates with a consolidative approach, together suggesting that upfront RT may confer improved response rates at early measurable timepoints. Then the question of SC vs LC… well, RAPIDO was basically asking the question of TNT vs standard CRT, and used a SC-TNT paradigm, but doesn’t help directly answer a SC vs LC question. While we don’t have a direct comparison of SC vs LC RT in a TNT paradigm, both TNT paradigms are associated with increased rates of pCR, and together with the notion that there may be select advantages to starting with RT (increased pCR, OP) this may negate the question of surgical timing, since consolidation chemo is a more protracted and uniform time interval to surgery (~3-4 months) than what we used to consider in the non-TNT era (e.g. <12 weeks). So in short, if you use a TNT approach starting with RT (SC or LC), this may be a more optimal timing to surgery to maximize pCR, and if you start with RT, the interval is the same for SC or LC.