The main objective of this randomized and controlled trial is to determine whether the use of a proactive strategy, systemic neoadjuvant treatment (FOLFOX) with or without hyperthermic intraperitoneal chemoterapy (HIPEC) with mitomycin C followed by postoperative systemic adjuvant treatment, increases disease-free survival at 36 months in patients with locally advanced colon cancer compared to standard treatment. Therefore, a phase III, randomized, academic, multicenter, controlled trial will be conducted. Patients with locally advanced colon adenocarcinoma (cT4, cT3 with invasion \>5mm) Nx and no metastases will be included. Control group (n=361) will receive standard treatment (surgery and adjuvant chemotherapy FOLFOX x 12 based); Experimental group 1 (n=361) = Neoadjuvant chemotherapy (FOLFOX x6) + surgery (associating HIPEC) and FOLFOX x 6; Experimental group 2 (n=361): Neoadjuvant chemotherapy (FOLFOX x6) + surgery and FOLFOX x 6. Randomization will be 1:1:1, stratified and centralized. The primary outcome will be disease-free survival at 36 months. Secondary outcomes will be tumor regression rate, ctDNA negativization, peritoneal relapse rate at 36 months, pattern of relapse, toxicity, morbidity and overall survival. Considering the results obtained with these two independent strategies (FOLFOX and HIPEC), a new trial is justified in order to provide strong evidence for this proactive treatment. The aim is to combine both to obtain a better benefit, which opens the direct possibility of increasing the current percentage of disease-free survival. The results of this study will have important scientific and social impact, since is aimed at improving the outcomes of one subpopulation of patients with locally advanced colon cancer whose current treatment, is not enough to avoid the recurrence of disease.
Patients of both sexes, aged ≥18 years and ≤75 years (patients between 70-75 years old will be discussed in committee).
Adenocarcinoma of the colon, sigmoid colon and rectum-sigmoid junction that is cT4a/b according to the American Joint Committee on Cancer (AJCC) TNM eight edition. Pre-treatment diagnosis by imaging test (CT scan or MRI). High-risk cT3 with invasion into surrounding fat greater than 5mm may be included.
Nodal extension: cN0, the presence of cN1/2 according to AJCC TNM 8th edition is allowed as long as they can be resected. Pre-treatment diagnosis by imaging test (CT scan or MRI).
Metastatic extension: cM0. Patients with cM1 are not allowed to be included.
Presence of metastases (M1). If liver or peritoneal metastases are present at the time of surgery, the patient will be excluded from the study and treated according to the new stage.
Presence of un-resectability criteria in the pretreatment work-up, un-resectability will be discussed in MDT with expert oncologic surgeons.
Presence of microsatellite instability (dMMR).
Presence of deficit of DPD.
Parallel
Mitomycin (MM)
DrugMitomycin 30mg/m2/4 litres of perfusion liquid (dextrose 1.5%). Single intraoperative dose.
FOLFOX (5-fluorouracil, Leucovorin, Oxaliplatin)
DrugFOLFOX6 consists in oxaliplatin 85 mg/m2 iv. on day 1, 5FU 400 mg/m2 iv. in bolus followed by 2400 mg/m2 in a continuous infusion for 46 hours. Leucovorin: 400mg/m2 folinic acid (racemid dl) in a continuous infusion for 2 hours. Repeat every 2 weeks. Haematological recovery to ANC \>1.5x109/L and platelets \>75x109/L should be ensured prior to Day 1 of each 14-day cycle.
Cytoreductive surgery
Procedure/SurgeryCytoreductive surgery will be defined as complete tumour resection including oncologic colectomy and adjacent structures with suspicious of infiltration to achieve a R0, bilateral oophorectomy is recommended in post-menopausal women
Disease-free survival absolute
Absolute disease-free survival in months. The event will be defined by patient death from any cause or tumour recurrence
Disease-free survival probability
Tumour disease-free survival at 3 years of follow-up (%). The event will be defined by patient death from any cause or tumour recurrence up to 36 months after treatment.
Absolute Overall survival
The event will be defined by patient death from any cause
Probability overall survival
Probability of survival at 3 years. The event will be defined by patient death from any cause up to 36 months after treatment
Tumour regression
Tumour regression grade (Dworak's scale)
ctDNA rate
Negative rate of ctDNA after treatment and association of detected levels with tumour recurrence and survival.
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Maimónides Biomedical Research Institute of Córdoba
Lead sponsor
Spanish Cooperative Group for the Treatment of Digestive Tumours (TTD)
Collaborator
Spanish Association of Surgeons (AEC)
Collaborator
Sociedad Española de Oncología Quirúrgica
Collaborator
