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

The SHAPERS study is a multicentre, open-label, randomised, pragmatic clinical trial, comparing standard-of-care neoadjuvant treatment options for older (i.e., ≥70 years) subjects with high-risk stage II and stage III rectal cancer.

Subjects meeting all eligibility criteria will be randomised in a 1:1 ratio to either the conventional arm or the TNT arm (The study design is shown in figure 3.1 and 3.2).

Conventional arm consists of:

• SCRT (5 fractions of 5 Gy), followed by
• Surgery (according to the principles of TME) or watch & wait, followed by
• Optional adjuvant chemotherapy OR
• LCCRT (25-28 fractions of 1.8-2.0 Gy each +/- a boost to the primary tumour and involved lymph nodes, for a total of 50-56 Gy of radiation combined with either continuous infusion fluorouracil or capecitabine) followed by
• Surgery (according to the principles of TME) or watch & wait, followed by
• Optional adjuvant chemotherapy

TNT arm Different treatment regimens can be used in the TNT arm including Rapido, Rapido light, OPRA INCT-CRT or OPRA CRT-CNCT. The regimen to use will be decided by the investigator and will need to be declared before randomisation. No switch between regimens is allowed during the study treatment period.

The Rapido regimen consists of:

• SCRT (5 fractions of 5 Gy), followed by
• Up to 18 weeks of oxaliplatin based chemotherapy (mFOLFOX6 or CAPOX), followed by
• Surgery (according to the principle of TME) or "watch & wait".

The Rapido light regimen consists of:

• SCRT (5 fractions of 5 Gy), followed by
• Up to 12 weeks of oxaliplatin based chemotherapy (mFOLFOX6 or CAPOX), followed by
• Surgery (according to the principle of TME) or "watch & wait".

The OPRA with induction chemotherapy (INCT-CRT) regimen, consists of:

• Up to 16 weeks of oxaliplatin-based chemotherapy (mFOLFOX6 or CAPOX), followed by
• CRT (25-28 fractions of 1.8-2.0 Gy each +/- a boost to the primary tumour and involved lymph nodes, for a total of 50-56 Gy of radiation combined with either continuous infusion fluorouracil or capecitabine) followed by
• Surgery (according to the principle of TME) or "watch & wait"

The OPRA with consolidation chemotherapy (CRT-CNCT) regimen consists of:

• CRT (25-28 fractions of 1.8-2.0 Gy each +/- a boost to the primary tumour and involved lymph nodes, for a total of 50-56 Gy of radiation combined with either continuous infusion fluorouracil or capecitabine) followed by
• Up to 16 weeks of oxaliplatin-based chemotherapy (mFOLFOX6 or CAPOX), followed by
• Surgery (according to the principle of TME) or "watch & wait".

Inclusion criteria

• Age ≥ 70 years old
• 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.
• 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.

Exclusion criteria

• 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.
• Presence of metastatic disease or recurrent rectal tumour.
• Presence of grade ≥2 peripheral neuropathy according to the Common Toxicity Criteria for Adverse Events (CTCAE) v.5.0.
• 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 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.
• 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).
• Patients with a prior or concurrent malignancy whose natural history or treatment has the potential to interfere with the safety or efficacy assessment.
• 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 within the past 6 months.
• Complete dihydropyrimidine dehydrogenase (DPD) deficiency.
• Any previous treatment for rectal cancer.
• Use of brivudine, sorivudine or their chemically related analogues.