Neoadjuvant FOLFOXIRI prior to chemoradiotherapy for high-risk (“ugly”) locally advanced rectal cancer: study protocol of a single-arm, multicentre, open-label, phase II trial (MEND-IT)

Abstract

Background The presence of mesorectal fascia (MRF) invasion, grade 4 extramural venous invasion (EMVI), tumour deposits (TD) or extensive or bilateral extramesorectal (lateral) lymph nodes (LLN) on MRI has been suggested to identify patients with indisputable, extensive locally advanced rectal cancer (LARC), at high risk of treatment failure. The aim of this study is to evaluate whether or not intensified chemotherapy prior to neoadjuvant chemoradiotherapy improves the complete response (CR) rate in these patients. Methods This multicentre, single-arm, open-label, phase II trial will include 128 patients with non-metastatic high-risk LARC (hr-LARC), fit for triplet chemotherapy. To ensure a study population with indisputable, unfavourable prognostic characteristics, hr-LARC is defined as LARC with on baseline MRI at least one of the following characteristics; MRF invasion, EMVI grade 4, enlarged bilateral or extensive LLN at high risk of an incomplete resection, or TD. Exclusion criteria are the presence of a homozygous DPD deficiency, distant metastases, any chemotherapy within the past 6 months, previous radiotherapy within the pelvic area precluding standard chemoradiotherapy, and any contraindication for the planned treatment. All patients will be planned for six two-weekly cycles of FOLFOXIRI (5-fluorouracil, leucovorin, oxaliplatin and irinotecan) prior to chemoradiotherapy (25 × 2 Gy or 28 × 1.8 Gy with concomitant capecitabine). A resection will be performed following radiological confirmation of resectable disease after the completion of chemoradiotherapy. A watch and wait strategy is allowed in case of a clinical complete response. The primary endpoint is the CR rate, described as a pathological CR or a sustained clinical CR one year after chemoradiotherapy. The main secondary objectives are long-term oncological outcomes, radiological and pathological response, the number of resections with clear margins, treatment-related toxicity, perioperative complications, health-related costs, and quality of life. Discussion This trial protocol describes the MEND-IT study. The MEND-IT study aims to evaluate the CR rate after intensified chemotherapy prior to concomitant chemoradiotherapy in a homogeneous group of patients with locally advanced rectal cancer and indisputably unfavourable characteristics, defined as hr-LARC, in order to improve their prognosis. Trial registration Clinicaltrials.gov: NCT04838496, registered on 02–04-2021 Netherlands Trial Register: NL9790. Protocol version Version 3 dd 11–4-2022.

Post-operative complications following dose adaptation of intra-operative electron beam radiation therapy in locally advanced or recurrent rectal cancer

“…Although data on toxicity due to pre-operative chemotherapy is lacking in LRRC, RAPIDO trial with LARC patients reported no increase in post-operative complications after 6 cycles of CAPOX [ 7 ]. Moreover, in the current study, the proportion of patients treated with induction chemotherapy in LARC showed an increasing trend (44% vs. 60%, p = 0.129), in part due to MEND-IT trial investigating the benefit of FOLFOXIRI induction chemotherapy in LARC [ 24 ]. Nevertheless, in patients with LARC, no increase in toxicity was observed.…”

Implementation of an Enhanced Recovery after Surgery Protocol in Advanced and Recurrent Rectal Cancer Patients after beyond Total Mesorectal Excision Surgery: A Feasibility Study

“…LARCs were standardly treated with neoadjuvant (chemo)radiotherapy, whereas LRRC patients underwent neoadjuvant chemoradiotherapy or chemo re-irradiation in the case of previous pelvic irradiation [ 14 ]. Some patients received induction chemotherapy before chemoradiotherapy [ 15 , 16 ]. After neoadjuvant treatment, a bTME was performed.…”

Recent Advancements, Limitations, and Future Perspectives of the use of Personalized Medicine in Treatment of Colon Cancer

“… 67 Chemotherapeutic combinations commonly used are FOLFOX, a combination of 5-FU, leucovorin, and oxaliplatin; FOLFOXIRI, a combination of 5-FU, leucovorin, irinotecan, and oxaliplatin; and FOLFIRI, a combination of 5-FU, leucovorin, and irinotecan. 68 – 70 …”