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).

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. 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. 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. Clinicaltrials.gov: NCT04838496 , registered on 02-04-2021 Netherlands Trial Register: NL9790. Version 3 dd 11-4-2022.

van den Berg K ，Schaap DP ，Voogt ELK ，Buffart TE ，Verheul HMW ，de Groot JWB ，Verhoef C ，Melenhorst J ，Roodhart JML ，de Wilt JHW ，van Westreenen HL ，Aalbers AGJ ，van 't Veer M ，Marijnen CAM ，Vincent J ，Simkens LHJ ，Peters NAJB ，Berbée M ，Werter IM ，Snaebjornsson P ，Peulen HMU ，van Lijnschoten IG ，Roef MJ ，Nieuwenhuijzen GAP ，Bloemen JG ，Willems JMWE ，Creemers GJM ，Nederend J ，Rutten HJT ，Burger JWA ... -  《BMC CANCER》

Total neoadjuvant treatment to increase the clinical complete response rate for distal locally advanced rectal cancer (TESS): A study protocol of a prospective, open-label, multicenter, single-arm, phase 2 trial.

Standard treatment of locally advanced rectal cancer (LARC) was neoadjuvant chemoradiotherapy (CRT), followed by total mesorectal excision (TME). Total neoadjuvant treatment (TNT), a new concept, attempts to deliver both systemic chemotherapy and neoadjuvant CRT prior to surgery. Patients treated with neoadjuvant chemotherapy were more likely to show higher tumor regression. The objective of this trial was to increase complete clinical rate (cCR) for LARC patients by optimizing tumor response, using TNT regimen as compared to conventional chemoradiotherapy. TESS, a prospective, open-label, multicenter, single-arm, phase 2 study, is underway. Main inclusion criteria include cT3-4aNany or cT1-4aN+ rectal adenocarcinoma aged 18-70y; Eastern Cooperative Oncology Group (ECOG) performance 0-1; location ≤5 cm from anal verge. Ninety-eight patients will receive 2 cycles of neoadjuvant chemotherapy Capeox (capecitabine + oxaliplatin) before, during, and after radiotherapy 50Gy/25 fractions, before TME (or other treatment decisions, such as Watch and Wait strategy) and adjuvant chemotherapy capecitabine 2 cycles. Primary endpoint is the cCR rate. Secondary endpoints include ratio of sphincter preservation strategy; pathological complete response rate and tumor regression grade distribution; local recurrence or metastasis; disease-free survival; locoregional recurrence-free survival; acute toxicity; surgical complications; long-term anal function; late toxicity; adverse effect, ECOG standard score, and quality of life. Adverse events are graded per Common Terminology Criteria for Adverse Events V5.0. Acute toxicity will be monitored during antitumor treatment, and late toxicity will be monitored for 3 years from the end of the first course of antitumor treatment. The TESS trial aims to explore a new TNT strategy, which is expected to increase the rate of cCR and sphincter preservation rate. This study will provide new options and evidence for a new sandwich TNT strategy in patients with distal LARC.

Liu S ，Wang X ，Zhuang Y ，Bai S ，Wu X ，Ye Y ，Luo H ，Yu H ，Wang Q ，Chang H ，Zeng Z ，Cai P ，Pan Z ，Gao Y ，Chen G ，Xiao W ... -  《Cancer Medicine》

Neoadjuvant chemotherapy with modified FOLFOXIRI for locally advanced rectal cancer to transform effectively EMVI and MRF from positive to negative: results of a long-term single center phase 2 clinical trial.

Chemoradiotherapy (CRT) remains the standard treatment for locally advanced rectal cancer (LARC). This phase 2 clinical trial was designed to evaluate the efficacy and safety of neoadjuvant triplet chemotherapy with mFOLFOXIRI (folinic acid, 5-fluorouracil, oxaliplatin, and irinotecan) in LARC. The patients with LARC (the lower edge more than 5 cm from the anal verge) received up to 5 cycles of mFOLFOXIRI. MRI was performed to assess the baseline and postchemotherapy TN stage. Radical resection was performed within 4-6 weeks from the last dose of chemotherapy if the tumor shrank or remained stable. Adjuvant chemotherapy with mFOLFOX6 or XELOX was recommended. Postoperative radiation was planned for R1 resection, ypT4b, ypN2 and a positive CRM. The primary endpoint was the pathological complete response (pCR) rate. From February 2016 to March 2019, 50 patients were enrolled. Forty-eight (96%) were clinically node-positive, 28 (56.5%) with MRF invasion and 39 (78.4%) were EMVI positive. The median cycle of neoadjuvant mFOLFOXIRI chemotherapy was 5 (range,1-5). A total of 46/50 (92%) patients underwent total mesorectal excision (TME) surgery, all with R0 resection. The pCR rate was 4.3% (2/46). Twenty-three of 46 (50%) patients with cN + achieved a pathological node-negative status. The proportions of pathologically positive CRM and EMVI were 2.2% and 34.7%, respectively. Adjuvant radiotherapy was given to 14/46 (30.4%) patients. The most common Grade 3 or > toxicities included neutrocytopenia (50%), leukopenia (14%) and diarrhea (12%) during the neoadjuvant chemotherapy period. Clinically meaningful postoperative complications included pneumonia (n = 1), pelvic infection (n = 1) and anastomotic fistula (n = 1). With a median follow-up time of 51.2 months, local recurrences and distant metastases were confirmed in 3 (6.5%) and 9 (19.6%) of cases, respectively. The 3-year disease free survival (DFS) and overall survival (OS)rates were 75.8% and 86.8%. Neoadjuvant chemotherapy with mFOLFOXIRI yielded a significant down-staging effect and seemed to be effective in eliminating EMVI and transforming the positive MRF to negative in LARC. The survival results are promising. The long-term follow-up showed promising DFS and OS rates accompanied by a favorable safety profile. ClinicalTrials.gov identifier: NCT03443661, 23/02/2018.

Zhang W ，Zhou H ，Jiang J ，Zhu Y ，Zou S ，Jiang L ，Tang Y ，Liang J ，Sun Y ，Jiang Z ，Qu W ，Li Y ，Zhou A ... -  《BMC CANCER》

Induction chemotherapy followed by chemoradiotherapy versus chemoradiotherapy alone as neoadjuvant treatment for locally recurrent rectal cancer: study protocol of a multicentre, open-label, parallel-arms, randomized controlled study (PelvEx II).

A resection with clear margins (R0 resection) is the most important prognostic factor in patients with locally recurrent rectal cancer (LRRC). However, this is achieved in only 60 per cent of patients. The aim of this study is to investigate whether the addition of induction chemotherapy to neoadjuvant chemo(re)irradiation improves the R0 resection rate in LRRC. This multicentre, international, open-label, phase III, parallel-arms study will enrol 364 patients with resectable LRRC after previous partial or total mesorectal resection without synchronous distant metastases or recent chemo- and/or radiotherapy treatment. Patients will be randomized to receive either induction chemotherapy (three 3-week cycles of CAPOX (capecitabine, oxaliplatin), four 2-week cycles of FOLFOX (5-fluorouracil, leucovorin, oxaliplatin) or FOLFORI (5-fluorouracil, leucovorin, irinotecan)) followed by neoadjuvant chemoradiotherapy and surgery (experimental arm) or neoadjuvant chemoradiotherapy and surgery alone (control arm). Tumours will be restaged using MRI and, in the experimental arm, a further cycle of CAPOX or two cycles of FOLFOX/FOLFIRI will be administered before chemoradiotherapy in case of stable or responsive disease. The radiotherapy dose will be 25 × 2.0 Gy or 28 × 1.8 Gy in radiotherapy-naive patients, and 15 × 2.0 Gy in previously irradiated patients. The concomitant chemotherapy agent will be capecitabine administered twice daily at a dose of 825 mg/m2 on radiotherapy days. The primary endpoint of the study is the R0 resection rate. Secondary endpoints are long-term oncological outcomes, radiological and pathological response, toxicity, postoperative complications, costs, and quality of life. This trial protocol describes the PelvEx II study. PelvEx II, designed as a multicentre, open-label, phase III, parallel-arms study, is the first randomized study to compare induction chemotherapy followed by neoadjuvant chemo(re)irradiation and surgery with neoadjuvant chemo(re)irradiation and surgery alone in patients with locally recurrent rectal cancer, with the aim of improving the number of R0 resections.

PelvEx Collaborative 《BJS Open》

Upfront radical surgery with total mesorectal excision followed by adjuvant FOLFOX chemotherapy for locally advanced rectal cancer (TME-FOLFOX): an open-label, multicenter, phase II randomized controlled trial.

Lee JB ，Kim HS ，Jung I ，Shin SJ ，Beom SH ，Chang JS ，Koom WS ，Kim TI ，Hur H ，Min BS ，Kim NK ，Park S ，Jeong SY ，Baek JH ，Kim SH ，Lim JS ，Lee KY ，Ahn JB ... -  《Trials》