The lights and shades of the new treatment for rectal cancer

Management of rectal cancer has evolved rapidly these days. Traditional treatment consisting of preoperative chemoradiation therapy (CRT) followed by total mesorectal excision (TME) has been successful in reducing the local recurrence. Still, it has failed to achieve significant survival benefits, although recent total neoadjuvant therapy (TNT) showed a modest increase in disease-free survival benefits (1,2).

Recent advances in treatment strategy include TNT and immunotherapy for microsatellite instability patients showing mismatch repair (MMR) deficiency (3). However, the proportion of MMR deficiency in rectal cancer patients is generally as low as 5%. The TORCH trial recently showed promising results with immune TNT (iTNT) for patients with proficient MMR (pMMR) status (4). This trial included 121 pMMR patients and randomly assigned patients into two groups (group A consolidation chemoimmunotherapy vs. group B induction chemoimmunotherapy). To improve the immunogenicity of rectal cancer, short-course radiation therapy (SCRT) is adopted. With the median follow-up of 19 months, pathologic complete response (pCR) was achieved in 56.5% of group A and 54.2% of group B, which is beyond the trial’s hypothesis.

The eligible patients were stage II, II rectal cancer located within 12 cm from the anal verge, and 10.0% of them were cT4, 25.6% of patients showed extramural venous invasion (EMVI), and 33.1% of patients had circumferential resection margin (CRM) involved. Usually, SCRT is not recommended for cT4 rectal cancer; the TORCH trial speculated SCRT stimulates the tumor immunogenicity rather than tumor regression.

Overall compliance with the treatment was as high as 80% in both groups. The grade 3–4 toxicity was relatively high, above 40%. However, the consolidation chemoimmunotherapy group (group A) showed a higher clinical complete response (cCR) of 43.5% and a lower grade 3–4 thrombocytopenia of 24.2%.

There were two deaths in group B patients, but the deaths were not related to treatment.

Radiotherapy can induce both immune-stimulating and -suppressive alterations, potentially mediating radio-resistance (5). The SCRT showed the immune-stimulating, but the long-course radiation therapy (LCRT) could cause bone marrow suppression and also mediate the radio-resistance.

The treatment of immune checkpoint inhibitor (ICI) therapy for deficient MMR (dMMR) rectal cancer showed an outstanding outcome (3). However, the proportion of dMMR rectal cancer is generally less than 5% of all patients.

Many trials are introducing ICI therapy for microsatellite instability stable (MSS) or pMMR rectal cancer patients. The results are inconsistent because ICI therapy is introduced with different treatment regimens.

NRG-GI002 trial failed to show the advantages of adding ICI therapy during CRT after a 6-cycle of induction chemotherapy (6). Another small group phase II trial with TNT with induction immunochemotherapy followed by long-course CRT reported 48% cCR with acceptable toxicities (7). The Japan trial, which was similar in design to the NRG-GI002 trial, included both pMMR and dMMR rectal cancer patients and reported 30% and 60% CR rates, respectively (8).

TORCH trial introduced the concept of induction or consolidation chemoimmunotherapy.

Although ICI therapy has the potential to improve CR in MSS or pMMR rectal cancer, we should consider its cost-effectiveness. A Japanese study sought to identify the best possible treatment response based on the immune markers of MSS or pMMR patients (8). Moreover, biomarkers that predict the potential responses in MSS or pMMR patients in rectal cancer are currently not available.

The follow-up period of the TORCH trial is relatively short at 19 months, which is insufficient to identify the local regrowth in W&W populations and the long-term immune-related adverse effects of ICIs (9-11). We need longer follow-up information in the future to clearly identify the benefits of immunochemotherapy.

As we have more and more trials using ICIs in MSS or pMMR rectal cancer patients, the optimal treatment sequence will soon be revealed.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Chinese Clinical Oncology. The article has undergone external peer review.

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Funding: None.

Conflicts of Interest: The author has completed the ICMJE uniform disclosure form (available at https://cco.amegroups.com/article/view/10.21037/cco-25-4/coif). The author has no conflicts of interest to declare.

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