Efficacy and Safety of SCRT Versus TNT in Older Patients With Locally Advanced Rectal Cancer

Study Overview
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Brief Summary
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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.

Detailed Description
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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 SCRT arm or the TNT arm (The study design is shown in figure 3.1 and 3.2). SCRT arm: The SCRT 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 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.

Official Title
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Efficacy and Safety of Short-course Radiotherapy (SCRT) Versus Total Neoadjuvant Therapy in Older Patients With Locally Advanced Rectal Cancer: a Multicentre, Open-label, Randomised Pragmatic Clinical Trial

Conditions
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Locally Advanced Rectal Cancer, Older People

Intervention / Treatment
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* Radiation: Short course radiotherapy
* Drug: Adjuvant chemotherapy (optional)
* Procedure: Total mesorectal excision
* Combination Product: Total neoadjuvant therapy


Participation Criteria
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Eligibility Criteria
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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 ≥1 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. Known complete dihydropyrimidine dehydrogenase (DPD) deficiency. Any previous treatment for rectal cancer.

Ages Eligible for Study
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Minimum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Health Services Research
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: SCRT arm<br>SCRT (5 fractions of 5 Gy) Surgery (according to the principle of TME) or watch & wait Optional adjuvant chemotherapy | Radiation: Short course radiotherapy<br>* Patients will receive 5 daily fractions of radiotherapy. Each fraction will consist of 5 Gy for a total dose of 25 Gy.<br>Drug: Adjuvant chemotherapy (optional)<br>* The choice of the adjuvant chemotherapy is to the investigator's discretion.<br>Procedure: Total mesorectal excision<br>* Surgery must be performed according to the principles of total mesorectal excision. A watch & wait approach is allowed for those subjects who have clinical complete response according to the local assessment.<br>|
| Active Comparator: TNT arm<br>Rapido regimen: SCRT (5 fractions of 5 Gy) Up to 18 weeks of oxaliplatin based chemotherapy (mFOLFOX6 or CAPOX) Surgery (according to the principle of TME) or watch & wait Or Rapido light regimen: SCRT Up to 12 weeks of oxaliplatin based chemotherapy Surgery or watch & wait Or OPRA with induction chemotherapy (INCT-CRT) regimen: Up to 16 weeks of oxaliplatin-based chemotherapy 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) Surgery or watch & wait Or OPRA with consolidation chemotherapy (CRT-CNCT) regimen: CRT Up to 16 weeks of oxaliplatin-based chemotherapy Surgery or watch & wait | Procedure: Total mesorectal excision<br>* Surgery must be performed according to the principles of total mesorectal excision. A watch & wait approach is allowed for those subjects who have clinical complete response according to the local assessment.<br>Combination Product: Total neoadjuvant therapy<br>* The choice of the TNT is left to the investigator's discretion. If RAPIDO: SCRT (5 fractions of 5 Gy), followed by Up to 18 weeks of oxaliplatin based chemotherapy (mFOLFOX6 or CAPOX) If RAPIDO light: SCRT (5 fractions of 5 Gy), followed by Up to 12 weeks of oxaliplatin based chemotherapy (mFOLFOX6 or CAPOX) If OPRA with induction chemotherapy: 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) If OPRA with consolidation chemotherapy: 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)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival | Overall survival (OS) will be calculated from randomisation to death from any cause. | At 3 years after randomisation | 
| Progression-free survival | Progression-free survival (PFS) will be calculated from randomisation to any of the following events: unresectable tumour due to local tumour progression, R2 resection of the primary tumour, loco-regional recurrence after an R0/R1 resection, distant metastases, or death from any cause. | At 3 years after randomisation | 
| Any grade peripheral sensory neuropathy | Any grade peripheral sensory neuropathy as assessed by the investigator according to the NCI-CTCAE v5.0 will be analysed. | At 3 years after randomisation | 
| Grade ≥3 toxicities during treatment | Grade ≥3 toxicities during treatment (i.e., from the 1st day of treatment until the EOT visit) as assessed by the investigator according to the NCI-CTCAE v5.0 will be analysed. | At 3 years after randomisation | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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rectal cancer