Upfront resection of an asymptomatic primary tumor does not improve survival over chemotherapy alone in stage IV colorectal cancer with unresectable synchronous metastases, according to a randomized trial in Japan with 165 patients.
Median overall survival was slightly more than 2 years with or without primary resection, plus upfront surgery delayed systemic treatment and had a 4% risk of fatal complications. The trial was terminated early because of futility.
“PTR [primary tumor resection] should no longer be considered a standard of care for patients with CRC with asymptomatic primary tumors and synchronous unresectable metastases,” said investigators led by Yukihide Kanemitsu, MD, a colorectal surgeon at National Cancer Center Hospital in Tokyo.
“This paper is important for establishing solid evidence-based decisions. Why perform an invasive procedure on a patient that introduces additional risks if it won’t change their disease course?” said colorectal surgeon Deborah Keller, MD, clinical assistant professor of surgery at the University of California at Davis Medical Center, when asked for comment.
She explained that, in general, when the primary tumor is not obstructing, the standard of care is upfront chemotherapy, as supported by National Comprehensive Cancer Network guidelines.
“However, there was a change in practice over the last few years” after several retrospective studies reported better overall survival with surgery before chemotherapy, but “the studies were not the highest quality of evidence,” she said.
To bring better data to bear, the Japanese team randomized 84 patients to chemotherapy alone and 81 to PTR followed by chemotherapy. Primary tumors were asymptomatic, and patients had no more than three unresectable metastases in the liver, lungs, distant lymph nodes, or peritoneum. Chemotherapy was either mFOLFOX6 plus bevacizumab or CapeOX plus bevacizumab at investigator discretion.
The trial was halted at interim analysis in September 2019. With a median follow-up of 22 months, median overall survival – the primary endpoint – was 25.9 months in the surgery-first arm and 26.7 months in the chemotherapy-alone group (P = .69). Subgroup analysis found no populations that benefited from PTR. Median progression free survival was 10.4 months with PTR first and 12.1 months with chemotherapy alone (P = .48)
Twenty-seven patients in the PTR arm had grade 3 or worse surgery-related adverse events, including anastomotic leakage in 3 and increased aspartate aminotransferase in 13. Three patients (4%) died within 30 days of surgery. Chemotherapy-related grade 3 or worse adverse events were more frequent and severe in the PTR arm (48% PTR versus 34% chemotherapy alone).
“For those who had been performing resections, this could push the paradigm back to chemotherapy alone,” Dr. Keller said.
Eleven patients (13%) in the chemotherapy-alone arm required surgery for intestinal obstruction or other primary tumor symptoms that developed after randomization, which means that 87% avoided surgery entirely, the investigators noted.
In the PTR group, surgery was performed within 21 days of enrollment, and chemotherapy started a median of 34 days after PTR. Chemotherapy was started within 14 days of enrollment in the chemotherapy-alone arm.
The groups were well balanced, including colon and rectosigmoid tumor locations in 93% of both arms and liver metastases in 73% of both. A bit over half the subjects were men and the median age was 65 years.
The team noted that early termination meant that the planned sample size was not achieved, which in turn limited the statistical power of the conclusions. “It is hoped that the comprehensive results of [ongoing trials] will clearly demonstrate the role of PTR for these patients,” they said.
The study was conducted by the Japan Clinical Oncology Group at 38 cancer centers in Japan. The work was funded by the Ministry of Health of Japan. The investigators had numerous industry ties, including Dr. Kanemitsu, who reported honoraria from Chugai Pharma, Ethicon, Covidien, and Intuitive Surgical, and being a Covidien adviser.