Perioperative systemic therapy: feasible, safe and tolerable in patients with isolated colorectal peritoneal metastases

In daily practice, there is considerable variation into how perioperative systemic therapy is being used in patients with isolated colorectal peritoneal metastases. To address the current lack of randomised data on the use of perioperative systemic therapy in this setting, the randomised CAIRO6 trial was initiated as a joint initiative of the Dutch Peritoneal Oncology group and the Dutch Colorectal Cancer Group. Despite major concerns in the field, the pilot phase of this study demonstrated that perioperative systemic therapy appears to be feasible, safe and tolerable in this setting. Moreover, perioperative systemic therapy was able to induce radiological and pathological tumour responses in patients with isolated colorectal peritoneal metastases.

Background

To date, no randomised trials on perioperative systemic therapy for isolated resectable colorectal peritoneal metastases have been performed, leading to a wide variety in its administration and timing across different countries, hospitals and physicians. In the CAIRO6 trial patients were randomised between perioperative (neoadjuvant and adjuvant) systemic therapy and cytoreductive surgery with HIPEC or cytoreductive surgery with HIPEC alone, which is the current standard of care in The Netherlands. Nevertheless, there were major concerns in the field with respect to neoadjuvant treatment and progression rates, secondary inoperability, toxicity, postoperative morbidity and the difficulty to enrol patients. Therefore, a pilot phase of the CAIRO6 study was conducted to assess the feasibility and safety of perioperative systemic therapy.

CAIRO6 is an investigator-initiated, open-label, parallel-group, randomised superiority trial conducted in all nine Dutch tertiary centres that organise surgical treatment for colorectal peritoneal metastases. The study enrolled 80 patients with pathologically proven, peritoneal metastases of non-appendiceal colorectal adenocarcinoma without extraperitoneal metastases. Study participants had resectable disease on laparoscopy or laparotomy and were not allowed to have received systemic therapy in the past six months. Also patients who received prior cytoreductive surgery with HIPEC were excluded from the study. Patients were randomised (1:1) to an experimental arm with perioperative systemic therapy or the control arm with cytoreductive surgery and HIPEC alone. At the physician’s discretion, perioperative treatment in the experimental arm could consist out of four neoadjuvant and adjuvant cycles of CAPOX  with bevacizumab during the first three neoadjuvant cycles, six neoadjuvant and adjuvant cycles of FOLFOX with bevacizumab during the first four neoadjuvant cycles or six neoadjuvant cycles of FOLFIRI and four or six adjuvant cycles of capecitabine or 5-FU-leucovorin (+ bevacizumab during the first four neoadjuvant cycles). Cytoreductive surgery and HIPEC (CRS-HIPEC) were performed according to the Dutch protocol and were standardised in all centres. Surgery was only performed if complete surgery was deemed achievable and HIPEC was only performed after complete surgery.

Primary outcomes of the trial were based on the previously mentioned major concerns in the field and included the number of patients with complete cytoreductive surgery with HIPEC, the number of patients in the experimental arm with Clavien-Dindo grade 3-5 postoperative morbidity and the feasibility of trial accrual. Other investigated outcomes were grade 3-5 systemic therapy-related toxicity, centrally assessed radiological response to neoadjuvant treatment and centrally assessed pathological regression after neoadjuvant treatment.

Results

Out of the 233 potentially eligible patients, 82 were not approached for participation and 71 refused participation, leaving 80 patients to enrolment and randomisation. In total, 37 patient started neoadjuvant therapy and 42 underwent upfront surgery. Of the patients in the neoadjuvant therapy arm, 76% completed all cycles and almost all patients experienced disease stabilization or a response to treatment (one patient had peritoneal progression). All of these patients underwent surgery and 89% had complete CRS-HIPEC. In total, 59% of patients started adjuvant therapy and 32% completed all cycles. In the control arm, 86% had complete CRS-HIPEC. As such, there was no statistical difference in the number of patients undergoing complete CRC-HIPEC (89% in experimental arm vs. 86% in control arm, p= 0.74) nor did the percentage of patients with major postoperative morbidity differ between both arms (22% vs. 33%, respectively, p= 0.25). No surgery-related deaths occurred in either arm. Overall, both trial accrual and neoadjuvant treatment thus seem feasible and safe.

Grade 3-5 systemic toxicity occurred in 35% of patients, without systemic therapy-related deaths and was comparable to 3-6 months of adjuvant systemic chemotherapy for resected stage III colon cancer. The objective radiological response rate according to RECIST was only 16%, with 59% of patients being non-evaluable. When using the radiological peritoneal cancer index, the objective radiological response rate was 28% with all patients being evaluable. The prognostic value of this peritoneal cancer index will now be validated in the ongoing phase III trial. The major pathological regression rate was 39%, with 24% of the patients having no residual cancer cells in their resected specimens. This major regression rate is comparable to the major regression rate in resected colorectal liver metastases after combination chemotherapy with bevacizumab.

Conclusions

The pilot phase of the randomised CAIRO6 trial suggests that perioperative systemic therapy is feasible, safe, tolerable and able to induce radiological and pathological tumour responses in patients with isolated colorectal peritoneal metastases. These findings justify continuation of the currently ongoing phase III trial, which will provide the first intention-to-treat overall survival comparison of perioperative systemic therapy and cytoreductive surgery with HIPEC alone in this setting.

Reference

Rovers KP. Perioperative systemic therapy versus surgery alone for isolated resectable colorectal peritoneal metastases: pilot phase of a randomised trial (CAIRO6). Presented at ESMO World GI 2020; Abstract LBA-6.