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Management of the Primary Tumor in Metastatic Colorectal Cancer



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Background Systemic therapy is the mainstay of treatment for stage IV colorectal cancer (CRC) and provides meaningful survival benefit. Currently, there is very low quality evidence available regarding benefit of primary tumor resection in patients with metastatic CRC. In spite of uncertain survival benefit, high rates of surgical resection have been reported in patients with unresectable metastatic disease. There is a lack of randomized clinical trial to address this important question in patients with stage IV CRC. Although several observational studies have suggested potential survival benefit of primary tumor resection, lack of randomization and failure to control important prognostic variables such as performance status, are major critiques to the findings of the observational studies. We have undertaken this large population-based cohort study to determine the survival benefit of primary tumor resection in stage IV CRC by minimizing various biases reported in the literature. Hypothesis We hypothesized that primary tumor resection in patients with stage IV CRC improves survival independent of chemotherapy and other known prognostic variables. Objectives  To systematically review the published literature and synthesize the data in relation to primary tumor resection in stage IV CRC.  To compare survival of patients with stage IV CRC who underwent primary tumor resection with the patients who did not have surgery and to determine the prognostic importance of surgery of the primary tumor in stage IV CRC.  To determine survival advantage of primary tumor resection in patients with stage IV CRC and minimally symptomatic or asymptomatic primary tumor.  To determine survival advantage of primary tumor resection in patients with stage IV CRC during the period of modern chemotherapy. Methods The study was conducted in two phases. During the first phase, a systematic review of published literature was performed using the Medline, EMBASE and CENTRAL databases. Studies were selected by using pre-specified eligibility criteria with restriction to publication dates from 1980 onward, English language, and human studies. Articles that met the inclusion criteria were assessed for quality by using the Ottawa-Newcastle score & GRADE. Data was collected and synthesized as per the PRISMA guideline. In the second phase, population-based retrospective cohort studies were performed. The study population was comprised of patients with stage IV CRC diagnosed during the period of January 1992 to December 2010 in the province of Saskatchewan, Canada. The prognostic significance of primary tumor resection was initially evaluated in patients’ cohort with stage IV CRC diagnosed during 1992-2005 period. The results were validated in a second patients cohort diagnosed during 2006-2010. Survival was calculated using the Kaplan-Meier method. Survival distributions of different groups were compared by the log-rank tests. Cox proportional multivariate regression analyses were performed to determine survival benefit of primary tumor resection by controlling the other prognostic variables. Results Systematic review: Of total of 3379 reports, 15 retrospective observational studies were selected. Of total 12456 patients, 8620 (69%) underwent primary tumor resection. Median overall survival of the resection group was 15.2 months (range: 10-30.7) compared with 11.4 months (range: 3-22) in the non-resection group. Hazard ratio (HR) for survival was 0.69 (95% CI: 0.61-0.79), which favors surgical resection. Mean postoperative mortality and nonfatal complications rates were 4.9% (95% CI: 0-9.7) and 25.9% (95% CI: 20.1-31.6), respectively. Cohort Studies: A total 1378 eligible patients were identified during the period of 1992-2005. Nine hundred and forty-four (68.5%) underwent primary tumor resection. Among 1378 patients, 42.3% received chemotherapy. Cox proportional analyses revealed that use of chemotherapy (HR 0.47, 95% CI: 0.41-0.54), primary tumor resection (HR 0.49, 95% CI: 0.41-0.58), second-line chemotherapy (0.47, 95% CI: 0.45-0.64), and metastasectomy (HR 0.54, 95% CI: 0.45-0.64) were correlated with superior survival. In a subcohort of 834 patients with asymptomatic or minimally symptomatic disease, primary tumor resection was correlated with better survival (HR 0.47; 0.39-0.57). Test for interaction between ≥1 metastatic sites and surgery was significant suggesting a larger benefit of surgery in patients with stage IVa disease. These findings were validated in a cohort of 569 patients with stage IV CRC diagnosed during the period of 2006-2010. Fifty seven percent patients received chemotherapy and 91.4% received modern chemotherapy. Median overall survival of patients who received all active agents and underwent primary tumor resection was 39 months (95% CI: 25.1-52.9). In multivariate analysis, primary tumor resection, hazard ratio (HR):0.44 (95% CI: 0.35-0.56), was correlated with superior survival. Conclusions Our study supports primary tumor resection in patients with stage IV CRC. It correlates with better survival independent of known prognostic variables such as chemotherapy, metastasectomy, performance status and comorbid illness. In a subgroup of asymptomatic or minimally symptomatic patients or who were treated with modern chemotherapy and biologics, primary tumor resection was correlated with better survival.



Colorectal Cancer, Primary Tumor, Surgery, Survival, Stage IV Colorectal cancer



Doctor of Philosophy (Ph.D.)


Community Health and Epidemiology




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