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

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

A propensity score matched analysis of oncological outcome after systemic therapy for stage IV colorectal cancer:Impact of synchronous ovarian metastases

The reported incidence of synchronous and metachronous ovarian metastases (OM) from colorectal cancer (CRC) is approximately 3.4%. OM from CRC are often considered sanctuary sites due to their lower sensitivity to systemic treatment. It has thus been hypothesized that the presence of OM decreases overall survival. Therefore, the purpose of this study was to evaluate the impact of synchronous OM on overall survival in female patients with stage IV CRC treated with systemic therapy alone with palliative intent. The present study used data from the Netherlands Cancer Registry and included female CRC patients with synchronous systemic metastases who were treated with systemic therapy between 2008 and 2018. A subsample was created using propensity score matching to create comparable groups. Propensity scores were determined using a logistic regression model in which the dependent variable was the presence of OM and the independent variables were the variables that differed significantly between both groups. This study included 5,253 patients with stage IV CRC that received systemic therapy. Among these patients, 161 (3%) had OM while 5,092 (97%) had extra-ovarian metastases only. Three-year overall survival rates did not show a significant difference between patients with OM compared to patients without ovarian metastases. Moreover, the propensity score matched analysis showed that the presence of OM in patients treated with systemic therapy for stage IV CRC disease was not associated with decreased three-year overall survival. However, the results of the present study should be interpreted with caution, due to its observational character and used selection criteria.</p

Insights into synchronous peritoneal metastases from hepatobiliary origin: Incidence, risk factors, treatment, and survival from a nationwide database

Introduction: – This population-based study aimed to investigate incidence, risk factors, treatment, and survival of synchronous peritoneal metastases (PM) of hepatobiliary origin. Methods: – All Dutch patients diagnosed with hepatobiliary cancer between 2009 and 2018 were selected. Factors associated with PM were identified with logistic regression analyses. Treatments for patients with PM were categorized into local therapy, systemic therapy, and best supportive care (BSC). Overall survival (OS) was investigated using log-rank test. Results: – In total, 12 649 patients were diagnosed with hepatobiliary cancer of whom 8% (n = 1066) were diagnosed with synchronous PM (12% [n = 882/6519] in biliary tract cancer [BTC] vs. 4% [n = 184/5248] in hepatocellular carcinoma [HCC]). Factors that were positively associated with PM were the female sex (OR 1.18, 95% CI 1.03–1.35), BTC (OR 2.93, 95% CI 2.46–3.50), diagnosis in more recent years (2013–2015: OR 1.42, 95% CI 1.20–1.68; 2016–2018: OR 1.48, 95% CI 1.26–1.75), T3/T4 stage (OR 1.84, 95% CI 1.55–2.18), N1/N2 stage (OR 1.31, 95% CI 1.12–1.53) and other synchronous systemic metastases (OR 1.85, 95% CI 1.62–2.12). Of all PM patients, 723 (68%) received BSC only. Median OS was 2.7 months (IQR 0.9–8.2) in PM patients. Conclusion: – Synchronous PM were found in 8% of all hepatobiliary cancer patients and occurred more often in BTC than in HCC. Most patients with PM received BSC only. Given the high incidence and dismal prognosis of PM patients, extended research in hepatobiliary PM is needed to achieve better outcome in these patients

The importance of integrating diagnostic modalities in patient selection for CRS-HIPEC in colorectal peritoneal metastases

Background Despite thorough preoperative work-up for cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS-HIPEC), so called open-close (OC) procedures as a result of irresectable disease remain common. Currently, diagnostic laparoscopy (DLS) is considered the gold standard, and consequently overrules the results of computed tomography (CT) scans; however, certain regions of the abdomen are difficult to assess and postoperative adhesion formation may further compromise staging during DLS.Purpose To determine whether better clinical assessment could be achieved by combining the results of DLS and preoperative CT scans during a multidisciplinary team (MDT) meeting.Material and Methods All patients who were eligible for CRS-HIPEC after DLS, but eventually underwent an OC procedure between 2010 and 2018 were selected. Radiological reassessment of CT scans was performed and combined with assessment of the DLS during a MDT meeting. The MDT was blinded for the outcome of the procedure (OC vs. CRS-HIPEC).Results The majority of the OC procedures (69%) was correctly predicted by the MDT. In most patients (88%), this conclusion was based on the combination of the radiological and surgical peritoneal cancer index (PCI). CT was particularly accurate for detection of larger tumor deposits in the abdominal regions, as 84%-86% was detected. Assessment of lesions in the small bowel regions is troublesome; 72% of lesions are missed on the preoperative CT scan.Conclusions A combination of radiological and surgical assessment of the PCI may lead to improved preoperative patient selection for CRS-HIPEC

Synchronous peritoneal metastases from lung cancer:incidence, associated factors, treatment and survival: a Dutch population-based study

Peritoneal metastases (PM) from lung cancer are rare and it is unknown how they affect the prognosis of patients with lung cancer. This population-based study aimed to assess the incidence, associated factors, treatment and prognosis of PM from lung cancer. Data from the Netherlands Cancer Registry were used. All patients diagnosed with lung cancer between 2008 and 2018 were included. Logistic regression analysis was performed to identify factors associated with the presence of PM. Cox regression analysis was performed to identify factors associated with the overall survival (OS) of patients with PM. Between 2008 and 2018, 129,651 patients were diagnosed with lung cancer, of whom 2533 (2.0%) patients were diagnosed with PM. The European Standardized Rate of PM increased significantly from 0.6 in 2008 to 1.4 in 2018 (p < 0.001). Age between 50 and 74 years, T3–4 tumour stage, N2–3 nodal stage, tumour morphology of a small cell lung cancer or adenocarcinoma, and the presence of systemic metastases were associated with the presence of PM. The median OS of patients with PM was 2.5 months. Older age, male sex, T3–4 tumour stage, N2–3 nodal stage, not receiving systemic treatment, and the presence of systemic metastases were associated with a worse OS. Synchronous PM were diagnosed in 2.0% of patients with lung cancer and resulted in a very poor survival

The impact of an open or laparoscopic approach on the development of metachronous peritoneal metastases after primary resection of colorectal cancer: results from a population-based cohort study

Background: This study aimed to assess the impact of open or laparoscopic resection of primary colorectal cancer (CRC) on the development of metachronous colorectal peritoneal metastases (CPM) in a population-based cohort. Materials and methods: This was a retrospective, population-based study of CRC patients who underwent open or laparoscopic resection of the primary tumour in the Netherlands between January 1st and June 30th 2015. Patients with synchronous metastases were excluded. CPM were considered metachronous if diagnosed ≥ 90 days after resection of primary CRC. Multivariable cox regression analysis was performed to correct for tumour location, histology, differentiation, and stage, nodal stage, tumour perforation, primary surgery type, and unclear resection margins. Results: In total, 1516 CRC patients underwent open resection and 3236 CRC patients underwent laparoscopic resection, with a 3-year cumulative incidence of metachronous CPM of 7.3% and 3.7%, respectively (p < 0.001), after median follow-up of 42 months. Open surgical approach was significantly associated with the development of metachronous CPM: HR 1.4 [95%CI 1.1–1.8]. Other prognostic factors were mucinous adenocarcinoma histology (HR 1.6, 95%CI 1.0–2.5), T4 stage (HR 3.2, 95%CI 2.3–4.5), N1 stage (HR 2.9, 95%CI 2.1–4.0), and N2 stage (HR 4.2, 95%CI 2.9–6.1). Conclusions: Patients treated with open resection had a significantly higher risk to develop metachronous CPM than patients treated with laparoscopic resection. The mechanisms underlying this phenomenon remain unknown but might be related to differences in per-operative specimen handling, tumour spill, surgical trauma and pro-inflammatory response. This finding might imply the need for a personalized follow-up after primary resection of CRC

The Impact of Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy (CRS-HIPEC) versus Conventional Surgery on Patient-Reported Outcomes: A Comparative Cohort Study between the CAIRO6 Trial and the PROCORE Study

Purpose&mdash;To compare patient-reported outcomes (PROs) of patients undergoing cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) for colorectal peritoneal metastases to PROs of colorectal cancer (CRC) patients undergoing conventional surgery. Methods&mdash;Data were extracted from the CAIRO6 trial (CRS-HIPEC group) and the PROCORE study (conventional surgery group). Nine predefined PROs (derived from the EORTC QLQ-C30 questionnaire) were compared at baseline, in the early postoperative period and one year postoperatively, with correction for treatment with systemic therapy using linear mixed modeling. Results&mdash;In total, 331 patients were included: 71 in the CRS-HIPEC group and 260 in the conventional surgery group. All predefined PROs (fatigue, diarrhea, C30 summary score, Global Health Status, physical, role, emotional, cognitive, and social functioning) did not differ significantly between the groups at all three timepoints, and differential effects over time for all PROs did not differ significantly between the groups. Significant worsening of fatigue, C30 summary score, physical and role functioning (both groups), and cognitive and social functioning (conventional surgery group only) was present in the early postoperative period. All scores returned to baseline at one year postoperatively, except for physical and cognitive functioning in the conventional surgery group. Emotional functioning improved postoperatively in both groups compared to baseline. Conclusion&mdash;Despite a more extensive procedure with greater risk of morbidity, CRS-HIPEC in patients with colorectal peritoneal metastases did not have a greater negative impact on PROs than conventional surgery in patients with CRC. Further, systemic therapy did not affect these PROs. These findings may facilitate future patient counseling and shared decision making in clinical practice

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