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.
Age ≥ 70 years old
≤1 if age > 75 years old
≤2 if age ≤ 75 years old
Histologically or cytologically confirmed adenocarcinoma of the rectum
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.
Parallel
Short course radiotherapy
RadiationPatients will receive 5 daily fractions of radiotherapy. Each fraction will consist of 5 Gy for a total dose of 25 Gy.
Adjuvant chemotherapy (optional)
DrugThe choice of the adjuvant chemotherapy is to the investigator's discretion.
Total mesorectal excision
Procedure/SurgerySurgery 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.
Total neoadjuvant therapy
Combination productThe 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)
Long course chemoradiotherapy
RadiationPatients will receive 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
Overall survival
Overall survival (OS) will be calculated from randomisation to death from any cause.
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.
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.
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.
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