Should the primary tumor, if asymptomatic, be resected in patients with colon cancer with synchronous unresectable metastases? Study results hint that the answer is no.
Combined results from the SYNCHRONOUS (ISRCTN30964555) and CCRe-IV (NCT02015923) studies demonstrate that undergoing resection of primary colon tumors and high rectal tumor with synchronous unresectable metastases, did not prolong overall survival (OS).1
An intention-to-treat (ITT) analysis showed that at a median follow-up of 36 months, the median survival of all patients was 17.8 months (95% CI, 15.6-19.6), the median survival in those who received systemic chemotherapy alone was 18.6 months (95% CI, 16.2-22.3), and the median survival was 16.7 months (95% CI, 13.2-19.2) in those who underwent primary tumor resection followed by systemic chemotherapy. No statistically significant difference was observed between the arms.
Investigators also performed a Cox regression model pertaining to the primary end point of OS as part of the ITT analysis, which revealed that the random group surgery vs no surgery was not linked with survival (HR, 0.946; 95% CI, 0.740-1.209; P = .658), but those who did not receive chemotherapy experienced a worse survival (HR, 5.32; 95% CI, 3.55-8.00; P < .001). Moreover, older age was also associated with worse survival (HR, 1.013; 95% CI, 1.001-1.026; P = .033).
“Colorectal cancer is a very prevalent disease, with roughly 20% to 25% of cases presenting as stage IV. Unfortunately, the majority of these patients have unresectable distant disease and will, therefore, only undergo palliative chemotherapy,” Jüergen Weitz, MD, head and professor of surgery in the Department of Visceral, Thoracic, and Vascular Surgery at the University Hospital Carl Gustav Carus of the Technical University Dresden, said in a presentation on the data. “The question that always comes up is: Should the primary tumor, if asymptomatic, be resected in these patients?”
The arguments in favor of resection are that the procedure will prevent primary tumor complications; serve to avoid emergency surgery, which can be dangerous for the patient as they undergo chemotherapy; and that it might improve the prognosis of the patient. Several retrospective papers have suggested this, according to Weitz.
The arguments against primary tumor resection are that the OS of patients is most likely determined by distant disease; that the primary tumor is mostly asymptomatic and will continue to be so during the course of the disease—especially if chemotherapy proves to be effective; and that surgery comes with the risk of complications that can delay palliative chemotherapy for these patients, Weitz added.
“The evidence [that we saw] in 2012 was unclear,” Weitz noted. “A Cochrane analysis concluded at that time that there is still enough doubt with regard to the published papers to justify [for] further randomized trials to be done [to answer that question], so that is exactly what we [decided to do].”
To be included in the analysis, patients were required to have newly diagnosed, histologically confirmed colon or high rectal cancer with synchronous metastases that is not amenable to curative therapy. The primary tumor needed to be resectable and asymptomatic. Moreover, patients needed to be at least 18 years of age, have an ECOG performance status of 0 to 2, and be able to tolerate surgery and chemotherapy. Those with peritoneal metastases were excluded.
Study participants were randomized in a 1:1 fashion to the investigative arm, where they would undergo primary tumor resection before systemic therapy, or the control arm, where they would just receive up-front systemic treatment without resection of the primary tumor. “Of note in both arms, the chemotherapy was undefined, so it was left to the discretion of the treating team,” Weitz said.
The primary end point of the trial was OS. Key secondary end points in the control arm were time to local tumor symptoms, intervention because of primary tumor complications, interventions with curative intent, administration of chemotherapy, and quality of life (QOL). In the investigative arm, perioperative morbidity and mortality, interventions with curative intent, administration of chemotherapy, and QOL, all served as secondary end points.
For the SYNCHRONOUS trial, the sample size was based on an assumption that surgery would improve the median OS from 20 months to 26 months (HR, 1.3); it was calculated to be 800 patients. In December 2014, low patient recruitment resulted in a protocol amendment after a pooled estimated for median OS for both groups following 166 patients was 18 months. As such, the revised sample size was calculated to show an improvement of the median OS with resection from 15 months to 21 months; this equated to 392 patients.
Moreover, an agreement was made with the principal investigator of the CCRe-IV trial to pool the data from the trials, Weitz added. “This could be done [because] the inclusion criteria and the interventions were virtually identical between the trials,” Weitz explained.
A total of 393 patients underwent randomization at 100 sites between November 2011 and March 2017; this included 295 patients enrolled to 82 sites as part of the SYNCHRONOUS trial, and 98 patients enrolled to 18 sites as part of the CCRe-IV trial. Of the 393 patients included in the analysis, 206 received chemotherapy alone and 187 underwent primary tumor resection followed by chemotherapy; 187 and 164 patients, respectively, received the allocated intervention.
Demographic and disease characteristics between the investigative and control arms were comparable, according to Weitz. In the investigative and control arms, 44.9% and 46.6% of patients, respectively, had right-sided tumors, and the predominant site of metastases was the liver (95.2% vs 95.1%, respectively), followed by the lung (27.8% vs 29.6%) and the nonregional lymph nodes (21.4% vs 15.0%). Most patients in the surgery/chemotherapy and chemotherapy-alone arms had 1 metastatic site (58.8% vs 61.2%, respectively), followed by 2 to 5 sites (40.6% vs 38.3%).
Among those in the investigative arm, 87.7% had their primary tumor resected, and 54.3% had a laparotomy. Moreover, 39.6% of patients underwent a right hemicolectomy, 17.1% underwent a left hemicolectomy, 32.3% underwent a sigmoid colectomy, 5.5% had a segmental resection, and 5.5% underwent another surgical procedure that was not specified. Lastly, 23.2% of patients underwent surgery with an anastomosis fashioned, according to Weitz.
“Of note, one-quarter of patients who were randomized to the surgery-only arm never saw chemotherapy,” Weitz noted. “Of those who received chemotherapy, 90% received [a] doublet or triplet [regimen].”
Moreover, in the investigative and control arms, respectively, some patients received chemotherapy plus bevacizumab (Avastin; 38.0% vs 43.2%), chemotherapy plus an EGFR antibody (26.8% vs 17.4%), or chemotherapy plus bevacizumab and an EGFR antibody (0% vs 0.5%).
Investigators also conducted a subgroup analysis. “There was no subgroup where intervention or control was associated with better survival,” Weitz reported.
Regarding safety, 10.2% of those on the surgery/chemotherapy arm and 18.0% of those on the chemotherapy-alone arm experienced at least 1 serious adverse effect (SAE); gastrointestinal (GI) tract–related SAEs occurred in 4.8% and 10.7% of patients, respectively. “This was a statistically significant difference,” Weitz noted. Most of the GI tract–related SAEs were ileus/bowel obstruction (9.1% in investigative arm vs 41.9% in the control arm).
Analyses pertaining to secondary end points are pending and will be reported at a later date, Weitz concluded.
Rahbari NN, Biondo S, Feißt M, et al. Randomized clinical trial on resection of the primary tumor versus no resection prior to systemic therapy in patients with colon cancer and synchronous unresectable metastases. J Clin Oncol. 2022;40(suppl 17):LBA3507. doi:10.1200/JCO.2022.40.17_suppl.LBA3507