In the phase II portion of a Dutch phase II/III trial (CAIRO6) reported in JAMA Surgery, Rovers et al found that the addition of perioperative systemic therapy to cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) was feasible and safe for the treatment of patients with resectable colorectal peritoneal metastases.
Study Details
In the open-label multicenter trial, 79 patients with isolated resectable colorectal peritoneal metastases and no systemic therapy within the prior 6 months were randomly assigned between June 2017 and January 2019 to receive perioperative systemic therapy followed by CRS-HIPEC (n = 37) or CRS-HIPEC alone (n = 42).
Perioperative systemic therapy was selected from among four 3-week neoadjuvant and adjuvant cycles of CAPOX (capecitabine and oxaliplatin), six 2-week neoadjuvant and adjuvant cycles of FOLFOX (fluorouracil [5-FU], leucovorin, and oxaliplatin), or six 2-week neoadjuvant cycles of FOLFIRI (5-FU, leucovorin, and irinotecan) and either four 3-week adjuvant cycles of capecitabine or six 2-week adjuvant cycles of 5-FU with leucovorin; bevacizumab was added to the first three CAPOX or four FOLFOX/FOLFIRI neoadjuvant cycles.
Restaging was performed after three or four neoadjuvant cycles; for disease progression, study treatment was stopped; for peritoneal progression alone, CRS (if resectable) and HIPEC (if completely resected) were performed with no further systemic therapy; for stable disease or response, neoadjuvant treatment was completed and CRS and HIPEC were performed.
The primary outcome measures were proportions of macroscopic complete CRS-HIPEC and Clavien-Dindo grade ≥ 3 postoperative morbidity. Outcomes were analyzed in the modified intent-to-treat population, consisting of all patients who started systemic therapy in the perioperative systemic therapy group and all patients undergoing surgery in the CRS-HIPEC group.
In this randomized phase II trial in patients diagnosed with resectable colorectal peritoneal metastases, perioperative systemic therapy seemed feasible, safe, and able to induce response of colorectal peritoneal metastases, justifying a phase III trial.— Rovers et al
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Key Findings
All 37 patients in the perioperative systemic therapy group and all 42 in the CRS-HIPEC group were included in analysis. Among the 37 patients in the systemic perioperative therapy group, all proceeded to CRS (n = 36 with stable disease or response, n = 1 with peritoneal progression only); 4 stopped treatment due to unresectable colorectal peritoneal metastases. Among the 42 patients in the CRS-HIPEC group, 6 stopped treatment, 5 due to unresectable colorectal peritoneal metastases and 1 due to unexpected liver metastasis.
Macroscopic complete CRS-HIPEC was achieved in 33 (89%) of 37 patients in the perioperative systemic therapy group vs 36 (86%) of 42 patients in the CRS-HIPEC alone group (risk ratio [RR] = 1.04, 95% confidence interval [CI] = 0.88–1.23, P = .74).
Clavien-Dindo grade ≥ 3 postoperative morbidity occurred in 8 (22%) of 37 patients in the perioperative systemic therapy group vs 14 (33%) of 42 in the CRS-HIPEC alone group (RR = 0.65, 95% CI = 0.31–1.37, P = .25). No treatment-related deaths occurred.
Objective radiologic and major pathologic response rates to neoadjuvant treatment were observed in 9 (28%) of 32 evaluable patients and 13 (38%) of 34 evaluable patients, respectively, in the perioperative systemic therapy group.
The investigators concluded, “In this randomized phase II trial in patients diagnosed with resectable colorectal peritoneal metastases, perioperative systemic therapy seemed feasible, safe, and able to induce response of colorectal peritoneal metastases, justifying a phase III trial.”
The aim of the phase III portion of CAIRO6 is to enroll more than 350 patients to assess 3-year overall survival.
Ignace H.J.T. de Hingh, PhD, of the Department of Surgery, Catharina Cancer Institute, Eindhoven, is the corresponding author for the JAMA Surgery article.
Disclosure: The study was funded by the Dutch Cancer Society and F. Hoffmann-La Roche. For full disclosures of the study authors, visit jamanetwork.com.
