Dataset Information

Neoadjuvant treatment of sintilimab plus hypofractionated radiotherapy for MSI-H/dMMR rectal cancer: A prospective, multicenter, phase Ib study.

ABSTRACT:

Background

Neoadjuvant radiochemotherapy followed by radical surgery is the standard treatment strategy for local advanced rectal cancer (LARC). However, the efficacy of neoadjuvant radiochemotherapy is limited, especially for patients with DNA mismatch repair-deficient (dMMR)/microsatellite instability-high (MSI-H) rectal cancer. Considering the amazing therapeutic effect of immune check point inhibitors for metastatic colorectal cancer, we conduct this multicenter, phase Ib study to investigate the safety and efficacy of anti-PD-1 antibody, sintilimab combined with hypofractionated radiotherapy in MSI-H/dMMR rectal cancer patients.

Methods

Patients with MSI-H/dMMR LARC will receive hypofractionated radiotherapy (5 Gy × 5) and three cycles of sintilimab 200 mg IV every 2 weeks. Radical surgery will be performed 6-8 weeks after radiotherapy. The primary endpoint is adverse reaction after neoadjuvant treatment and perioperative complications. Secondary endpoints include pathological response rate, complete resection rate, and quality of life.

Discussion

This is the first study to investigate the safety and effectiveness of neoadjuvant radiotherapy combined with immunotherapy for MSI-H/dMMR LARC. It is expected that this study will propose a brand new and effective treatment strategy for MSI-H/dMMR LARC.

SUBMITTER: Li X

PROVIDER: S-EPMC9741977 | biostudies-literature | 2022 Dec

REPOSITORIES: biostudies-literature

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Publications

Neoadjuvant treatment of sintilimab plus hypofractionated radiotherapy for MSI-H/dMMR rectal cancer: A prospective, multicenter, phase Ib study.

Li Xiaofen X Fang Chao C Wang Xin X Yu Yongyang Y Wang Ziqiang Z Qiu Meng M

Cancer medicine 20220329 23

<h4>Background</h4>Neoadjuvant radiochemotherapy followed by radical surgery is the standard treatment strategy for local advanced rectal cancer (LARC). However, the efficacy of neoadjuvant radiochemotherapy is limited, especially for patients with DNA mismatch repair-deficient (dMMR)/microsatellite instability-high (MSI-H) rectal cancer. Considering the amazing therapeutic effect of immune check point inhibitors for metastatic colorectal cancer, we conduct this multicenter, phase Ib study to in ...[more]

PMID: 35352512

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Project description:BackgroundPatients with colorectal carcinoma and high-grade microsatellite instability (MSI-H) or deficiency in mismatch repair (dMMR) exceptionally respond to immune checkpoint inhibitors (ICIs). ICIs are more active in treatment-naïve patients than in patients with refractory MSI-H/dMMR metastatic colorectal cancer and even more active in patients with locally advanced tumors.Material and methodsA 33-year-old male patient with Lynch syndrome was diagnosed with a locally advanced rectal cancer and refused standard neoadjuvant chemoradiation because of the potential harm of sexual dysfunction. MMR and microsatellite instability status were analyzed by immunohistochemistry and fragment length polymerase chain reaction followed by capillary electrophoresis.ResultsAfter MSI-H/dMMR was confirmed, the patient was treated with ICIs (1 mg/kg ipilimumab at day 1 and 3 mg/kg nivolumab at day 1 and 15). A complete clinical response was documented at day 21 after start of treatment. The patient underwent a total mesorectal excision at day 30. In the extirpated tissue, a complete pathological response was confirmed.ConclusionIn MSI-H/dMMR locally advanced rectal cancer short-course ICI treatment is highly effective and may be discussed in patients with dMMR locally advanced rectal cancer.Key pointsImmune checkpoint inhibitors are more active in treatment-naïve patients than in patients with refractory high-grade microsatellite instability (MSI-H)/deficiency in mismatch repair (dMMR) colorectal cancer. Standard neoadjuvant chemoradiation is less effective in MSI-H/dMMR rectal cancer patients than in patients with proficient mismatch repair. A young patient with Lynch syndrome and MSI-H/dMMR locally advanced rectal cancer refused chemoradiation in order to preserve his fertility. After neoadjuvant treatment with one dose of ipilimumab and two doses of nivolumab a complete clinical and pathological response was documented. Clinical trials are needed to first establish neoadjuvant treatment with immune checkpoint inhibitors in patients with locally advanced MSI-H/dMMR rectal cancer and thereafter to evaluate organ-preservation strategies.

Project description:IntroductionIn locally advanced rectal cancer, longer delay to surgery after neoadjuvant radiotherapy increases the likelihood of histopathological tumour response. Chronomodulated radiotherapy in rectal cancer has recently been reported as a factor increasing tumour response to neoadjuvant treatment in patients having earlier surgery, with patients receiving a larger proportion of afternoon treatments showing improved response. This paper aims to replicate this work by exploring the impact of these two temporal factors, independently and in combination, on histopathological tumour response in rectal cancer patients.MethodsA retrospective review of all patients with rectal adenocarcinoma who received long course (≥24 fractions) neoadjuvant radiotherapy with or without chemotherapy at a tertiary referral centre was conducted. Delay to surgery and radiotherapy treatment time were correlated to clinicopathologic characteristics with a particular focus on tumour regression grade. A review of the literature and meta-analysis were also conducted to ascertain the impact of time to surgery from preoperative radiotherapy on tumour regression.ResultsFrom a cohort of 367 patients, 197 patients met the inclusion criteria. Complete pathologic response (AJCC regression grade 0) was seen in 46 (23%) patients with a further 44 patients (22%) having at most small groups of residual cells (AJCC regression grade 1). Median time to surgery was 63 days, and no statistically significant difference was seen in tumour regression between patients having early or late surgery. There was a non-significant trend towards a larger proportion of morning treatments in patients with grade 0 or 1 regression (p = 0.077). There was no difference in tumour regression when composite groups of the two temporal variables were analysed. Visualisation of data from 39 reviewed papers (describing 27379 patients) demonstrated a plateau of response to neoadjuvant radiotherapy after approximately 60 days, and a meta-analysis found improved complete pathologic response in patients having later surgery.ConclusionsThere was no observed benefit of chronomodulated radiotherapy in our cohort of rectal cancer patients. Review of the literature and meta-analysis confirms the benefit of delayed surgery, with a plateau in complete response rates at approximately 60-days between completion of radiotherapy and surgery. In our cohort, time to surgery for the majority of our patients lay along this plateau and this may be a more dominant factor in determining response to neoadjuvant therapy, obscuring any effects of chronomodulation on tumour response. We would recommend surgery be performed between 8 and 11 weeks after completion of neoadjuvant radiotherapy in patients with locally advanced rectal cancer.

Dataset Information

Neoadjuvant treatment of sintilimab plus hypofractionated radiotherapy for MSI-H/dMMR rectal cancer: A prospective, multicenter, phase Ib study.

Background

Methods

Discussion

Publications

Neoadjuvant treatment of sintilimab plus hypofractionated radiotherapy for MSI-H/dMMR rectal cancer: A prospective, multicenter, phase Ib study.

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