Evaluating the Impact of GLP-1 Receptor Agonists With Total Neoadjuvant Therapy in Rectal Cancer

Summary

The goal of this clinical trial is to see if adding a weight loss medication (GLP-1 receptor drug) to patients with an increased BMI receiving treatment for rectal cancer prior to surgery (total neoadjuvant chemoradiotherapy) improves cancer outcomes. The main questions it aims to answer is 1. Does the drug increase weight loss in rectal cancer patients with a high BMI 2. Does the drug improve response rates to chemotherapy and radiotherapy 3. Does the drug improve survival outcomes and if cancer returns Researchers will compare this drug in one group against a group of patients receiving preoperative total neoadjuvant chemoradiotherapy without the drug Patients will be required to 1\) take the GLP-1 receptor agonist drug during TNT or just having TNT alone as per standard hospital protocols Body weight will be measured at three predefined time points: 1. Baseline: Prior to initiation of semaglutide or TNT 2. Pre-TNT: Start of TNT (for the intervention arm, this is 4 weeks after semaglutide initiation) 3. Post-TNT: Within 7 days following completion of TNT and prior to definitive surgery Patients will complete their treatment and go on to have surgery as per standard methods for treating rectal cancer

Timeline

Start

2026-04

Primary completion

2028-09

Completion

2028-09

Publications

• Results Kazi T, McKechnie T, Lee Y, Alsayari R, Talwar G, Doumouras A, Hong D, Eskicioglu C. The impact of obesity on postoperative outcomes following surgery for colorectal cancer: analysis of the National Inpatient Sample 2015-2019. ANZ J Surg. 2024 Jul-Aug;94(7-8):1305-1312. doi: 10.1111/ans.19135. Epub 2024 Jun 18.
• Results Martin-Carnicero A, Ramalle-Gomara E, Rubio-Mediavilla S, Alonso-Lago M, Zorrilla-Larraga M, Manrique-Abos I, de Las Heras-Duena ME, Larrayoz IM, Martinez A. Prognostic and Predictive Biomarkers in Patients with Locally Advanced Rectal Cancer (LARC) Treated with Preoperative Chemoradiotherapy. J Clin Med. 2022 Oct 16;11(20):6091. doi: 10.3390/jcm11206091.
• Results Dizdarevic E, Hansen TF, Jakobsen A. The Prognostic Importance of ctDNA in Rectal Cancer: A Critical Reappraisal. Cancers (Basel). 2022 Apr 30;14(9):2252. doi: 10.3390/cancers14092252.
• Results Chen C, Douglas MP, Ragavan MV, Phillips KA, Jansen JP. Clinical Validity and Utility of Circulating Tumor DNA (ctDNA) Testing in Advanced Non-small Cell Lung Cancer (aNSCLC): A Systematic Literature Review and Meta-analysis. Mol Diagn Ther. 2024 Sep;28(5):525-536. doi: 10.1007/s40291-024-00725-x. Epub 2024 Aug 2.
• Results Ryan EJ, Creavin B, Sheahan K. Delivery of Personalized Care for Locally Advanced Rectal Cancer: Incorporating Pathological, Molecular Genetic, and Immunological Biomarkers Into the Multimodal Paradigm. Front Oncol. 2020 Aug 14;10:1369. doi: 10.3389/fonc.2020.01369. eCollection 2020.
• Results Silverii GA, Marinelli C, Bettarini C, Del Vescovo GG, Monami M, Mannucci E. GLP-1 receptor agonists and the risk for cancer: A meta-analysis of randomized controlled trials. Diabetes Obes Metab. 2025 Aug;27(8):4454-4468. doi: 10.1111/dom.16489. Epub 2025 May 29.
• Results Ochiai K, Bhutiani N, Ikeda A, Uppal A, White MG, Peacock O, Messick CA, Bednarski BK, You YN, Skibber JM, Chang GJ, Konishi T. Total Neoadjuvant Therapy for Rectal Cancer: Which Regimens to Use? Cancers (Basel). 2024 May 31;16(11):2093. doi: 10.3390/cancers16112093.
• Results Johnson GGRJ, Park J, Helewa RM, Goldenberg BA, Nashed M, Hyun E. Total neoadjuvant therapy for rectal cancer: a guide for surgeons. Can J Surg. 2023 Apr 21;66(2):E196-E201. doi: 10.1503/cjs.005822. Print 2023 Mar-Apr.
• Results Lin A, Ding Y, Li Z, Jiang A, Liu Z, Wong HZH, Cheng Q, Zhang J, Luo P. Glucagon-like peptide 1 receptor agonists and cancer risk: advancing precision medicine through mechanistic understanding and clinical evidence. Biomark Res. 2025 Mar 27;13(1):50. doi: 10.1186/s40364-025-00765-3.
• Results Miousse IR. GLP-1 receptor agonists in the context of cancer: the road ahead. Am J Physiol Cell Physiol. 2025 Jun 1;328(6):C1822-C1828. doi: 10.1152/ajpcell.00245.2025. Epub 2025 Apr 26.
• Results Wilding JPH, Batterham RL, Calanna S, Davies M, Van Gaal LF, Lingvay I, McGowan BM, Rosenstock J, Tran MTD, Wadden TA, Wharton S, Yokote K, Zeuthen N, Kushner RF; STEP 1 Study Group. Once-Weekly Semaglutide in Adults with Overweight or Obesity. N Engl J Med. 2021 Mar 18;384(11):989-1002. doi: 10.1056/NEJMoa2032183. Epub 2021 Feb 10.
• Results Wang L, Xu R, Kaelber DC, Berger NA. Glucagon-Like Peptide 1 Receptor Agonists and 13 Obesity-Associated Cancers in Patients With Type 2 Diabetes. JAMA Netw Open. 2024 Jul 1;7(7):e2421305. doi: 10.1001/jamanetworkopen.2024.21305.
• Temperley HC, Coalter M, Creavin B, Jordan P, Hogan A, O'Sullivan J, O'Shea D, McCormick PH, Harrold E, Kelly ME. Evaluating the impact of GLP-1 receptor agonists in combination with total neoadjuvant therapy for locally advanced rectal cancer. Br J Surg. 2026 Apr 9;113(4):znag029. doi: 10.1093/bjs/znag029.

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Indications