Organ preservation for rectal cancer patients in the era of neoadjuvant immunotherapy

Correspondence to: Zhongtao Zhang (email: zhangzht@ccmu.edu.cn)

Department of General Surgery

Beijing Friendship Hospital

Capital Medical University

Beijing

100050

China

BJS, https://doi.org/10.1093/bjs/znaf057, published 22 March 2025

Organ preservation has long been one of the most influential topics in the field of rectal cancer surgery, and surgeons are increasingly aware of the pivotal role of neoadjuvant treatment in achieving this goal. Likewise, the POLARSTAR trial1 represents a first step of our endeavor to evaluate the potential of the radiation + immune combination in facilitating organ preservation.

Currently, total neoadjuvant therapy (TNT) is the primary and most recommended treatment plan among all neoadjuvant treatment modalities to implement organ-preservation for locally advanced rectal cancer (LARC)2,3. On the other hand, neoadjuvant stand-alone immunotherapy also displayed a strong potential in facilitating the watch and wait strategy for mismatch-repair deficient (dMMR) LARC4. Yet such dMMR cases account for less than 5% among all LARC patients. The POLARSTAR trial is designed in this context, with the aim of exploring a new possible route (i.e. radiotherapy plus immunotherapy) to achieve organ preservation, apart from the current mainstream of TNT approach.

The tested treatment for our trial is, obviously, neoadjuvant chemoradiation plus PD1 blockade5. And the chemoradiation plan we chose for the trial is composed of 50Gy long-course radiotherapy (intensity-modulated radiation therapy, IMRT) and oral capecitabine tablets, which is a plan with the weakest chemotherapy content among all neoadjuvant plans for rectal cancer. We adopted this specific chemoradiation plan for the trial because our primary objective was to confirm the synergism between radiotherapy and immune checkpoint inhibitor (ICI), and the weak chemotherapy is designed to avoid its potential influence on ICI efficacy, considering its widely known inhibitory effect on circulating lymphocytes. For the first randomized trial to test this novel treatment modality (chemoradiation plus ICI), we used pathological complete response (pCR) instead of clinical complete response (cCR) as the primary endpoint, because we need concrete evidences to confirm its enhanced tumor regression. And with pCR as the primary endpoint, the results would be both convincing and easily repeatable, whereas the criteria of cCR is much more complex, not to mention the fact that diverse cCR criteria are used among different trials. In general, we intended for the trial to be as simplified as possible, so as to yield straightforward evidences that are easily interpretable regarding this novel neoadjuvant modality, at a time when most surgical oncologists are unfamiliar with it.

Precisely for the above considerations in the trial design, results of the POLARSTAR trial can now be used as a solid cornerstone to design subsequent trials. We sincerely appreciate the pointed recommendations, which are genuinely enlightening and constructive. But before integrating the recommended points into future trial designs to achieve organ-preservation, several problems should be addressed first:

(1) The optimal radiotherapy dose and fractionation is still to be explored, as mechanistically hypofractionated radiotherapy with high dose for each fraction (e.g. 5×5Gy short-course radiotherapy) might be more efficient in inducing immunogenic cell death of cancer cells; The optimal amount of ICI cycles is also to be explored, and 3 cycles as in our trial might not be sufficient for some patients, especially during a watch-and-wait process;

(2) The rationality of adding substantial chemotherapy into the radiation + ICI combination is not yet established. Specifically, will it be better if chemotherapy is NOT administered simultaneously with ICI so as to avoid possible inhibition on circulating T lymphocytes?

(3) In the context of watch and wait with immunotherapy, a unified cCR criteria is especially needed. Due to the observed substantial discrepancy between pre-operative radiology and post-operative pathology (i.e. pCR hardly comes from radiological CR) in our trial, we suggest biopsy be compulsory in this scenario.

In summary, the neoadjuvant radiotherapy plus ICI approach displays potential in assisting rectal cancer organ-preserving strategy, but more research work needs to be done before its wider application, where collaboration and multi-center trials are essential to realize this vision.