The optimal timing for the interval to surgery after short course preoperative radiotherapy (5 ×5 Gy) in rectal cancer - are we too eager for surgery?

Abstract

Background:The improved overall survival (OS) after short course preoperative radiotherapy (SCPRT) using 5 × 5 Gy reported in the early rectal cancer trials could not be replicated in subsequent phase III trials. This original survival advantage is attributed to poor quality of surgery and the large differential in local recurrence rates, with and without SCPRT. Immuno-modulation during and after SCPRT and its clinical implications have been poorly investigated. We propose an alternative explanation for this survival benefit in terms of immunological mechanisms induced by SCPRT and the timing of surgery, which may validate the concept of consolidation chemotherapy. Material and methods: We reviewed randomized controlled trials (RCTs) and studies of SCPRT from 1985 to 2019. We aimed to examine the precise timing of surgery in days following SCPRT and identify evidence for immune modulation, neo-antigens and memory cell induction by radiation. Results: Considerable variability is reported in randomised trials for median overall treatment time (OTT) from start of SCPRT to surgery (8-14 days). Only three early trials showed a benefit in terms of OS from SCPRT, although the level of benefit in preventing local recurrence was consistent across all trials. Different patterns of immune effects are observed within days after SCPRT depending on the OTT, but human leukocyte antigen (HLA)-1 expression was not upregulated. Conclusions: SCPRT has a substantial immune-stimulatory potential. The importance of the timing of surgery after SCPRT may have been underestimated. An optimal interval for surgery after 5 × 5 Gy may lead to better outcomes, which is possibly exploited in total neoadjuvant therapy schedules using consolidation chemotherapy. Individual patient meta-analyses from appropriate SCPRT trials examining outcomes for each day and prospective trials are needed to clarify the validity of this hypothesis. The interaction of SCPRT with tumour adaptive immunology, in particular the kinetics and timing, should be examined further.

The immune microenvironment landscape shows treatment-specific differences in rectal cancer patients

“…Furthermore, we have shown that acute RT (SRT) affects the presence of T-cyt and T-helper cell populations the most. Strikingly, this is less evident with LRT, suggesting repopulation takes place in the interval that distinguishes SRT and LRT, which is in line with previous models (4,24,30). Previously, Mezheyeuski (17) has shown that memory T-helper, memory T-cyt cells, and macrophage counts decreased immediately after radiotherapy and were increased after longer treatment intervals.…”

Phase II, single-arm trial of preoperative short-course radiotherapy followed by chemotherapy and camrelizumab in locally advanced rectal cancer

“…A time interval of at least 7 days after SCRT has been reported to be probably required to achieve a favorable immune response, suggesting that the choice of the timing of immunotherapy after SCRT is important. 35 The PACIFIC trial reported that the initiation of durvalumab within 2 weeks after chemoradiotherapy (rather than ≥2 weeks) was linked to a higher clinical benefit. 36 Therefore, we have reasons to believe that our choice of timing for the initiation of immune checkpoint inhibitor camrelizumab in this study (median 12 days) is appropriate.…”

Shrinkage versus fragmentation response in neoadjuvantly treated oesophageal adenocarcinoma: significant prognostic relevance

“…Through activation of cytotoxic T cells, remaining vital tumour cells are directly and indirectly targeted by dendritic, B or T helper cells. To date, the link between the anti‐tumour immune response and tumour regression has focused upon high or low immune infiltrates predicting patient outcome 27,28 . As therapy interplays with the tumour immune landscape, it seems plausible that the immune response could influence the pattern of response.…”

“…To date, the link between the anti-tumour immune response and tumour regression has focused upon high or low immune infiltrates predicting patient outcome. 27,28 As therapy interplays with the tumour immune landscape, it seems plausible that the immune response could influence the pattern of response. Further studies on these specific immune cell subsets and their possible link to patterns of response are therefore needed.…”