Efficacy and safety of conventional neoadjuvant therapy versus total neoadjuvant therapy in older patients with locally advanced rectal cancer: a multicentre, open-label, randomised pragmatic clinical trial

Prior treatment

• Extensive growth into cranial part of the sacrum (above S2/3 junction) or the lumbosacral nerve roots indicating that surgery will never be possible even if substantial tumour down-sizing is achieved.
• Patients with a prior or concurrent malignancy whose natural history or treatment has the potential to interfere with the safety or efficacy assessment.
• Any previous treatment for rectal cancer
• Any contraindication to pelvic irradiation as evaluated by the investigator.
• Known hypersensitivity reactions to the study drugs or to any excipients, premedications or non-investigational medicinal products or concomitant medications.

Other illness

• Clinically significant (i.e., active) cardiovascular disease: cerebral vascular accident/stroke, myocardial infarction, unstable angina, congestive heart failure (grade III or IV as classified by the New York Heart Association), or serious cardiac arrhythmia requiring medication medication within the past 6 months.
• Presence of metastatic disease or recurrent rectal tumour.
• Significant medical, neuro-psychiatric, or surgical condition, currently uncontrolled by treatment, which, in the principal investigator’s opinion, may interfere with completion of the study.
• Any investigational anti-cancer therapy other than the protocol specified therapies (participation in other prospective studies which do not imply any specific intervention may be allowed after discussion with the Study Chair).

Other

• Use of brivudine, sorivudine or their chemically related analogues.
• Complete dihydropyrimidine dehydrogenase (DPD) deficiency.
• Presence of grade ≥2 peripheral neuropathy according to the Common Toxicity Criteria for Adverse Events (CTCAE) v.5.0.

• Age ≥ 70 years old
• Signed Informed Consent form (ICF) obtained prior to any study related procedure.
• Male subjects with partners of childbearing potential must agree to use condom during the course of this study and for at least 6 months after the last administration of study drugs.
• ECOG performance status (PS): ≤1 if age > 75 years old, ≤2 if age ≤ 75 years old
• Histologically or cytologically confirmed adenocarcinoma of the rectum
• Distal border of the tumour below the peritoneal reflection and within 15 cm of the anal verge
• Operable stage III or high-risk stage II rectal cancer (high-risk tumours defined as those having ≥1 of the following features: T4, mesorectal fascia (MRF) involvement/threatening [i.e.,tumour within 1 mm of the MRF], extramural venous invasion). Patient with involvement of lateral pelvic lymph nodes are also eligible.
• Adequate bone marrow function as defined below: - Absolute neutrophil count ≥1,500/µL - Haemoglobin ≥9 g/dL - Platelets ≥100,000/µL
• Adequate liver function as defined below: - Serum total bilirubin ≤1.5 x ULN. In case of known Gilbert’s syndrome <3xUNL is allowed - AST (SGOT) and ALT (SGPT) ≤2.5 x ULN - Alkaline phosphatase ≤2.5 x ULN
• Adequate renal function as defined by estimated glomerular filtration rate (GFR) ≥30 mL/min/1.73m² (according to the CKD-EPI 2021 equation)
• Absence of clinical conditions that in the opinion of the investigator, would contraindicate neoadjuvant therapy and/or surgery.