Overview
The primary objective is to prove non-inferiority of thermal ablation compared to hepatic resection in patients with at least one resectable and ablatable colorectal liver metastases (≤3cm) and no extrahepatic disease.
Description
Study design:
COLLISION is a single-blind prospective multi-center phase-III randomized controlled trial. We hypothesize that thermal ablation is non-inferior to surgery for the selected patient groups in terms of the primary objective (overall survival). The Cox proportional hazards model (1-sided; non-inferiority or superiority) is used for sample size calculations. Given the superior safety profile we consider a hazard ratio of 1.3 to represent the upper limit of non-inferiority (non-inferiority margin). An HR of 1.3 corresponds to a 56.5% chance of the ablated patients to die first ((P = HR/(1 + HR) = 1.3/(1 + 1.3) = 0.565 (56.5%)). With 3 years of patient accrual and five years of follow-up we will have reached 60% of events (death) in approximately 6.5 years (overall probability of event, pE =0.6). The calculated sample size therefore is 599 (NS).To account for a 10% drop-out ratio (NDO=69) prior to randomization and a 3% loss to follow-up (NLTFU=18) after randomization we need to include 687 patients (NI). A total number of 618 patients will be randomized (NR) into one of two arms: arm A will undergo surgical resection (n=309) and arm B thermal ablation (n=309) for appointed target lesions.
Study population:
Patients with ≥1 resectable and ablatable CRLM (≤3cm), no extrahepatic disease and a good performance status (WHO 0-2) are considered eligible. Supplementary resections for resectable lesions >3cm and thermal ablations for unresectable CRLM ≤3cm are allowed with a maximum number of CRLM of 10.
- Intervention
Eligible patients will be stratified into low-, intermediate- and high disease burden after assessment by an expert panel. The panel, consisting of at least two diagnostic radiologists, two interventional radiologists and two hepatobiliary and/or oncological surgeons, will appoint lesions that are resectable and ablatable as target lesions, resectable and unablatable lesions as unablatable lesions and ablatable but unresectable lesions as unresectable lesions. All unablatable lesions should be resectable and all unresectable lesions should be ≤3cm and ablatable.
With the exception of patients that are suitable for laparoscopic resection or percutaneous ablation (low disease burden), eligibility needs to be reconfirmed during the surgical procedure. Hereafter patients will be randomized to undergo surgical resection of the target lesions (allowing thermal ablation for additional unresectable lesions) or thermal ablation (allowing resection for additional unablatable lesions). For open procedures randomization will be performed shortly after surgical inspection and IOUS with the patient under general anaesthesia. Both the experimenter(s) and the participant will be unaware of the eventual treatment arm prior to the procedure; after the procedure the patient will remain unaware (single-blind).
Conferring to national guidelines follow-up will include imaging, laboratory tests including tumour markers (CEA) and clinical examination every 3 months for the first year and every 6 months hereafter. Follow-up cross-sectional imaging should include at least an abdominal ceCT or upper abdominal ceMRI at the given time-points. Participating centres are free to add 18F-FDG PET-CTs at specific time-points or to use alternating specific modalities, as long as the follow-up protocol is pre-approved by the trial coordinators and as long as follow-up imaging is identical for both treatment arms. Quality of life questionnaires will be assessed at baseline, every 3 months for the first year and every 6 months hereafter accordingly.
Patients with recurrences that are considered unsuitable for additional focal therapy will be re-referred to their medical oncologist to assess additional systemic chemotherapy. In the event of chemotherapeutic down-staging hereafter, focal therapy can be reconsidered.
Eligibility
Most important inclusion criteria:
- At least one CRLM size ≤ 3 cm eligible for both surgical resection and thermal ablation (target lesions);
- Additional unresectable CRLM should be ≤ 3 cm and ablatable (unresectable lesions);
- Additional unablatable CRLM should be resectable (unablatable lesions);
- Maximum number of CRLM 10;
- Resectability and ablatability should be re-confirmed intra-operatively by US plus full exploration for hepatic, peritoneal and regional lymph node metastases;
- ASA 1-3.
Most important exclusion criteria:
- No target lesions suitable for both resection and ablation;
- Radical treatment unfeasible or unsafe (e.g. insufficient FLR);
- The presence of extrahepatic nodal or non-nodal metastases;
- Immunotherapy or chemotherapy ≤ 6 weeks prior to the procedure;
- Any surgical resection or focal ablative liver therapy for CRLM prior to inclusion