#VisualAbstract: Immunotherapy-Based Total Neoadjuvant Therapy for Locally Advanced Rectal Cancer

1. The complete response rates (pathological and clinical) were similar (~55%) in both groups.

2. Grade 3-4 adverse events rates were similar (~43%) in both groups with thrombocytopenia and neutropenia being the most common.

Evidence Rating Level: 2 (Good)

Study Rundown: Total neoadjuvant therapy (TNT) for locally advanced rectal cancer showed superiority compared to traditional approaches, however still have a low pathological complete response rate. Some recent studies have shown promise with a combination of TNT with immune checkpoint inhibitors (ICIs). This trial investigated the efficacy of combining short-course radiotherapy (SCRT) with immunochemotherapy in pMMR/MSS locally advanced rectal cancer. The primary endpoint was complete response (CR) rate and secondary endpoints included safety. SCRT was 25Gy in five fractions, and immunochemotherapy consisted of CAPOX with toripalimab. Median follow-up time was 19 months (11-27). For patients who underwent surgery, pCR was 50% in group A and 50% in group B, and major pathological regression occurred in 67.5% and 70.6%, respectively. There were 15 patients in each group who had cCR and remained in the watch-and-wait approach until the end of follow-up, and 1 patient in each group who started with watch-and-wait and then received salvage surgery in the 10^th (group A) and 7^th (group B) month. The total CR (cCR and pCR) rates were 56.5% in group A vs 54.2% in group B, with OR 0.91 (non-significant) between the two groups. It was found that early age at onset was an independent risk factor of incomplete response to iTNT, with OR 4.46 (significant). Anal sphincter preservation was achieved in 82.3% in group A and 86.4% in group B. With regards to safety, grade 3-4 adverse events occurred in 45.2% of group A and 42.4% in group B, with the most common grade 3-4 adverse events being thrombocytopenia (24.2% vs 33.9%) and neutropenia (11.3% vs 5.1%), respectively. The strength of this study included its methodology and the limitations included a small sample size, short follow-up time, and lack of a standard treatment arm. Overall, this study found that TNT with immunochemotherapy and SCRT (regardless of order) resulted in favourable CR rates in pMMR/MSS locally advanced rectal cancer.

Click to read the study in JCO

In-Depth [randomized controlled trial]: This multicenter, open-label, phase II trial enrolled adults with clinical stage II/III rectal adenocarcinoma and randomized them (1:1) into group A (SCRT followed by six cycles of consolidation immunochemotherapy, n=62) and group B (two cycles of induction immunochemotherapy followed by SCRT and the rest four doses, n=59). SCRT was 25Gy in five fractions, and immunochemotherapy consisted of CAPOX with toripalimab. Depending on the tumour response, the patient then had total mesorectal excision or a watch-and-wait approach. Most patients (90.1%) had stage III disease. Median follow-up time was 19 months (11-27). For patients who underwent surgery, pCR was 50% in group A and 50% in group B, and major pathological regression occurred in 67.5% and 70.6%, respectively. There were 15 patients in each group who had cCR and remained in the watch-and-wait approach until the end of follow-up, and 1 patient in each group who started with watch-and-wait and then received salvage surgery in the 10^th (group A) and 7^th (group B) month. The total CR (cCR and pCR) rates were 56.5% in group A vs 54.2% in group B, with OR 0.91 (95%CI, 0.45-1.87, p=0.807) between the two groups. It was found that early age at onset was an independent risk factor of incomplete response to iTNT, with OR 4.46 (95%CI, 1.34-14.83, p=0.015). Anal sphincter preservation was achieved in 82.3% in group A and 86.4% in group B. With regards to safety, grade 3-4 adverse events occurred in 45.2% of group A and 42.4% in group B, with the most common grade 3-4 adverse events being thrombocytopenia (24.2% vs 33.9%) and neutropenia (11.3% vs 5.1%), respectively. Overall, this study found that TNT with immunochemotherapy and SCRT (regardless of order) resulted in favourable CR rates in pMMR/MSS locally advanced rectal cancer.

Image: PD

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