Impact of multimodal treatment on patient outcomes and prognosis in colorectal peritoneal metastases

The present thesis focussed on patients with colorectal peritoneal metastases: a disease which is known for its poor survival, even though treatment strategies have improved over the past years. Furthermore, population-based studies in this thesis showed that the incidence of colorectal peritoneal metastases is increasing. To further improve survival in this growing group of patients, the CAIRO6 study was initiated, in which the value of perioperative (before and after surgery) chemotherapy is being investigated. Safety and feasibility results of this study are depicted in this thesis. Also, patient-reported outcomes from this trial were investigated. Intra-operative treatment strategies with regard to the choice of HIPEC chemotherapeutic regimen, as well as adjuvant systemic chemotherapy after surgery, both investigated in nationwide cohorts are elaborated in this thesis. In summary, this thesis highlighted the relevance of this disease among Dutch colorectal cancer patients, elaborated new treatment options to further improve patient survival and elicted the impact of this disease on patients’ quality of life in patient-reported outcome studies. The present thesis will contribute to better knowledge, insight, treatment and patient education for physicians treating, and patients suffering from colorectal peritoneal metastases

Patient-reported outcomes during repetitive oxaliplatin-based pressurized intraperitoneal aerosol chemotherapy for isolated unresectable colorectal peritoneal metastases in a multicenter, single-arm, phase 2 trial (CRC-PIPAC)

BACKGROUND: CRC-PIPAC prospectively assessed repetitive oxaliplatin-based pressurized intraperitoneal aerosol chemotherapy (PIPAC-OX) as a palliative monotherapy (i.e., without concomitant systemic therapy in between subsequent procedures) for unresectable colorectal peritoneal metastases (CPM). The present study explored patient-reported outcomes (PROs) during trial treatment. METHODS: In this single-arm phase 2 trial in two tertiary centers, patients with isolated unresectable CPM received 6-weekly PIPAC-OX (92 mg/m(2)). PROs (calculated from EQ-5D-5L, and EORTC QLQ-C30 and QLQ-CR29) were compared between baseline and 1 and 4 weeks after the first three procedures using linear mixed modeling with determination of clinical relevance (Cohen’s D ≥ 0.50) of statistically significant differences. RESULTS: Twenty patients underwent 59 procedures (median 3 [range 1–6]). Several PROs solely worsened 1 week after the first procedure (index value − 0.10, p < 0.001; physical functioning − 20, p < 0.001; role functioning − 27, p < 0.001; social functioning − 18, p < 0.001; C30 summary score − 16, p < 0.001; appetite loss + 15, p = 0.007; diarrhea + 15, p = 0.002; urinary frequency + 13, p = 0.004; flatulence + 13, p = 0.001). These PROs returned to baseline at subsequent time points. Other PROs worsened 1 week after the first procedure (fatigue + 23, p < 0.001; pain + 29, p < 0.001; abdominal pain + 32, p < 0.001), second procedure (fatigue + 20, p < 0.001; pain + 21, p < 0.001; abdominal pain + 20, p = 0.002), and third procedure (pain + 22, p < 0.001; abdominal pain + 22, p = 0.002). Except for appetite loss, all changes were clinically relevant. All analyzed PROs returned to baseline 4 weeks after the third procedure. CONCLUSIONS: Patients receiving repetitive PIPAC-OX monotherapy for unresectable CPM had clinically relevant but reversible worsening of several PROs, mainly 1 week after the first procedure. TRIAL REGISTRATION: Clinicaltrials.gov: NCT03246321; Netherlands trial register: NL6426. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00464-021-08802-6

Quality of life and symptoms in patients undergoing CRS-HIPEC with or without perioperative systemic treatment for colorectal peritoneal metastases:Results from the randomised CAIRO6 trial

Background:To investigate the effect of perioperative systemic therapy in addition to cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) on quality of life (QoL) and symptoms during and after treatment for colorectal peritoneal metastases.Methods:During this phase II, randomized, controlled trial, all consecutive patients were randomized 1:1 for a) CRS-HIPEC (control group) and b) CRS-HIPEC with perioperative systemic treatment (experimental group). Analyses were performed on the per-protocol study population. QoL and symptoms were measured at baseline, after neoadjuvant treatment (experimental group only), and at 3 and 6 months after surgery. The EORTC QLQ-C30, QLQ-CR29, and EQ5D-5L questionnaires were used.Results:Eighty patients were included: 43 in the control group and 37 in the experimental group. Response rates were 100%, 94.9%, 83.5%, and 74.9% at baseline, after neoadjuvant treatment, at 3 and 6 months after surgery, respectively. The C30 summary score, EQ-VAS score, and index score were similar between the groups at baseline, at 3 and at 6 months after CRS-HIPEC. Also, all EORTC QLQ-C30 and CR29 functional and symptom scores were not significantly different between the groups at any point. In the experimental group, higher index scores were observed in patients who received adjuvant systemic treatment compared with patients who did not at 6 months after surgery.Conclusion:Perioperative systemic therapy in patients undergoing CRS-HIPEC for colorectal peritoneal metastases did not significantly deteriorate QoL or worsen symptoms. Furthermore, in both groups, all QoL and symptom scores returned to baseline values at 3 or 6 months after surgery

Concomitant intraperitoneal and systemic chemotherapy for extensive peritoneal metastases of colorectal origin: protocol of the multicentre, open-label, phase I, dose-escalation INTERACT trial

INTRODUCTION: Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) has become standard of care for patients with peritoneal metastases of colorectal origin with a low/moderate abdominal disease load. In case of a peritoneal cancer index (PCI) score >20, CRS-HIPEC is not considered to be beneficial. Patients with a PCI >20 are currently offered palliative systemic chemotherapy. Previous studies have shown that systemic chemotherapy is less effective against peritoneal metastases than it is against haematogenous spread of colorectal cancer. It is suggested that patients with peritoneal metastases may benefit from the addition of intraperitoneal chemotherapy to systemic chemotherapy. Aim of this study is to establish the maximum tolerated dose of intraperitoneal irinotecan, added to standard of care systemic therapy for colorectal cancer. Secondary endpoints are to determine the safety and feasibility of this treatment and to establish the pharmacokinetic profile of intraperitoneally administered irinotecan. METHODS AND ANALYSIS: This phase I, '3+3' dose-escalation, study is performed in two Dutch tertiary referral centres. The study population consists of adult pa