Two sides to a story: primary tumor resection and sidedness in metastatic oolorectal cancer

Abstract

This thesis explores the role of primary tumor resection (PTR) in patients with metastatic colorectal cancer (mCRC) and unresectable metastases treated with systemic therapy. It also examines whether PTR’s benefit depends on tumor sidedness—right-sided (RCC) versus left-sided (LCC)—in relation to overall survival (OS). While PTR is standard in symptomatic patients, its value in asymptomatic or minimally symptomatic individuals remains uncertain. Another focus is the prognostic role of sidedness and its link to metastatic patterns and survival outcomes. Sidedness is a known prognostic factor, with LCC generally associated with better outcomes than RCC. It also predicts response to targeted therapies; for example, anti-EGFR antibodies are more effective in LCC with RAS wild-type tumors. Chapter 2 analyzes data from two randomized trials (CAIRO and CAIRO2) to assess whether the relationship between PTR and OS differs by sidedness. Adjusted analyses showed PTR was associated with better OS in both RCC (HR 0.59) and LCC (HR 0.70), though the interaction was not statistically significant. These findings suggest PTR benefits may not clearly depend on sidedness when modern systemic therapy is used. However, selection bias may have influenced results, as only patients fit for treatment were included. To assess this in a real-world setting, Chapter 3 uses data from the Netherlands Cancer Registry (NCR) and SEER. Here, the OS benefit from PTR appeared greater in LCC. In NCR, PTR was associated to a 4.3-month OS benefit in LCC versus 1.9 months in RCC; in SEER, the difference was 8.0 versus 6.0 months. Early postoperative mortality in RCC may partly explain the reduced difference. However, both datasets lacked details on symptom severity and other clinical confounders. Both datasets also confirmed longer OS in LCC. To explore this, Chapter 4 analyzed metastatic patterns using NCR data from 1989–2014. RCC patients had more peritoneal metastases (33%), while rectal cancers more often spread to the lungs (28%). Even after adjusting for metastatic site, RCC patients had worse survival, suggesting that tumor biology may play a role. Chapter 5 evaluated whether sidedness’ prognostic value changes over time. Multivariable Cox models showed sidedness violated the proportional hazards assumption, indicating its effect varies during the disease course. A systematic review and meta-analysis confirmed this: hazard ratios for LCC vs. RCC OS were 0.71 in first-line, 0.76 in second-line, and 1.01 in third-line treatments. These findings may reflect tumor evolution or selection of fitter patients, suggesting that sidedness loses prognostic value in later lines. To assess PTR’s impact prospectively, Chapter 6 analyzed early mortality in the CAIRO4 trial, where patients were randomized to upfront PTR followed by systemic therapy or systemic therapy alone. Sixty-day mortality was higher in the PTR arm (11% vs. 2%), with some patients dying from rapid disease progression before starting systemic therapy. Subgroup analysis suggested that patients with elevated LDH, AST, ALT, and neutrophils were particularly vulnerable, warranting caution in these cases. Chapter 7 presents the main outcome of CAIRO4: overall survival. Among 204 randomized patients, median OS did not differ significantly—20.1 months with PTR vs. 18.3 without (p=0.32). Progression-free survival and serious adverse events were similar. In the non-PTR group, only 13% required surgery for symptom relief. These findings indicate that routine PTR should not be standard care in asymptomatic mCRC patients. In conclusion, although PTR is associated with improved OS in retrospective studies, randomized data do not support its routine use in mCRC patients without severe symptoms. Tumor sidedness remains a valuable prognostic marker, but its relevance appears to diminish over time and with successive treatments.