Liver-First, Bowel-First, or Simultaneous Resection for Synchronous Colorectal Liver Metastases: Outcomes, Quality of Life, and Cost-Effectiveness

Background Patients with colorectal cancer who have liver metastases detected at the time of diagnosis (synchronous colorectal liver metastases, CRLM) require removal of both the bowel tumor and the liver metastases to achieve cure. Three surgical strategies are available: removing the bowel tumor first (bowel-first), removing the liver metastases first (liver-first), or removing both in a single operation (simultaneous resection). There is currently no consensus on which strategy is best, and practice varies considerably between hospitals and surgeons.

Study 1: Treatment Completion and Survival (Primary Study)

This prospective observational study enrolls all patients with synchronous CRLM discussed at a multidisciplinary team (MDT) meeting at participating Swedish university hospitals, where curative treatment of both the primary tumor and liver metastases is considered possible. Enrollment runs from May 2025 to May 2027, with follow-up continuing for up to 5 years.

Participation does not influence treatment in any way - all surgical and oncological decisions are made entirely according to routine clinical practice. Because the study is observational and involves no change to clinical care, an opt-out consent procedure is applied: patients are informed about the study and data collection, and are given four weeks to decline participation. If no objection is received, prospective data collection begins. Patients may withdraw at any time, and all their data will be deleted upon withdrawal.

The primary outcome is failure to Return to Intended Oncological Treatment (RIOT) - that is, the proportion of patients who do not complete their planned surgical treatment and the reasons for this. In a staged approach, this most commonly occurs when disease progression during the interval between the first and second operation renders the second operation unfeasible. Secondary outcomes include 3- and 5-year overall survival, recurrence-free survival, 90-day mortality, 30-day readmission, and complication severity assessed by the Comprehensive Complication Index and Clavien-Dindo classification.

Study 2: Health-Related Quality of Life Nested within the Study 1 cohort, this sub-study examines how the three surgical strategies affect patients' health-related quality of life (HRQoL) over time. Patients provide active informed consent to participate. Quality of life is measured using three validated questionnaires - the EORTC QLQ-C30 (general cancer), QLQ-LM21 (liver metastases-specific), and QLQ-CR29 (colorectal cancer-specific) - at multiple time points from diagnosis through 36 months after completion of surgical treatment. The time points vary according to whether the patient undergoes simultaneous or staged resection, and whether chemotherapy is administered before or after surgery. A total of 200 patients (100 undergoing simultaneous resection, 100 undergoing staged resection) are needed to detect a clinically meaningful difference in quality of life between groups.

Study 3: Healthcare Costs and Cost-Effectiveness All patients consenting to Study 2 are also included in this health economic sub-study. Direct and indirect healthcare costs are collected over the 12 months following diagnosis, covering hospital admissions, chemotherapy, radiotherapy, imaging, and multidisciplinary team meetings. Costs are obtained using Diagnosis-Related Group (DRG) and Cost Per Patient (CPP) measures and will be presented in multiple currencies. The primary endpoint is the incremental cost-effectiveness ratio (ICER), expressed as cost per quality-adjusted life year (QALY) gained, comparing the three surgical strategies.

Study 4: Health Literacy Also nested within the Study 2 consent framework, this sub-study assesses patients' ability to access, understand, and apply health information - referred to as health literacy - using the validated Swedish version of the European Health Literacy Survey Questionnaire (HLS-EU-Q16). Questionnaires are administered at three time points: at inclusion before any treatment, at 6 months, and at 12 months. The study examines whether health literacy levels are associated with treatment outcomes and quality of life, which may inform how clinical teams communicate with and support patients through complex treatment decisions.

• Overall Survival [Time frame: Time frame: 3 and 5 years from diagnosis]
• Recurrence-Free Survival [Time frame: 3 and 5 years from completion of treatment.]
• 90-Day Mortality [Time frame: 90 days from first surgery.]
• 30-Day Readmission [Time frame: 30 days from each surgical procedure.]
• Major complications [Time frame: 30 and 90 days from each surgical procedure]
• Full Treatment Completion [Time frame: From MDT discussion to completion of intended treatment, assessed up to 24 months.]
• Health-Related Quality of Life (Study 2) [Time frame: At inclusion, then at multiple time points through 36 months after completion of surgical treatment, varying by treatment scenario.]
• Incremental Cost-Effectiveness Ratio (Study 3) [Time frame: Time frame: 12 months from diagnosis.]
• Health Literacy (Study 4) [Time frame: At inclusion before any treatment, at 6 months, and at 12 months from inclusion.]