Feasibility and Safety of Laparoscopic D2 Gastrectomy in Combination with Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC) in Patients with Gastric Cancer at High Risk of Recurrence-The PIPAC-OPC4 Study.

BACKGROUND: Patients with gastric adenocarcinoma (GAC) are at high risk of peritoneal recurrence despite perioperative chemotherapy and radical resection. This study evaluated feasibility and safety of laparoscopic D2 gastrectomy in combination with pressurized intraperitoneal aerosol chemotherapy (PIPAC). METHODS: This was a prospective, controlled bi-institutional study in patients with GAC at high risk of recurrence treated with PIPAC with cisplatin and doxorubicin (PIPAC C/D) after laparoscopic D2 gastrectomy. High risk was defined as a poorly cohesive subtype with predominance of signet-ring cells, clinical stage ≥ T3 and/or ≥ N2, or positive peritoneal cytology. Peritoneal lavage fluid was collected before and after resection. Cisplatin (10.5 mg/m2) and doxorubicin (2.1 mg/m2) were aerosolized after anastomosis (flow 0.5-0.8 ml/s, maximum pressure 300 PSI). Treatment was feasible and safe if ≤ 20% had Dindo-Clavien ≥ 3b surgical complications or CTCAE ≥ 4 medical adverse events within 30 days. Secondary outcomes were length of stay (LOS), peritoneal lavage cytology, and completion of postoperative systemic chemotherapy. RESULTS: Twenty-one patients were treated with a D2 gastrectomy and PIPAC C/D. The median age was 61 years (range 24-76), there were eleven female patients, and 20 patients had preoperative chemotherapy. There was no mortality. Two patients had grade 3b complications that were potentially related to PIPAC C/D (one anastomotic leakage, and one late duodenal blow-out). One patient had severe neutropenia, and nine patients had moderate pain. The LOS was 6 days (4-26). One patient had positive peritoneal lavage cytology before resection, and none were positive after. Fifteen patients had postoperative chemotherapy. CONCLUSIONS: Laparoscopic D2 gastrectomy in combination with PIPAC C/D is feasible and safe.

Treatment of Peritoneal Metastasis with Pressurized Intraperitoneal Aerosol Chemotherapy: Results from the Prospective PIPAC-OPC2 Study.

BACKGROUND: Pressurized Intraperitoneal Aerosol chemotherapy (PIPAC) is a local treatment for peritoneal metastasis (PM). Prospective data are scarce and evaluation of treatment response remains difficult. This study evaluated the use of the Peritoneal Regression Grading score (PRGS) and its prognostic value. PATIENTS AND METHODS: This was a prospective, controlled phase II trial in patients with PM from gastrointestinal, gynaecological, hepatopancreatobiliary, primary peritoneal, or unknown primary cancer. Patients in performance status 0-1, with a non-obstructed gastrointestinal tract, and a maximum of one extraperitoneal metastasis were eligible. Colorectal or appendiceal PM had PIPAC with oxaliplatin, other primaries had PIPAC with cisplatin and doxorubicin. Biopsies were taken at each PIPAC and evaluated using the PRGS. Quality-of-life questionnaires were reported at baseline and after three PIPACs. RESULTS: One hundred ten patients were treated with 336 PIPACs (median 3, range 1-12). One hundred patients had prior palliative chemotherapy and 45 patients received bidirectional treatment. Complete or major histological response to treatment (PRGS 1-2) was observed in 38 patients (61%) who had three PIPACs, which was the only independent prognostic factor in a multivariate analysis. The median overall survival (mOS) from PIPAC 1 was 10 months, while patients with PM from gastric, colorectal, and pancreatic cancer had a mOS of 7.4, 16.7, and 8.2 months, respectively. Global health scores were significantly reduced, but patients were less fatigued, nauseated, constipated, and had better appetite after three PIPACs. CONCLUSIONS: PIPAC with oxaliplatin or cisplatin and doxorubicin was able to induce a major or complete histological response during three PIPACs, which may provide significant prognostic information, both at baseline and after treatment.

Encorafenib, Binimetinib, and Cetuximab in BRAF V600E-Mutated Colorectal Cancer.

BACKGROUND: Patients with metastatic colorectal cancer with the BRAF V600E mutation have a poor prognosis, with a median overall survival of 4 to 6 months after failure of initial therapy. Inhibition of BRAF alone has limited activity because of pathway reactivation through epidermal growth factor receptor signaling. METHODS: In this open-label, phase 3 trial, we enrolled 665 patients with BRAF V600E-mutated metastatic colorectal cancer who had had disease progression after one or two previous regimens. Patients were randomly assigned in a 1:1:1 ratio to receive encorafenib, binimetinib, and cetuximab (triplet-therapy group); encorafenib and cetuximab (doublet-therapy group); or the investigators' choice of either cetuximab and irinotecan or cetuximab and FOLFIRI (folinic acid, fluorouracil, and irinotecan) (control group). The primary end points were overall survival and objective response rate in the triplet-therapy group as compared with the control group. A secondary end point was overall survival in the doublet-therapy group as compared with the control group. We report here the results of a prespecified interim analysis. RESULTS: The median overall survival was 9.0 months in the triplet-therapy group and 5.4 months in the control group (hazard ratio for death, 0.52; 95% confidence interval [CI], 0.39 to 0.70; P<0.001). The confirmed response rate was 26% (95% CI, 18 to 35) in the triplet-therapy group and 2% (95% CI, 0 to 7) in the control group (P<0.001). The median overall survival in the doublet-therapy group was 8.4 months (hazard ratio for death vs. control, 0.60; 95% CI, 0.45 to 0.79; P<0.001). Adverse events of grade 3 or higher occurred in 58% of patients in the triplet-therapy group, in 50% in the doublet-therapy group, and in 61% in the control group. CONCLUSIONS: A combination of encorafenib, cetuximab, and binimetinib resulted in significantly longer overall survival and a higher response rate than standard therapy in patients with metastatic colorectal cancer with the BRAF V600E mutation. (Funded by Array BioPharma and others; BEACON CRC ClinicalTrials.gov number, NCT02928224; EudraCT number, 2015-005805-35.).

Primary tumor location and bevacizumab effectiveness in patients with metastatic colorectal cancer.

BACKGROUND: There is an unmet need for predictive markers for the antiangiogenic agent bevacizumab in metastatic colorectal cancer (mCRC). We aimed to assess whether the location of the primary tumor is associated with bevacizumab effectiveness when combined with capecitabine and oxaliplatin (CAPEOX) in the first-line treatment of patients with mCRC. PATIENTS AND METHODS: A cohort of 667 consecutive patients with mCRC from the general community treated from 2006 to 2011 with CAPEOX and bevacizumab as standard first-line therapy was compared with a cohort of 213 patients treated with CAPEOX from 2003 to 2006, before bevacizumab was approved. Main outcome measures were progression-free survival (PFS) and overall survival (OS). Differences in outcome were tested using Kaplan-Meier curves and log-rank tests, and multivariate analyses were carried out using Cox Proportional Hazards models. RESULTS: Patients treated with CAPEOX and bevacizumab with primary tumors originating in the sigmoid colon and rectum had a significantly better outcome than patients with primary tumors originating from the cecum to the descending colon, both for PFS (median PFS 9.3 versus 7.2 months; hazard ratio (HR) 0.68, 95% confidence interval (CI) 0.56-0.82) and for OS (median OS 23.5 versus 13.0 months; HR 0.47, 95% CI 0.38-0.57). This difference was confirmed in multivariate analyses after adjustment for other potentially prognostic factors. For patients treated with CAPEOX, there was no association between primary tumor location and outcome, neither in unadjusted nor adjusted analyses. CONCLUSIONS: The addition of bevacizumab to CAPEOX in first-line treatment of patients with mCRC may primarily benefit patients with primary tumors originating in the rectum and sigmoid colon. This hypothesis needs to be validated in data from completed randomized trials. CLINICALTRIALSGOV IDENTIFICATION NUMBER: NCT00212615.