Surgery before chemotherapy does not extend OS for certain patients with colorectal cancer
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Primary tumor resection before chemotherapy did not improve OS compared with chemotherapy alone among patients with unresectable stage IV colorectal cancer, according to phase 3 study results published in Journal of Clinical Oncology.
Elucidating the clinical significance of primary tumor resection for this patient population remained an important unmet need worldwide when this trial began, amid high anticipation of the results of ongoing randomized controlled trials in Germany, the Netherlands, Spain, France, Korea and China, according to Yukihide Kanemitsu, MD, researcher in the department of colorectal surgery at National Cancer Center Hospital in Japan.
“In theory, surgery delays the start of effective systemic therapy and bears the risk for severe complications and mortality from colorectal cancer. However, surgery may prevent development of complications caused by the primary tumor that may subsequently require emergency interventions that are associated with increased perioperative mortality, as well as less favorable long-term outcome,” Kanemitsu told Healio. “Given that patients with metastatic disease have prolonged survival of 2 years or more with modern systemic therapy, the need for delayed emergency surgery may be increasing.”
Several studies demonstrated that removal of the primary tumor may positively affect OS, according to Kanemitsu.
“Although the underlying mechanisms remain unexplained at this stage, numerous recent papers have suggested a survival benefit for patients undergoing primary tumor resection compared with patients who do not have this treatment,” he said. “However, these studies were all retrospective comparative survival analyses without randomization or clear explanation of the indications for resection, and are at great risk for bias and misleading results.”
For this reason, investigators of the Japan Clinical Oncology Group compared survival outcomes of 165 patients (median age, 65 years; 54.5% men) with unresectable stage IV asymptomatic colorectal cancer and synchronous unresectable metastases who had been randomly assigned to primary tumor resection before chemotherapy (n = 81) or chemotherapy alone (n = 84). Patients had up to three unresectable metastases confined to the liver, lungs, distant lymph nodes or peritoneum.
OS served as the primary endpoint of the intention-to-treat analysis.
The trial was stopped due to futility, as per the recommendation of the data and safety monitoring committee, when 114 of the 227 expected events occurred among 160 patients at the first interim analysis.
At a median follow-up of 22 months, results at the interim analysis showed median OS of 25.9 months (95% CI, 19.9-31.5) with primary tumor resection plus chemotherapy compared with 26.7 months (95% CI, 21.9-32.5) with chemotherapy alone (HR = 1.1; 95% CI, 0.76-1.59).
“Regarding tumor location, 30% of patients had tumors on the right side and 70% were on the left side among both groups, and there was a prominent difference depending on the side in terms of OS,” Kanemitsu said. “Based on subgroup analysis, right-sided colon cancers have worse prognosis than left-sided cancers in the primary tumor resection-followed-by-chemotherapy arm. Thus, for patients in poor condition, [with a performance status of 1], or with a right-sided tumor that is considered biologically more aggressive, primary tumor resection may have had a negative impact on survival.”
Results of an updated analysis including all 165 patients showed 3-year OS rates of 33% (95% CI, 22.5-43.9) among those assigned chemotherapy alone vs. 32.9% (95% CI, 22.2-44) among those assigned primary tumor resection followed by chemotherapy, with no significant difference in median OS (26.4 months vs. 25.9 months; HR = 1.11; 95% CI, 0.78-1.58).
Three deaths occurred after surgery in the primary tumor resection-plus-chemotherapy group.
“These results should change the practice of surgeons who resect asymptomatic primaries in unresectable metastatic colorectal cancer,” Kanemitsu said. “This study rigorously defined the definition of unresectable factors and the chemotherapeutic regimen used in first-line treatment. The only difference between the two groups is the difference in primary tumor resection on and off. This result could be applicable to patients even if the first-line chemotherapy regimen changes. Real-world data cannot replace such a randomized controlled trial.”
The results provide the strongest evidence to date to end the debate over whether asymptomatic primary tumor resection for patients with synchronous unresectable metastases can improve survival — it does not, according to an editorial accompanying the study by George J. Chang, MD, MS, of the department of colon and rectal surgery at The University of Texas MD Anderson Cancer Center.
“It also notably demonstrates that random assignment to two treatment strategies for colorectal cancer that include surgery vs. no surgery is possible,” Chang wrote. “Several other randomized trials have been initiated around the world with the goal of determining whether primary tumor resection in addition to chemotherapy can improve survival. ... Although these results continue to be awaited, the current data suggest that a significant survival benefit of primary tumor resection in the setting of unresectable metastasis is unlikely.”
References:
Kanemitsu Y, et al. J Clin Oncol. 2021;doi:10.1200/JCO.20.02447.
Chang GJ. J Clin Oncol. 2021;doi:10.1200/JCO.21.00057.
For more information:
Yukihide Kanemitsu, MD, can be reached at National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan; email: ykanemit@ncc.go.jp.
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