Locally Advanced Rectal Carcinoma

Although standard neoadjuvant chemoradiotherapy (nCRT) for locally advanced rectal cancer (LARC) effectively reduces local recurrence, radiotherapy-related toxicities and surgical complications severely impair patients' quality of life, making a radiotherapy-free strategy urgently needed. However, chemotherapy alone yields a pathological complete response (pCR) rate of only 6.6%-15%, which is far from satisfactory. The pMMR/MSS subtype, accounting for 90% of rectal cancers, is "immune-cold" and shows almost no response to PD-1 monotherapy; nonetheless, chemotherapy can reshape the tumor immune microenvironment, and multiple studies have demonstrated that combining chemotherapy with PD-1 inhibitors (without radiotherapy) can elevate pCR rates to 26.8%-42.9%, yet further improvement remains desirable. A recent mechanistic study published in Cell Metabolism (2026) revealed that a single 16-hour fasting episode before treatment promotes isoleucine accumulation in the tumor microenvironment, which enhances CD8+T-cell cytotoxic function and reduces exhaustion through acetyl-CoA metabolism and epigenetic reprogramming, thereby significantly sensitizing PD-1 inhibitors-and this intervention is non-invasive, low-cost, and easily adoptable by patients. Based on the above evidence, we hypothesize that the neoadjuvant triple-combination regimen of "16-hour fasting + chemotherapy + PD-1 inhibitor" (radiotherapy-free) in pMMR/MSS locally advanced mid-to-low rectal cancer may further increase pCR rates and tumor regression, offering a novel, highly effective, and low-toxicity therapeutic option for LARC patients.

The aim of this clinical study is to increase the rate of pathological responses up to 70% by means of improved patient selection operated by a radiobiological index called ERI\_TCP and by an increase in the dose of radiotherapy in the final concomitant boost of preoperative radiochemotherapy treatment for rectal adenocarcinoma.

This phase I trial investigates how well short-course radiation therapy followed by combination chemotherapy works in treating patients with stage II-III rectal cancer. Radiation therapy uses high energy x-rays to kill tumor cells and shrink tumors. Chemotherapy drugs, such as leucovorin, fluorouracil, oxaliplatin, and capecitabine, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving short-course radiation therapy and combination chemotherapy may reduce the need for surgery and therefore improve quality of life.

The aim of this clinical trial is to compare triplet induction therapy (FOLFOXIRI) with doublet induction therapy (CAPOX/FOLFOX), followed by chemoradiotherapy and either surgery or a watch-and-wait approach, in patients with high-risk locally advanced rectal cancer. The primary questions it seeks to address are whether triplet induction therapy results in higher complete response rates, improved quality of life, and better long-term oncological outcomes compared to doublet induction therapy, despite the anticipated increased risk of toxicity.

Colorectal cancer of Mismatch Repair-proficient (pMMR)/ Microsatellite Stability (MSS) accounts for approximately 85% of all colorectal cancer patients, which might be insensitive to immunotherapy. Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Chemotherapy, such as CAPEOX regimen, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Celecoxib, a COX-2 inhibitor, can improve the immune microenvironment and have a potential to synergy with immunotherapy. Chemotherapy can improve the immunogenicity of cancer cells that might enhance the efficacy of immunotherapy. The aim of this study is to explore whether chemotherapy and cyclooxygenase (COX) inhibitors combined with anti-PD-1 monoclonal antibody (mAb) could improve efficacy for resectable colorectal cancer patient with the pMMR/MSS phenotype.

The goal of this clinical trial is to investigate if the addition of modulated electro-hyperthermia (mEHT) improves tumor down-staging and pathological response in adult patients (20 years and above) with locally advanced rectal adenocarcinoma (cT3N0M0 with high risk of recurrence, cT3N1-2M0, or cT4N0-2M0). The main questions it aims to answer are: * Does the addition of mEHT to the Total Neoadjuvant Therapy (TNT) regimen significantly increase the rate of tumor down-staging (ypT and ypN) compared to TNT alone? * Does the combination therapy improve the pathological complete response (pCR) rate and long-term outcomes (such as disease-free survival) compared to standard TNT? Researchers will compare participants randomized to receive Total Neoadjuvant Therapy (TNT) plus mEHT using the Oncotherm EHY-2030 device to participants receiving TNT alone to see if the adjunctive mEHT therapy enhances tumor regression and improves patient prognosis. Participants will be randomized (1:1) into one of the two groups and will undergo the following regimen: * Receive standard TNT, which includes 5-6 weeks of chemoradiotherapy (CRT) followed by 4-6 months of neoadjuvant chemotherapy. * Patients in the experimental group will receive mEHT twice a week during the CRT period.

The goal of this clinical trial is to compare the efficacy and safety of neoadjuvant chemoradiotherapy combined with tirelizumab compared with neoadjuvant chemoradiotherapy alone for neoadjuvant therapy in patients with locally advanced rectal cancer. The main questions it aims to answer are: To evaluate the efficacy and safety of neoadjuvant chemoradiotherapy combined with tirelizumab compared with neoadjuvant chemoradiotherapy alone for neoadjuvant therapy in patients with locally advanced rectal cancer To assess rectal or anal retention as well as quality of life. Participants will receive a long course of NCRT (50 Gy / 25f, capecitabine 850-1000 mg / m2, BID, PO, D1-D5, QW) within the first 5 weeks. In regard to tumor immunotherapy, enrolled patients will receive tislelizumab (200 mg, iv) on the first day at week 2,5, and 8 after initiation of radiotherapy. Thereafter, patients will be treated with two 14-day cycles of the CAPOX（Q 3 w; D1 oxaliplatin, 130mg/m2,iv.gtt; D1-D14, capecitabine, 850-1000mg / m2, BID, PO）regimen. Two CAOPX regimens were treated one week apart.

The goal of this observational study is to evaluate the prognostic significance of radiological markers, including the Likert Score derived from diffusion-weighted MRI (DWI), in patients with locally advanced rectal cancer (LARC) treated with total neoadjuvant therapy (TNT). Specifically, the study investigates the association between the Likert Score on restaging MRI and key clinical outcomes, such as overall survival (OS) and time to progression (TTP). Furthermore, it examines the impact of other MRI-derived markers-extramural venous invasion (EMVI), tumor deposits (TDs), and mesorectal fascia invasion (MFI)-on disease progression and patient prognosis. This study retrospectively analyzes 179 patients who underwent TNT followed by surgery between 2009 and 2022. Participants were required to have pre- and post-treatment MRI scans. MRI imaging data and patient outcomes, including overall survival (OS) and time to progression (TTP), will be analyzed over a follow-up period extending until July 31, 2024. Findings from this study may help refine MRI-based prognostic tools for personalized treatment strategies in rectal cancer.

This is a single arm feasibility study of exercise for improving long- course neoadjuvant chemoradiotherapy (NACRT) efficacy in people diagnosed with locally advanced rectal cancer. The study aims to recruit up to 30 patients from the Queen's Centre for Oncology and Haematology of Castle Hill Hospital, Cottingham, diagnosed with locally advanced rectal cancer. Consenting patients will be provided with an 11-week course of structured aerobic exercises and resistance training in the periods before, during and after their chemoradiotherapy treatment. The patients will be followed up for 6 months post long course neoadjuvant chemoradiotherapy (NACRT), with a total of 3 assessment periods.

Rectal cancer still remains one of the most popular tumors, however, distance metastasis still remains as high as 30% and the long-term survival outcomes are still unsatisfying. The recent conception of total neoadjuvant therapy and immune therapy is becoming popular and the oncologic effects are encouraging, especially in terms of circulating tumor DNA (ctDNA), the prognostic value of ctDNA has been demonstrated by our prior study. This study will carry out accurate ctDNA-guided neoadjuvant therapy on the basis of previous studies of the research group, and give appropriate treatment plans and treatment intensity to patients with different disease degrees. At the same time, combined with the latest progress in clinical diagnosis and treatment, the potential beneficiaries of immunotherapy were screened scientifically, and the combined immunotherapy was implemented accordingly.

The goal of this prospective phase II feasibility study is to evaluate two additional local treatment options in rectal cancer patients with a good clinical response after neoadjuvant (chemo)radiation: contact x-ray brachytherapy versus extension of the waiting interval with or without local excision, and to investigate which rate of organ preservation can be achieved.