Multicentre, open-label, randomised, controlled, parallel arms clinical trial of induction chemotherapy followed by chemoradiotherapy versus chemoradiotherapy alone as neoadjuvant treatment for locally recurrent rectal cancer

Rationale: The overall survival of patients undergoing curative multimodality treatment for locally recurrent rectal cancer (LRRC) remains poor, with a 5-year overall survival of approximately 30%. The most important prognostic factor for survival is a clear resection margin (R0 resection). Neoadjuvant chemoradiotherapy aims at downstaging local disease, thus facilitating radical resection. However, even with neoadjuvant chemoradiotherapy, radical resections are achieved in only ±60% of patients. The addition of induction chemotherapy prior to neoadjuvant chemoradiotherapy may improve downstaging of the tumour and thereby result in more R0 resections. Subsequently, increasing the rate of R0 resections should decrease local re-recurrence and thereby improve quality of life and overall survival in patients with LRRC.
Objective: The primary objective of this study is to determine the rate of resections with clear resection margins after treatment with induction chemotherapy followed by neoadjuvant chemoradiotherapy and surgery compared to treatment with neoadjuvant chemoradiotherapy and surgery alone. The secondary objectives are to determine the local re-recurrence free survival, progression free survival, metastasis free survival, disease free survival, overall survival, radiological response, pathologic response, toxicity, surgical complications, quality of life and costs for both arms.
Study design: This is a multicentre, open-label, phase III, parallel arms, randomised controlled trial that randomises eligible patients in a 1:1 ratio to receive induction chemotherapy followed by neoadjuvant chemoradiotherapy and surgery (experimental arm) or neoadjuvant chemoradiotherapy and surgery alone (control arm).
Study population: Patients diagnosed with locally recurrent rectal cancer who previously underwent a partial or total mesorectal excision for rectal cancer with or without (chemo)radiation, without distant metastases or contraindications for the planned intervention are eligible for inclusion.
Intervention: Patients allocated to the experimental arm will receive induction chemotherapy which consists of three 3-weekly courses CAPOX or four 2-weekly courses FOLFOX/FOLFIRI, followed by restaging with pelvic MRI and thoracoabdominal CT-scan. In case of distant metastases or progressive unresectable local disease, palliative treatment will be offered. In case of progressive but resectable local disease, patients will start chemoradiotherapy within 3-5 weeks. In case of responsive or stable disease, one additional 3-weekly course CAPOX or two additional 2-weekly courses FOLFOX/FOLFIRI will be administered. Subsequently, but not earlier than 3 weeks after the first day of the last cycle of induction chemotherapy, chemoradiotherapy will be administered. Chemoradiotherapy will be administered according to standard of care. The radiotherapy dose will be either 30 or 50 Gy, depending on whether the patient received previous radiotherapy. After restaging with MRI and CT-scan, surgery will be performed 10-14 weeks after the last day of chemoradiotherapy. If deemed necessary and feasible, intra-operative radiotherapy will be administered. Patients allocated to the control arm receive chemoradiotherapy alone followed by surgery.
Main study parameters/endpoints: The primary endpoint of the study is the rate of clear resection margins after surgery. Secondary endpoints are local re-recurrence free survival, progression free survival, distant metastasis free survival, disease free survival, overall survival, pathologic response, radiological response, systemic therapy related toxicity (NCI-CTCAE v5.0 grade ≥3), the number of patients completing neoadjuvant treatment, surgical characteristics, major postoperative complications (Clavien-Dindo ≥3) up to 90-days postoperatively, quality of life and cost-effectiveness.

The hypothesize is, that treatment with induction chemotherapy will lead to a 15% increase of the R0 resection rate compared to treatment with neoadjuvant chemoradiotherapy and surgery alone.

4 years of inclusion, 5 years of follow-up

Induction chemotherapy