Perioperative Systemic Therapy Plus CRS-HIPEC Appears Safe, Feasible in Resectable CPM

The addition of perioperative systemic therapy may be a safe and worthwhile option compared with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) alone in patients with resectable colorectal peritoneal metastases (CPM), according to data from the randomized, phase 2 CAIRO6 trial (NCT02758951) published in JAMA Surgery.¹

Results from the trial indicated that the proportion of patients who underwent macroscopic complete CRS-HIPEC did not differ significantly across cohorts. In the experimental arm, 89% of patients achieved macroscopic complete status (n = 33/37) vs 86% of those in the control arm (n = 36/42; risk ratio, 1.04; 95% CI, 0.88-1.23; P = .74). In a modified intent-to-treat population, Clavien-Dindo postoperative morbidity of grade 3 or higher occurred in 22% of patients in the experimental arm (n = 8/37) and 33% of those in the control arm (n = 14/42; risk ratio, 0.65; 95% CI, 0.31-0.37; P = .25).

“In the present, multicenter, randomized phase 2 trial, perioperative systemic therapy seemed feasible and safe in patients diagnosed with resectable CPM,” wrote the authors of the study. “Neoadjuvant treatment induced objective radiologic [28%] and major pathologic [38%] responses of CPM.”

National and international guidelines have recommended CRS-HIPEC for certain patients with resectable CPM, although the benefit of the strategy has been a topic of discussion in the field.^2-4 The concept of adding perioperative systemic therapy has also been cause for debate. Although the regimen could potentially benefit patients by downstaging tumors and eliminating micrometastases prior to surgery, it is possible that toxicities could increase patient morbidity—especially with the addition of bevacizumab (Avastin)—or even lead to inoperability due to preoperative intraperitoneal progression.⁵ As there have not yet been any randomized trials evaluating perioperative systemic therapy in patients with resectable CPM, according to investigators, the parallel randomized CAIRO6 trial was launched.

The study was conducted across 9 Dutch cancer centers, which provided patients with isolated resectable CPM with surgical resection. Patients were randomized 1:1 to either the perioperative systemic therapy arm or the CRS-HIPEC alone arm. Those who enrolled were stratified based on peritoneal cancer index, onset of CPM, whether they received previous systemic therapy for colorectal cancer, and planned HIPEC regimen. In the experimental arm, patients needed to begin perioperative systemic therapy within 4 weeks of randomization vs 6 weeks in the control arm.

Thirty-seven patients were randomized to the experimental arm and were given perioperative systemic therapy consisting of either 3 weeks of neoadjuvant or adjuvant of capecitabine and oxaliplatin (CAPOX) for 4 cycles, 2 weeks of neoadjuvant or adjuvant fluorouracil , leucovorin, and oxaliplatin (FOLFOX) for 6 cycles, or 2 weeks of neoadjuvant fluorouracil, leucovorin, and irinotecan (FOLFIRI) for 6 cycles, followed by 3 weeks of capecitabine for 4 cycles or 2 weeks of adjuvant fluorouracil with leucovorin for 6 cycles. Bevacizumab was included in the first 3 neoadjuvant cycles of the CAPOX regimen or the first 4 neoadjuvant cycles of FOLFOX or FOLFIRI, the authors reported. The remaining 42 patients served as the control arm and received CRS-HIPEC alone.

In order to enroll on the study, patients needed to have a World Health Organization performance status of 0 or 1; pathologically-proven, isolated nonappendiceal CPM; resectable disease; and a peritoneal cancer index of 20 or less. Additionally, patients could not receive systemic therapy within 6 months of enrollment. The primary outcomes of the trial were proportions of macroscopic complete CRS-HIPEC and Clavien-Dindo grade 3 or higher postoperative morbidity.

Seventy-nine patients were enrolled between June 2017 and January 2019 of 233 potentially eligible patients. Within the modified intent-to-treat population, patients had an average age of 62 years, and a slight majority (54%) were men. Additionally, 47% of patients were given neoadjuvant therapy and 53% underwent surgical resection up front.

Additional findings identified a radiologic objective response rate of 28% in those who received neoadjuvant treatment and the major pathologic response rate was 38%. No treatment-related deaths were reported. Moreover, 25% of patients had a complete pathologic response.

In total, 35% of patients enrolled on the trial experienced grade 3 or higher toxicity by Common Terminology Criteria for Adverse Events related to systemic therapy without any related deaths. Moreover, no deaths related to surgery were reported.

Patient-reported outcomes from the trial will be published separately. Those data, the authors wrote, “may increase insight into the burden of perioperative systemic therapy in this setting.”

The investigators concluded that, while many questions remain unanswered, the potential of perioperative systemic therapy in this patient population warrants additional investigation.

“In this randomized phase 2 trial in patients diagnosed with resectable CPM, perioperative systemic therapy seemed feasible, safe, and able to induce response of CPM,” they concluded. “These results justify a phase 3 trial.”

Reference

1. Rovers KP, Bakkers C, Nienhuijs SW, et al. Perioperative systemic therapy vs cytoreductive surgery and hyperthermic intraperitoneal chemotherapy alone for resectable colorectal peritoneal metastases: a phase 2 randomized clinical trial. JAMA Surg. Published online May 19, 2021. doi:10.1001/jamasurg.2021.1642

2. Evard S. Autopsy of an expert consensus: end of hyperthermic intraperitoneal chemotherapy in colorectal carcinomatosis. EJSO. 2018;44(12):P1845-1846. doi:10.1016/j.ejso.2018.07.061

3. Ceelen W. HIPEC with oxaliplatin for colorectal peritoneal metastasis: The end of the road? EJSO. 2019;45(3);P400-402. doi:10.1016/j.ejso.2018.10.542

4. Klaver CEL, Groenen H, Morton DG, et al. Recommendations and consensus on the treatment of peritoneal metastases of colorectal origin: a systematic review of national and international guidelines. Colorectal Disease. 2017;19(3):224-236. doi:10.1111/codi.13593

5. Franko J, Shi Q, Meyers JP, et al. Prognosis of patients with peritoneal metastatic colorectal cancer given systemic therapy: an analysis of individual patient data from prospective randomised trials from the Analysis and Research in Cancers of the Digestive System (ARCAD) database. Lancet Oncol. 2016;17(12):P1709-1719. doi:10.1016/S1470-2045(16)30500-9