TYMS genotype-directed neoadjuvant chemoradiation for rectal cancer

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 4028-4028
Author(s):  
H. L. McLeod ◽  
R. J. Myerson ◽  
B. Zehnbauer ◽  
K. Trinkaus ◽  
R. S. Malyapa ◽  
...  
Keyword(s):  
Rectal Cancer ◽  
Randomized Study ◽  
Locally Advanced ◽  
Pathologic Complete Response ◽  
Rectal Adenocarcinoma ◽  
Transrectal Ultrasound ◽  
Risk Groups ◽  
Recurrence Rates ◽  
Risk Patients ◽  
Good Risk

4028 Background: Downstaging (DS) of rectal cancers is achieved in 45% of pts with neoadjuvant 5FU and radiation (XRT). A 28bp repeats in the thymidine synthase gene (TYMS) appears to define disparate DS rates (60% vs 22%). We conducted a prospective single-institution Phase II study using TYMS genotyping to direct neoadjuvant chemoRT for pts with rectal cancer. Methods: Pts with T3/ T4, N0–2, M0–1 rectal adenocarcinoma staged with transrectal ultrasound (TRUS) or CT/MRI are eligible. After informed consent is obtained, pts with TYMS *2/*2, *2/*3, or *2/*4 (Good-risk) are treated with 50.4 Gy 3-D XRT and 5FU continuous infusion at 225 mg/m2/d throughout XRT. Patients with TYMS *3/*3 or *3/*4 (Bad-risk) are treated with 5FU and XRT plus irinotecan at 50 mg/m2 IV weekly x 5. Pts underwent restaging and resection 6–10 weeks after therapy. The 1o endpoints are DS and pathologic complete response (pCR) rates. 2o endpoints include toxicity, recurrence rates and OS. Adjuvant therapy was directed by the pt's physician. The study was powered to ascertain whether DS was significantly >45% in ‘good risk‘ patients and >22% in ‘bad risk‘ patients. Results: Overall, 135 pts (median age 56, range 26–85; M:F 2:1; black-18, white-119) are enrolled, of which 27.4% (37/135) are ‘bad risk‘. DS, pCR and toxicity rates were evaluable in 121 patients and are shown below. The rate of DS met the a priori criteria for significance for both the ‘good risk‘ and ‘bad risk‘ groups. 1 death/1 perforation was observed in each group. Conclusions: This is the first study to prospectively use TYMS genotyping to direct neoadjuvant chemoXRT in pts with rectal cancer. The high efficacy of 5FU/XRT in ‘good risk‘ pts was prospectively confirmed. High rates of DS and pCR were also achieved among ‘bad risk‘ pts with the addition of irinotecan to neoadjuvant 5FU/XRT. These results are encouraging for the conduct of a randomized study of genotype-guided neoadjuvant therapy for locally advanced rectal cancer. [Table: see text] [Table: see text]

scholarly journals Thymidylate Synthase Genotype-Directed Neoadjuvant Chemoradiation for Patients With Rectal Adenocarcinoma

2011 ◽  
Vol 29 (7) ◽  
pp. 875-883 ◽  
Author(s):  
Benjamin R. Tan ◽  
Fabienne Thomas ◽  
Robert J. Myerson ◽  
Barbara Zehnbauer ◽  
Kathryn Trinkaus ◽  
...  
Keyword(s):  
Rectal Cancer ◽  
Thymidylate Synthase ◽  
Randomized Study ◽  
Locally Advanced ◽  
Rectal Adenocarcinoma ◽  
Risk Groups ◽  
Advanced Rectal Cancer ◽  
Recurrence Rates ◽  
Poor Risk ◽  
Good Risk

Purpose Downstaging (DS) of rectal cancers is achieved in approximately 45% of patients with neoadjuvant fluorouracil (FU) -based chemoradiotherapy (CRT). Polymorphisms in the thymidylate synthase gene (TYMS) had previously defined two risk groups associated with disparate tumor DS rates (60% v 22%). We conducted a prospective single-institution phase II study using TYMS genotyping to direct neoadjuvant CRT for patients with rectal cancer. Patients and Methods Patients with T3/T4, N0-2, M0-1 rectal adenocarcinoma were evaluated for germline TYMS genotyping. Patients with TYMS *2/*2, *2/*3, or *2/*4 (good risk) were treated with standard chemoradiotherapy using infusional FU at 225 mg/m2/d. Patients with TYMS *3/*3 or *3/*4 (poor risk) were treated with FU/RT plus weekly intravenous irinotecan at 50 mg/m2. The primary end point was pathologic DS. Secondary end points included complete tumor response (ypT0), toxicity, recurrence rates, and overall survival. Results Overall, 135 patients were enrolled, of whom 27.4% (37 of 135) were considered poor risk. The prespecified statistical goals were achieved, with DS and ypT0 rates reaching 64.4% and 20% for good-risk and 64.5% and 42% for poor-risk patients, respectively. Conclusion To our knowledge, this is the first study to prospectively use TYMS genotyping to direct neoadjuvant CRT in patients with rectal cancer. High rates of DS and ypT0 were achieved among both risk groups when personalized treatment was based on TYMS genotype. These results are encouraging, and further evaluation of this genotype-based strategy using a randomized study design for locally advanced rectal cancer is warranted.

Rectal cancer and systemic therapy of colorectal cancer

2016 ◽  
pp. 408-443
Author(s):  
Regina Beets-Tan ◽  
Bengt Glimelius ◽  
Lars Påhlman
Keyword(s):  
Rectal Cancer ◽  
Locally Advanced ◽  
Treatment Decision ◽  
Well Being ◽  
Risk Groups ◽  
Preoperative Chemoradiotherapy ◽  
Recurrence Rates ◽  
Short Course ◽  
Rectal Cancer Treatment ◽  
Long Course

In rectal cancer treatment, surgery is most important. Dissection outside the mesorectal fascia, total mesorectal excision is required for cure in most cases; a local procedure is possible in the earliest tumours. Appropriate staging is required prior to treatment decision to stratify patients into risk groups. In early tumours surgery alone is sufficient whereas in intermediate cancers local recurrence rates are too high and preoperative radiotherapy is indicated. A short-course schedule is convenient, low toxic, although some prefer long-course chemoradiotherapy. The addition of a fluoropyrimidine enhances the radiotherapy. In locally advanced tumours preoperative chemoradiotherapy is required. The value of adjuvant chemotherapy in rectal cancer is controversial, particularly if preoperative chemoradiotherapy was used. Palliative chemotherapy prolongs life and improves well-being in patients with metastatic disease. Targeted drugs further improves the results to some extent. In some patients, chemotherapy may convert non-readily resectable metastases to resectable, and result in long-term cure.

Evidence for improved pathologic complete response (PCR) rate after preoperative chemoradiotherapy with 5-FU/oxaliplatin (5FU/OX) for rectal cancer

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 3567-3567 ◽  
Author(s):  
C. M. Dolinsky ◽  
N. N. Mahmoud ◽  
R. Mick ◽  
W. Sun ◽  
R. W. Whittington ◽  
...  
Keyword(s):  
Rectal Cancer ◽  
Retrospective Study ◽  
Residual Disease ◽  
Locally Advanced ◽  
Pathologic Complete Response ◽  
Rectal Adenocarcinoma ◽  
Preoperative Chemoradiotherapy ◽  
Malignant Cells ◽  
Long Term Outcomes

3567 Background: The use of preoperative chemoradiotherapy (chemo/RT) with 5-FU for locally advanced rectal cancer has increased dramatically. The addition of oxaliplatin (OX) to preoperative 5-FU may be a more active regimen than 5-FU alone. This retrospective study was undertaken to describe clinical outcomes in patients (pts) with rectal cancer treated with 5FU/OX or 5-FU alone. Methods: Between 11/90 and 4/05, 114 pts with rectal adenocarcinoma underwent preoperative chemo/RT at the University of Pennsylvania. Chemotherapy consisted of 5FU/OX in 36 (32%) pts and 78 (68%) pts received 5-FU. All pts received preoperative RT (median dose 5040 cGy). The two groups were balanced in terms of demographic and tumor related factors including tumor size, stage and distance from the anal verge. Median follow-up from preoperative chemo/RT was 24 months (range 2–125 months). A total of 105 (92%) pts had surgical resections; 61 (58%) with LAR, 44 (42%) with APR. PCR was defined as either no evidence of viable malignant cells in specimen or scattered, isolated malignant cells without gross residual disease. Non-surgical pts were counted as treatment failures. Results: The PCR rate was 36.1% (95% CI 20.4–51.8%) in 5FU/OX pts and 12.8% (95% CI 5.4–20.2%) in 5-FU pts. The probability of observing 13 PCRs in 36 5FU/OX pts if the actual PCR rate was 15% is equal to 0.001. Rates of any grade III/IV toxicity were similar between each regimen (20% 5FU/OX vs. 17% 5FU). Long term outcomes (2yr rate±SE) of local control, freedom from distant failure and progression-free survival in 23 pts who achieved a PCR were: 100%, 94%±6% and 94%±6%, respectively. In 85 pts with gross residual disease, these rates were: 87%±5, 77%±5% and 71%±6%, respectively. Conclusion: In this retrospective study, patients receiving 5FU/OX with radiation had a higher rate of PCR than those receiving 5FU alone. Overall, a PCR may lead to improved long-term outcomes. A prospective randomized trial to test superiority of the 5FU/OX regimen is warranted. [Table: see text]

Addition of bevacizumab to induction plus concomitant capecitabine-oxaliplatin (XELOX) chemoradiotherapy (CRT) in MRI poor prognosis locally advanced rectal cancer: Avacross study

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 4100-4100
Author(s):  
M. Nogue ◽  
A. Salud ◽  
P. Vicente ◽  
C. Pericay ◽  
A. Arriví ◽  
...  
Keyword(s):  
Rectal Cancer ◽  
Clinical Stage ◽  
Locally Advanced ◽  
Pathologic Complete Response ◽  
Rectal Adenocarcinoma ◽  
Activity Level ◽  
Growth Delay ◽  
Wound Complications ◽  
Induction Phase ◽  
Induction Cycle

4100 Background: Concomitant CRT with 5-FU followed 6–8 weeks later by TME surgery is well accepted standard treatment for locally advancer rectal cancer. This approach focuses only into local control. Trimodal induction approaches with chemo, radiation and anti VEGFR therapy may induce additional tumor growth delay. Methods: Eligible patients (pts) had high-risk rectal adenocarcinoma defined by MRI: distal T3 at/below levators, T3 at any other level within 2 mm of mesorectal fascia, resectable T4 and any T3 with nodal metastases. We excluded pts with any antecedent of heart disease. Treatment consisted in four 21 day cycles of oxaliplatin 130 mg/m2 d 1, bevacizumab 7.5 mg/kg d 1 and capecitabine 1000 mg/m2/12 h d 1–14. After 3–4 weeks they received concomitant RT (50.4 Gy in 28 fractions) with capecitabine 825 mg/m2/12 h plus bevacizumab 5 mg/kg, three biweekly doses. TME was planned 6–8 weeks after CRT. Primary end point was pathologic complete response rate with standarized pathology examination. Results: From July 2007 to July 2008, 47 pts were enrolled. Median age was 58 (30–78). Median KPS was 90%. Clinical stage was T3N1: 51.1%, T3N2: 25.5%, T4N0–2: 10.6%, T3N0: 8.5% of pts. 40 pts completed the induction phase: G 3–4 toxicity were diarrhea 12.7%, neutropenia 8.5%, peripheral neuropathy 6.3% and thrombocytopenia 4.2%.. 39 pts completed the CRT phase. Grade 3–4 toxicity were rectitis, linfopenia and hipertrigliceridemia in 2.5% of pts. Until now we have data on 35 resections, 2 with only one induction cycle. R0 resections were achieved in 34 pts (R1 resection in a patient with only one induction cycle). There were 7 wound complications and 10 pts required surgical reintervention. pCR were obtained in 13 pts (37,1 %, 95% CI:21.1–53.2) with 18 (51.4%) additional pts with only residual microscopic foci. There were two treatment related-deaths: one sudden death and one grade 4 diarrhea and diabetic ketoacidosis. Conclusions: Preliminary results show that our preoperative schedule appears feasible, with impressive activity level (pCR + Tmic of 88.5%), achieving downstaging in nearly all pts. Toxicity was manageable, nevertheless we stress caution with cardiac and GI events and surgical complications. No significant financial relationships to disclose.

Phase I study of preoperative capecitabine and lenvatinib with external radiation therapy in locally advanced rectal adenocarcinoma.

2020 ◽  
Vol 38 (4_suppl) ◽  
pp. 125-125
Author(s):  
Ankita Tandon ◽  
Jessica Frakes ◽  
Rutika Mehta ◽  
Sarah E. Hoffe ◽  
Maria E Martinez Jimenez ◽  
...  
Keyword(s):  
Rectal Cancer ◽  
Growth Factor ◽  
Locally Advanced ◽  
Pathologic Complete Response ◽  
Rectal Adenocarcinoma ◽  
Advanced Rectal Cancer ◽  
Locally Advanced Rectal Cancer ◽  
External Beam Radiation ◽  
Beam Radiation ◽  
Rectal Pain

125 Background: Neoadjuvant chemo-radiation is a standard of care for locally advanced rectal cancer. Patients with pathologic complete response (pCR) have improved outcomes with less local and systemic failure. Dual targeting with platelet derived growth factor (PDGF) and vascular endothelial growth factor receptor (VEGFR) in combination with radiation can escalate tumor response with radiation. Lenvatinib is an oral multi-kinase inhibitor and had shown potent anti-tumor activity in xenograft models cultured with human colorectal cancer (CRC) lines. Methods: Patients with stage II or III rectal cancer, confirmed by endoscopic ultrasound or MRI, were recruited in 3 cohorts of 3 patients per dose level, with an expansion cohort at the MTD. Lenvatinib oral daily dose started at 14 mg (cohort 1) and was escalated to 20 mg (cohort 2) followed by 24 mg (cohort 3). In this 3+3 design, patients received dose escalation of lenvatinib with standard doses of capecitabine (850 mg/m2 PO BID) concurrent with external beam radiation on days 1-5 weekly for 28 treatments. Following completion patients underwent surgery in 6-10 weeks. Results: Twenty patients with median age of 55 were enrolled in 3 cohorts (1 patient was ineligible). There were no dose limiting toxicity at the maximum tested dose of lenvatinib (24 mg). Two patients are still awaiting surgery. 12 patients have undergone low anterior resection and 5 patients have had abdominoperineal resection. Therefore, out of 17 patients, 29.4% (5/17) showed pCR, and downstaging was observed in 71% of the patients (12/17). The mean neoadjuvant rectal cancer score (NAR) was 11.4 and median NAR was 8.43. Six patients had grade 3 adverse events (AEs) (1 rectal pain,1 transaminitis, 2 lymphopenia, 1 HTN, 1 with both leukocytosis and hyponatremia). No grade 4 AEs were noted. Most common AEs were hypertension, rectal pain, nausea, diarrhea, fatigue and dermatitis. No peri operative complications were observed. Conclusions: The study shows that the combination of lenvatinib and capecitabine with radiation is well tolerated in locally advanced rectal cancer with promising mean NAR score. The encouraging results will need to be validated in a randomized study. Clinical trial information: NCT02935309.

Rectal cancer and systemic therapy of colorectal cancer

2016 ◽  
pp. 408-443
Author(s):  
Regina Beets-Tan ◽  
Bengt Glimelius
Keyword(s):  
Rectal Cancer ◽  
Locally Advanced ◽  
Treatment Decision ◽  
Well Being ◽  
Risk Groups ◽  
Preoperative Chemoradiotherapy ◽  
Recurrence Rates ◽  
Short Course ◽  
Rectal Cancer Treatment ◽  
Long Course

In rectal cancer treatment, surgery is most important. Dissection outside the mesorectal fascia, total mesorectal excision is required for cure in most cases; a local procedure is possible in the earliest tumours. Appropriate staging is required prior to treatment decision to stratify patients into risk groups. In early tumours surgery alone is sufficient whereas in intermediate cancers local recurrence rates are too high and preoperative radiotherapy is indicated. A short-course schedule is convenient, low toxic, although some prefer long-course chemoradiotherapy. The addition of a fluoropyrimidine enhances the radiotherapy. In locally advanced tumours preoperative chemoradiotherapy is required. The value of adjuvant chemotherapy in rectal cancer is controversial, particularly if preoperative chemoradiotherapy was used. Palliative chemotherapy prolongs life and improves well-being in patients with metastatic disease. Targeted drugs further improves the results to some extent. In some patients, chemotherapy may convert non-readily resectable metastases to resectable, and result in long-term cure.

scholarly journals Nonsurgical Management of Rectal Cancer

2019 ◽  
Vol 15 (3) ◽  
pp. 123-131 ◽  
Author(s):  
Mehmet Akce ◽  
Bassel F. El-Rayes
Keyword(s):  
Rectal Cancer ◽  
Neoadjuvant Therapy ◽  
Surgical Resection ◽  
Locally Advanced ◽  
Pathologic Complete Response ◽  
Rectal Adenocarcinoma ◽  
Neoadjuvant Chemoradiotherapy ◽  
Management Approach ◽  
Nonsurgical Management ◽  
Salvage Resection

Neoadjuvant chemoradiotherapy followed by surgical resection is the standard of care for locally advanced rectal adenocarcinoma. Up to one third of patients achieve pathologic complete response (CR) with neoadjuvant therapy. Promising disease-free and overall survival outcomes have been reported in patients who achieve clinical CR after neoadjuvant therapy without surgical resection. Furthermore, patients who have local recurrence have acceptable disease control outcomes with salvage resection. With consideration of morbidities associated with surgical resection and similar clinical outcomes, interest in nonsurgical management of low rectal cancers has emerged. Randomized clinical trials are being conducted to evaluate a nonsurgical approach in rectal cancer. Lack of consensus on the definition of clinical CR, molecular biomarkers, and standardized nonsurgical management protocols is a significant barrier for routine clinical implementation of a nonsurgical management approach. This article aims to provide a concise review of the clinical experience and practical approach to the nonsurgical management of locoregional rectal adenocarcinoma.

scholarly journals Outcome of Adjuvant Concurrent Chemo-Radiation in Operated Locally Advanced Rectal Cancer

2015 ◽  
Vol 5 (3) ◽  
pp. 139-144
Author(s):  
Syed Arshad Mustafa ◽  
M Ismail ◽  
Saquib Zaffar ◽  
Ghulam Hassan ◽  
Waseem Qureshi ◽  
...  
Keyword(s):  
Rectal Cancer ◽  
Cancer Patients ◽  
Randomized Study ◽  
Locally Advanced ◽  
Advanced Rectal Cancer ◽  
Treatment Interruption ◽  
Locally Advanced Rectal Cancer ◽  
Adjuvant Radiation ◽  
Recurrence Rates ◽  
High Death

Background: Rectal cancer is one of the most common cancers in Kashmir, India. The clinical course of patients treated with surgery alone has been characterized by a high death rate and also by the pain and disability associated with pelvic recurrence of the tumor. Adjuvant radiation combined with chemotherapy has been studied for prevention of such recurrences. We treat more than 200 rectal cancer patients annually at our center. Most of the patients registered at our center are those who have been already subjected to surgery at the peripheral hospitals. We studied role of 5-fluorouracil (5-FU) and calcium leucovorin concurrently with radiotherapy in Dukes’ stage B2 and C and toxicities thereof in the adjuvant setting.Objective: To assess the outcome of concurrent chemoradiation in operated locally advanced treated cancer patients.Materials and Methods: In operated Dukes’ B2 and C rectal cancer patients, we conducted a prospective non-randomized study comprising of 40 patients between 2012 and 2014. Patients were treated with two hours protracted infusion of calcium leucovorin 500 mg/m2 on day 1 followed by 5-fluorouracil 500 mg/m2 on days 1 to 5 and repeated four weekly for total of six cycles. Radiotherapy of 45 Gray in 20 fractions was delivered concurrently with chemotherapy for first two cycles.Results: Combination of chemotherapy and radiotherapy in a concurrent setting appears to be more efficient in reducing local recurrence rates and improving survival than either modality alone. Toxicities with this schedule were mostly gastrointestinal mucositis, but no treatment interruption was needed.Conclusion: A combination of 5-fluorouracil and radiotherapy can be administered in operated locally advanced rectal cancer patients.J Enam Med Col 2015; 5(3): 139-144

Effect of adjuvant chemotherapy following pathologic complete response on long-term survival in rectal cancer: A propensity score matched analysis.

2017 ◽  
Vol 35 (4_suppl) ◽  
pp. 717-717 ◽  
Author(s):  
Ali Mokdad ◽  
Sergio Huerta ◽  
Rebecca M Minter ◽  
John C. Mansour ◽  
Michael A. Choti ◽  
...  
Keyword(s):  
Rectal Cancer ◽  
Overall Survival ◽  
Adjuvant Chemotherapy ◽  
Clinical Stage ◽  
Locally Advanced ◽  
Pathologic Complete Response ◽  
Rectal Adenocarcinoma ◽  
Complete Response ◽  
Term Survival

717 Background: The role of adjuvant chemotherapy following resection in patients with rectal cancer that achieve pathologic complete response (pCR) after neoadjuvant therapy is unclear. Current data have been limited by small sample size series. This study examined the impact of adjuvant chemotherapy following pCR on overall survival in a national cohort of patients. Methods: Patients with rectal adenocarcinoma were identified in the National Cancer Data Base between 2006 and 2012. Those with locally advanced tumor (clinical stage II or III) that achieved pCR (defined as ypT0N0 in surgical specimens) after neoadjuvant chemoradiotherapy (nCRT) were included in the study. We matched by propensity score patients that received adjuvant chemotherapy (ACT) and patients that did not receive postoperative treatment (no-ACT) controlling for demographic as well as perioperative patient and tumor characteristics. Overall survival was compared using a Cox proportional hazards model. Results: We identified 2,543 patients (ACT: 732, no-ACT: 1,811 patients) with resected locally advanced rectal adenocarcinoma that achieved pCR after nCRT. Among patients that received ACT, 711 were matched with 711 patients in the no-ACT group. Adjuvant chemotherapy was associated with improved overall survival compared to no-ACT (hazard ratio[HR] = 0.46, 95% confidence interval [CI] = 0.29 – 0.75). Overall survivals at 1, 3, and 5 years in the ACT and no-ACT groups were 100% vs 98% (P=0.1), 98% vs 94% (P<0.01), and 94% vs 89% (P<0.01), respectively. In subgroup analyses, adjuvant chemotherapy improved overall survival in patients with clinical stage II (HR = 0.43, 95% CI = 0.22 – 0.85) as well as stage III tumor (OR = 0.50, 95% CI = 0.26 – 0.98). Among patients that received adjuvant chemotherapy, there was no difference in overall survival between single agent and multiagent regimens (HR = 1.37, 95% CI = 0.57 – 3.29). Conclusions: Adjuvant chemotherapy may providea small long-term survival benefit in patients with resected locally advanced rectal cancer and pCR after nCRT.

A phase II study of induction PD-1 blockade in subjects with locally advanced mismatch repair-deficient rectal adenocarcinoma.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. TPS4123-TPS4123
Author(s):  
Andrea Cercek ◽  
Zsofia Kinga Stadler ◽  
Jenna L. Cohen ◽  
Jill A Weiss ◽  
Michelle F. Lamendola-Essel ◽  
...  
Keyword(s):  
Rectal Cancer ◽  
Mismatch Repair ◽  
Locally Advanced ◽  
Pathologic Complete Response ◽  
Rectal Adenocarcinoma ◽  
Complete Response ◽  
Advanced Rectal Cancer ◽  
Locally Advanced Rectal Cancer ◽  
Blood Draw ◽  
Rectal Cancers

TPS4123 Background: The treatment of patients with locally advanced rectal cancer includes total neoadjuvant therapy with chemotherapy, chemoradiation followed by surgery. While most rectal cancers respond to combination induction chemotherapy, patients with mismatch repair deficient (dMMR) or MSI-H tumors have a significantly higher chance of progression with this treatment regimen. dMMR or MSI-H tumors have shown remarkable responses to PD-1 blockade, but the effect of neoadjuvant checkpoint inhibition has not been well studied. In this trial we will determine the pathologic complete response rate (pCR) of neoadjuvant anti-PD-1 blockade followed by standard chemoradiation in dMMR or MSI-H locally advanced rectal cancer. We hypothesize that treatment naïve dMMR or MSI-H rectal cancers will achieve a robust clinical response to PD-1 blockade and that the total neodjuvant therapy with PD-1 blockade followed by chemoradiation will improve pCR rates. Methods: Eligible patients ≥18 years of age with Stage II (T3-4, N-) or Stage III (any T, N+) histologically confirmed dMMR or MSI-H (by NGS) rectal adenocarcinoma will be enrolled. Patients will receive TSR-042 (500mg IV) every 3 weeks for a maximum of 8 cycles (6 months of treatment). Imaging, internal endoscopic exam and ctDNA blood draw will be performed at 6 weeks and every 3 months during induction anti-PD-1 treatment. Adverse events and surgical complications will be graded according to the NCI CTCAE v5 and the Clavien-Dindo classification, respectively. Following neoadjuvant checkpoint blockade, patients will undergo conventional chemoradiotherapy followed by surgical resection. The primary endpoint is pathologic complete response compared with historical control in pMMR patients. Patients will be followed up every 6 months for assessment of disease-free survival for up to five years. Clinical trial information: NCT04165772 .

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