Neoadjuvant Systemic Therapy Promising For Resectable Colorectal Peritoneal Metastases

Perioperative systemic therapy seemed feasible, safe and capable of inducing a response in a phase 2 trial comparing the treatment to cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) alone for resectable colorectal peritoneal metastases (CPM).

The results justify moving ahead with the phase 3 randomized CAIRO6 trial, according to Dr. Ignace H. J. T. de Hingh of the Catharina Cancer Institute in Eindhoven, the Netherlands and colleagues.

"In the CAIRO6-trial, we aim to prove that adding systemic treatment to CRS and HIPEC will prolong survival of patients with CPM," Dr. de Hingh told Reuters Health by email. "However, we as treating physicians - as well as our patients - generally have two major concerns with the addition of systemic treatment prior to CRS and HIPEC: Will the delay of surgical treatment allow the disease to progress beyond a curable stage? Will the addition of intensive systemic treatment before surgery increase the risk of postoperative complications?"

"Therefore," he said, "we performed this safety study, and to our relief, we found that postoperative complications did not increase in patients who had received systemic treatment and that the delay in surgical treatment had not resulted in progression of disease."

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As reported in JAMA Surgery, the open-label, parallel-group phase 2 randomized clinical trial enrolled CPM patients from nine Dutch centers between 2017 - 2019.

Perioperative systemic therapy consisted of either four 3-week neoadjuvant and adjuvant cycles of CAPOX (capecitabine and oxaliplatin), six 2-week neoadjuvant and adjuvant cycles of FOLFOX (fluorouracil, leucovorin, and oxaliplatin), or six 2-week neoadjuvant cycles of FOLFIRI (fluorouracil, leucovorin, and irinotecan) and either four 3-week adjuvant cycles of capecitabine or six 2-week adjuvant cycles of fluorouracil with leucovorin.

Bevacizumab was added to the first 3 (CAPOX) or 4 (FOLFOX/FOLFIRI) neoadjuvant cycles.

Seventy-nine patients (out of 233 eligible) were included in the analysis (mean age, 62; 54% men; mean age, 62).

No significant differences were seen in the proportions of macroscopic complete CRS-HIPEC in the neoadjuvant group patients compared with controls (89% vs. 86%; risk ratio, 1.04), or in Clavien-Dindo grade 3 or higher postoperative morbidity (22% vs. 33%; RR, 0.65).

No treatment-related deaths occurred. Twenty-eight percent of neoadjuvant patients achieved objective radiologic response rates, and 38% had major pathologic response rates.

Dr. de Hingh said, "We hope that (systemic therapy) will translate into better survival. We are now looking forward to the final results of the ongoing (CAIRO6) trial that will be evaluated after inclusion of 358 patients."

Dr. Rahul Narang, a colorectal surgeon at NYU Langone's Perlmutter Cancer Center in New York City, commented on the study in an email to Reuters Health. "Overall," he said, "this study is a good start to investigating systemic therapy in patients with resectable CPM disease compared to cytoreductive surgery and HIPEC."

Nonetheless, he added, "There are certainly some limitations. Of the 233 eligible patients, 35% of were not approached for trial participation for unknown reasons and 30% refused trial participation for various reasons."

The study may have not been adequately powered for statistical significance with a sample size of 80, he noted. "In addition, the authors may have missed the opportunity to standardize the study with different perioperative systemic regimes."

On the other hand, he said, "All trial participants who started neoadjuvant treatment underwent surgery in this study, which would suggest that fear of missing a window to operate due to progression of disease or toxic effects may (be unfounded)."

"As the authors suggested, a phase 3 trial will help to inform both clinicians and patients about the feasibility and safety of perioperative systemic therapy," Dr. Narang concluded.

The study was funded in part by an F. Hoffman-LaRoche grant. Dr. de Hingh and a coauthor have received funds from the company.

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