Efficacy and Safety of Conventional Neoadjuvant Therapy Versus Total Neoadjuvant Therapy in Older Patients With Locally Advanced Rectal Cancer

Inclusion Criteria:

1. Age ≥ 70 years old

2. ECOG performance status (PS):

• ≤1 if age > 75 years old

• ≤2 if age ≤ 75 years old

3. Histologically or cytologically confirmed adenocarcinoma of the rectum

4. Distal border of the tumour below the peritoneal reflection and within 15 cm of theanal verge

5. Operable stage III or high-risk stage II rectal cancer (high-risk tumours defined asthose having ≥1 of the following features: T4, mesorectal fascia (MRF)involvement/threatening [i.e.,tumour within 1 mm of the MRF], extramural venousinvasion). Patient with involvement of lateral pelvic lymph nodes are also eligible.

6. Adequate bone marrow function as defined below:

• Absolute neutrophil count ≥1,500/µL

• Haemoglobin ≥9 g/dL

• Platelets ≥100,000/µL

7. Adequate liver function as defined below:

• Serum total bilirubin ≤1.5 x ULN. In case of known Gilbert's syndrome <3xUNL isallowed

• AST (SGOT) and ALT (SGPT) ≤2.5 x ULN

• Alkaline phosphatase ≤2.5 x ULN

8. Adequate renal function as defined by estimated glomerular filtration rate (GFR) ≥30mL/min/1.73m² (according to the CKD-EPI 2021 equation).

9. Absence of clinical conditions that in the opinion of the investigator, wouldcontraindicate neoadjuvant therapy and/or surgery.

10. Signed Informed Consent form (ICF) obtained prior to any study related procedure.

11. Male subjects with partners of childbearing potential must agree to use condomduring the course of this study and for at least 6 months after the lastadministration of study drugs.

Exclusion Criteria:

1. Extensive growth into cranial part of the sacrum (above S2/3 junction) or thelumbosacral nerve roots indicating that surgery will never be possible even ifsubstantial tumour down-sizing is achieved.

2. Presence of metastatic disease or recurrent rectal tumour.

3. Presence of grade ≥2 peripheral neuropathy according to the Common Toxicity Criteriafor Adverse Events (CTCAE) v.5.0.

4. Significant medical, neuro-psychiatric, or surgical condition, currentlyuncontrolled by treatment, which, in the principal investigator's opinion, mayinterfere with completion of the study.

5. Any contraindication to pelvic irradiation as evaluated by the investigator.

6. Known hypersensitivity reactions to the study drugs or to any excipients,premedications or non-investigational medicinal products or concomitant medications.

7. Any investigational anti-cancer therapy other than the protocol specified therapies (participation in other prospective studies which do not imply any specificintervention may be allowed after discussion with the Study Chair).

8. Patients with a prior or concurrent malignancy whose natural history or treatmenthas the potential to interfere with the safety or efficacy assessment.

9. Clinically significant (i.e., active) cardiovascular disease: cerebral vascularaccident/stroke, myocardial infarction, unstable angina, congestive heart failure (grade III or IV as classified by the New York Heart Association), or seriouscardiac arrhythmia requiring medication within the past 6 months.

10. Complete dihydropyrimidine dehydrogenase (DPD) deficiency.

11. Any previous treatment for rectal cancer.

12. Use of brivudine, sorivudine or their chemically related analogues.