Personalising and Refining Neo-adjuvant Chemotherapy in Locally Advanced but Resecable Colon Cancer in the Elderly of 70 Years Old or More

Inclusion Criteria:

• Biopsy-confirmed adenocarcinoma of the colon (or upper rectum if too high forradiotherapy), high-grade dysplasia is not acceptable ,

• Patients with synchronous tumors are eligible, if the most advanced tumor meets thecriteria above

• Radiological stage T3/T4 and N0/N1/N2 and M0

• Patient eligible for curative surgery (without the need for of chemotherapy)

• No clinical, radiological and colonoscopy evidence of bowel obstruction

• Age ≥ 70 at the time of registration

• pMMR/MSS tumour status

• Fit to receive 6 weeks (3 courses) of NAC with FOLFOX (either full or 80% of FOLFOXdose) and surgery, as assessed by a colon cancer specialist or geriatric oncologist (if available on site).

• Uracilemia <16 ng/ml.

• Adequate full blood count: WBC >3.0 x109/l; platelets >100 x109/l and neutrophils ≥ 1.5 x x109/l Anaemia (Hb < 10.0 g/dl) is not an exclusion, but should be correctedby transfusion prior to surgery and chemotherapy. If Hb remains low despitetransfusions, surgery and chemotherapy can be given according to the decision of thesurgical and oncology teams.

• Serum electrolytes: Ca2+ > 2.1 mmol/L, Mg2+ > 0.65 mmol/L, K+> 3.4 mmol/LAdequaterenal biochemistry: GFR >50 ml/min as assessed by local standards

• Adequate hepatobiliary function:

• bilirubin < 1.5 x ULN (Patients with Gilbert's syndrome who have raisedbilirubin but otherwise normal liver function tests are eligible for the studyif bilirubin < 3 x ULN)

• AST/ALT < 2.5 x ULN

• Patient able to understand and willing to provide written informed consent for thestudy

• Patient affiliated to a social security scheme

Exclusion Criteria:

• Any patient for whom radiotherapy is advised by the MDT

• Strong evidence of distant metastases or peritoneal nodules (cM1), However, caseswith indeterminate abnormalities should be managed and investigated as per standardlocal MDT procedures and can be considered for trial entry if the MDT opinion isthat these are considered most likely to be benign.

• Peritonitis (secondary to perforated tumour)

• T1-T2

• Serious medical comorbidity, as assessed by leading clinician (such as uncontrolledangina)

• Any other malignant disease within the preceding 5 years with the exception ofnon-melanomatous skin cancer, carcinoma in situ and early stage disease with arecurrence risk <10%

• Known dMMR/ MSI-H tumour status

• Have a peripheral sensitive neuropathy with functional impairment (≥ grade 2according to NCI-CTCAE v5.0)

• Recent (within four weeks prior to randomisation) or concomitant treatment withbrivudine, sorivudine or their chemically related analogues

• Person under guardianship, curatorship, and safeguard of justice or person deprivedof liberty

• Impossibility to undergo the medical follow-up of the trial for geographical, socialor psychological reasons

• Known hypersensitivity to the active substance of the trial treatments or to any ofthe excipients

• Patient with poor nutritional status at appreciation by each clinician

• bone marrow hypoplasia

• Potentially severe infection within1 month before NAC

• Patients who have received live attenuated vaccines (yellow fever, varicella,shingles, measles, mumps, rubella, tuberculosis, rotavirus, influenza) within 1month before NAC

• Any case of clinically significant active heart disease or myocardial infarctionwithin 6 months,

• Any chronic condition not controlled in the last 6 months: Liver failure, renalfailure, respiratory failure,

• QT/QTc interval > 450 msec for men and > 470 msec for women

• Known Pernicious anaemia or other anaemias due to vitamin B12 deficiency