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Recently, a multi-center clinical study (TORCH study) led by the team from Fudan University Cancer Hospital confirmed that the "short-course radiotherapy combined with chemotherapy and immunotherapy full neoadjuvant therapy (iTNT)" regimen can effectively improve the withdrawal efficacy of locally advanced rectal cancer (LARC), with a complete tumor remission rate of more than 50%, which is expected to become a new choice for "anus-preserving" treatment for LARC patients.
The study confirmed the efficacy and safety of this combination therapy regimen for the first time in the world, and the results were published in the Journal of Clinical Oncology (IF: 42.1), a leading international journal in the field of oncology. The medical community is honored to invite the corresponding author of this study, Professor Zhang Zhen from Fudan University Cancer Hospital, and the first author, Professor Xia Fan, to come to the "Researcher Says" interview room to talk about the story behind the research.
Figure 1: Screenshot of the study Home
How to improve the quality of life of patients? The whole process of neoadjuvant treatment mode has broken the game strongly
Rectal cancer is one of the common malignant tumors in China, with a high incidence and mortality rate. At present, neoadjuvant therapy + radical rectal cancer resection + adjuvant therapy is the standard treatment option for patients with LARC. However, although neoadjuvant therapy reduced the rate of local recurrence, the incidence of distant metastases and long-term survival were not significantly improved. Clinically, there are still some rectal cancer patients with low tumor location and close to the anus facing the dilemma that it is difficult to preserve the anus after surgical radical remediation. In such patients, it will be more difficult to preserve the anus if local progression has occurred. Once the anus cannot be preserved, the patient's quality of life after treatment will be greatly affected.
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Full neoadjuvant therapy (TNT) refers to a treatment strategy that advances postoperative adjuvant therapy to preoperative therapy to minimize tumor size and eliminate potential systemic micrometastases, so as to improve the preoperative treatment effect and long-term prognosis of patients. "TNT usually includes radiotherapy, induction or consolidation chemotherapy, and can be combined with targeted therapy, immunotherapy, etc., all of which are performed before surgery. According to the specific situation of the patient and the characteristics of the tumor, a personalized treatment plan is developed, and continuous evaluation is carried out during the treatment process to guide the follow-up treatment strategy. TNT increases resectability by shrinking tumors; Increase the chances of anus preservation for patients who would otherwise not be able to undergo anal convalescence; At the same time, postoperative recurrence is reduced and distant metastases are minimized. ”
However, there are still some limitations to this model, Professor Zhang Zhen said: "In recent years, the TNT model has significantly improved the treatment effect of LARC, and successfully increased the tumor complete response rate from 10% to 30%. The goal of full-course neoadjuvant therapy is no longer limited to reducing the local recurrence rate, but focuses on improving the retention rate of patients' organs, prolonging the survival time of patients, and improving the quality of life of patients. However, how to further improve the preservation of organ function in LARC patients on the basis of existing treatment options needs to be further explored by the academic community. ”
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The complete tumor remission rate is over 50%! A new option for rectal cancer patients to "anus-preserving" treatment
The TORCH study is a prospective, multicenter, randomized phase II clinical study to explore the efficacy and safety of a short-course radiotherapy-based full-course neoadjuvant combined immunotherapy (iTNT) model in patients with LARC. Patients with stage II-III LARC were randomly assigned 1:1 to consolidation therapy (group A) or induction therapy (group B). Among them, group A patients were treated with short-course radiotherapy (25Gy/5Fx) + 6 cycles of toripalimab combined with capecitabine and oxaliplatin (CAPOX). Group B patients received 2 cycles of toripalimab plus CAPOX, followed by short-course radiotherapy, followed by 4 cycles of toripalimab plus CAPOX. The primary endpoint was complete response (CR) rate, i.e., pathologic complete response (pCR) rate + sustained clinical complete response (cCR) rate; Secondary endpoints included safety, adherence, surgical complications, and long-term treatment outcomes.
Figure 2: TORCH study design
■Nearly 40% of patients have access to non-surgical treatment
A total of 121 patients with pMMR/MSS LARC completed treatment evaluation (62 patients in group A; There were 59 patients in group B), of which 90.1% of the patients had stage III and 80.2% of the patients had tumors ≤ 5 cm from the anal margin. 74.2% (46 patients) and 86.4% (51 patients) of patients in group A and group B completed 6 cycles of CAPOX combined with toripalimab therapy, respectively, and the compliance of the two groups was good and there was no significant difference. After iTNT treatment, 39.7% (48 patients) of all patients achieved cCR, including 43.5% (27 cases) in group A and 35.6% (21 cases) in group B. Seventy-four patients underwent surgery (40 in group A; There were 34 cases in group B), 50% (37 cases) achieved pCR/TRG0, 11 cases had TRG 1, and 26 cases had TRG 2-3.
■More than 50% of patients had complete tumor remission
The CR rate of group A was 56.5% (15 cCR+20 pCR) and 54.2% (15 cCR+17 pCR) in group B, both of which met the primary endpoint, and there was no significant difference in CR rate between the two groups (P=0.807). Group A had a higher rate of cCR at the end of neoadjuvant therapy (43.5 versus 35.6 percent). The pathological regression of tumors in the two groups was better, and 67.5% and 70.6% of the patients in groups A and B achieved major pathological remission (MPR, residual tumor cells less than 10%), respectively.
Figure 3: Efficacy outcomes in both groups
■More than 80% of patients achieve "anal preservation"
In terms of safety, the overall safety profile was good during neoadjuvant therapy, with the main grade 3-4 adverse events (AEs) being thrombocytopenia (24.2% in group A versus 33.9% in arm B) and neutropenia (11.3% in arm A versus 5.1% in arm B). In terms of postoperative complications, there were only 2 patients in group A and 1 patient in group B with grade 3-4 complications, with no significant difference. By the end of follow-up, 82.3% (51) of patients in group A and 86.4% (51) of patients in group B had achieved anal sphincter preservation.
Short-course radiotherapy + chemotherapy + immunotherapy, combined to achieve "1+1+1>3"
In recent years, immunotherapy represented by PD-1 inhibitors has achieved remarkable efficacy in the treatment of a variety of malignant tumors, but patients with pMMR/MSS rectal cancer are relatively insensitive, and how to improve the sensitivity of such patients to immunotherapy has become a research hotspot in the oncology community. Preclinical studies have shown that radiotherapy can promote the body's anti-tumor immune response through various pathways, which is expected to increase the sensitivity of pMMR/MSS rectal cancer to immunotherapy. This opens a new window for the neoadjuvant treatment of pMMR/MSS locally advanced rectal cancer.
In addition, relevant research evidence shows that chemoradiotherapy combined with immunoneoadjuvant therapy for locally advanced rectal cancer has achieved more significant efficacy than traditional chemoradiotherapy. However, the choice of radiation dose fractionation for combination therapy, drug regimens, and sequencing with radiation therapy is still inconclusive. On this basis, the design of the TORCH study can be described as "forward-looking", and the combination of chemoradiotherapy and PD-1 inhibitor toripalimab is not a simple treatment superposition, but a "1+1+1>3" approach to enable different therapies to give full play to their respective advantages and ultimately achieve patient benefits.
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However, the endpoint of the TORCH study is not the endpoint of the LARC treatment exploration. When talking about safety-related topics, Professor Xia Fan shared: "For the main grade 3-4 AE thrombocytopenia, we put forward the following three countermeasures in terms of toxicity management. First of all, it is necessary to carefully screen patients, and communicate and intervene in advance for patients with low baseline platelet levels and abnormal platelet function due to underlying diseases. In addition, communication with patients should be strengthened, and patients should be reminded to cooperate closely with regular monitoring because they cannot perceive changes in their own platelet levels; Finally, timely intervention, for patients who have already developed thrombocytopenia, early drug intervention to reverse the toxic reaction. ”
Finally, Professor Zhang Zhen summarized and looked forward to the future: "The results of the TORCH study showed that the iTNT regimen significantly improved the overall response rate, and more than half of the LARC patients achieved complete tumor response with a controllable treatment safety. We look forward to this combination therapy model to break through the dilemma of pMMR/MSS LARC immunotherapy and provide more new treatment options for patients with low- and medium-level rectal cancer to improve efficacy and organ preservation." ”
"In addition, the results of the TORCH research will also help to extend the iTNT model to the treatment of patients with early and advanced rectal cancer, thereby benefiting a wide range of patient populations. Further, we also look forward to the extension of the treatment concept behind the iTNT model to other tumor types, and to optimize and adjust the treatment regimen accordingly based on the treatment characteristics of different tumor types. How to flexibly use the 'addition and subtraction' method of tumor treatment requires us to build on the effectiveness and select individualized treatment plans for patients. For example, which patients can be exempted from radiotherapy and which patients may avoid surgery? How to achieve the 'maximum benefit' of efficacy with 'minimum sacrifice'? Whether it's the continuous adjustment of individual treatment plans or the unremitting exploration of basic translational research, the goal of all our efforts is to provide patients with longer survival benefits and better quality of life. ”
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