Ki67 (MIB-1) as a Prognostic Marker for Clinical Decision Making Before Extended Pleurectomy Decortication in Malignant Pleural Mesothelioma

INTRODUCTION: The role of surgery for early stage malignant pleural mesothelioma (MPM) remains controversial. Current expert opinion is only to treat patients surgically as part of multimodality therapy. It is still challenging to identify patients who will not benefit from surgery. We specifically evaluated tumor-related parameters in combination with clinical parameters to identify prognostic markers for survival. METHODS: Clinical data of 27 consecutive patients with MPM treated with extended pleurectomy and decortication within a multimodality approach were collected and analyzed. Several tumor (immuno-)histopathologic characteristics were determined on resected tumor material, among which MTAP and Ki67 (MIB-1). Univariable and multivariable analyses served to correlate clinical and tumor-related parameters to overall survival (OS) and progression-free survival (PFS). RESULTS: The median PFS (mPFS) was 15.3, and the median OS (mOS) was 26.5 months. Patients with a Ki67 score greater than 10% had a significantly shorter PFS (mPFS = 8.81 versus 25.35 mo, p = 0.001) and OS (mOS 19.7 versus 44.5 mo, p = 0.002) than those with a Ki67 score less than or equal to 10. Receiver operating characteristic curve analysis for Ki67 revealed an area under the curve of 0.756 with a sensitivity of 90% and specificity of 71% for a cutoff of 10% for Ki67. Patients with loss of MTAP had a significantly shorter mPFS (9 versus 21.1 mo, p = 0.014) and mOS (19.7 versus 42.6 mo, p = 0.047) than those without MTAP loss. CONCLUSIONS: In our study, Ki67 was prognostic for OS and PFS in patients with MPM treated with extended pleurectomy/decortication in a multimodality approach. Determination of Ki67 before surgery combined with specific clinical parameters could assist in clinical decision making by identifying patients, with high Ki67, who are unlikely to benefit from surgery

The Accuracy of the Surgical Peritoneal Cancer Index in Patients with Peritoneal Metastases of Colorectal Cancer

Introduction : The peritoneal cancer index (PCI) is one of the most important prognostic factors in patients with peritoneal metastases from colorectal cancer undergoing cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS-HIPEC). The PCI is determined during laparotomy by 2 experienced surgeons and plays a major role in the decision to proceed with CRS-HIPEC. The primary objective of this study was to determine the accuracy of the surgical PCI (sPCI) by comparing it with the PCI confirmed by the pathologist (pPCI). Methods : All consecutive patients who underwent CRS-HIPEC for colorectal peritoneal metastases between February 2015 and June 2018 were identified. Relevant patient- and tumor-related characteristics were collected. Results : In total, 119 patients were included, 60 males (50.4%). The median age was 64 (IQR 55-71). The median sPCI (sPCI = 11, IQR 6-16) was significantly higher than the median pPCI (pPCI = 8, IQR 3-13, p < 0.001). The total pPCI was lower than the total sPCI in 80 patients (67.2%). In 21 patients (17.6%), the sPCI was overestimated with ≥5 points. Small lesions are more likely to be negative. In patients that underwent resection of their primary tumor prior to CRS-HIPEC, the difference between the sPCI and pPCI was significantly larger (p < 0.05). Conclusions : Surgical calculation of the PCI often results in overestimation. Far-reaching consequences are tied to the macroscopic evaluation of the sPCI, but this evaluation seems not very reliable

The Impact of Low Skeletal Muscle Mass on Short- and Long-Term Outcomes After Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy

Background: Cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) is a potentially curative treatment for peritoneal metastases from colorectal cancer (CRC) or pseudomyxoma peritonei (PMP). Because of the considerable morbidity of this treatment, optimal patient selection is key. This study aimed to assess the impact of low skeletal muscle mass (SMM) on outcomes after CRS-HIPEC. Methods: Patients who underwent CRS-HIPEC between 2014 and 2020 at a tertiary center were included. SMM was measured on computed tomography by means of the L3 muscle index. Postoperative complications and survival outcomes were compared between groups by use of logistic regression and Kaplan-Meier survival analyses. Results: Of 284 included patients, 149 had low SMM. Occurrence of severe postoperative complications did not differ between groups (28.9% for patients with low vs. 34.1% for patients with normal SMM). Low SMM was not associated with postoperative complications (p = 0.344). For CRC patients, no significant differences were observed in disease-free (DFS) or overall survival (OS) between patients with low (median DFS 7 months [IQR 4–14], median OS 33 months [IQR 14–NR]) and patients with normal SMM (median DFS 8 months [IQR 5–20], median OS 35 months [IQR 18–NR]). Regarding PMP, survival outcomes did not significantly differ between groups (3-year DFS 47.3% for patients with low SMM vs. 54.5% for patients with normal SMM, p = 0.676; 3-year OS 70.8% vs. 90.9% respectively, p = 0.172). Conclusions: Low SMM could not be identified as a predictor of severe complications or survival outcomes after CRS-HIPEC

Treatment and Survival Outcomes for Patients with Colorectal Peritoneal Metastases Deemed Ineligible for Cytoreductive Surgery (CRS) with Hyperthermic Intraperitoneal Chemotherapy (HIPEC): Results of a Retrospective Study

Background: Cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) is a treatment option for selected patients with colorectal peritoneal metastases (PM). This report provides an overview of treatment and survival outcomes for patients deemed ineligible for CRS-HIPEC.  Methods: Colorectal PM patients referred to a tertiary center from 2014 to 2020 that were ineligible for CRS-HIPEC were included. Patient, tumor, and treatment characteristics were provided. Survival analyses were performed using the Kaplan-Meier method.  Results: Of 476 patients referred for CRS-HIPEC, 227 (48%) were deemed ineligible. Median follow-up was 15 months [IQR 10–22]. Data on follow-up treatment was available for 198 patients, of which 73% received systemic therapy. These patients had a median overall survival (OS) of 17 months [IQR 9–25]. For patients receiving best supportive care (BSC) median OS was 4 months [IQR 2–9]. The main reason for ineligibility was extensive PM (42%), with a median OS of 11 months [IQR 5–18]. Patients deemed ineligible due to (extensive) liver (9%) or lung metastases (8%) showed longer OS (median 22 months, IQR 8–27, and 24 months, IQR 12–29, respectively) than patients with extensive PM (median 11 months, IQR 5–18) or distant lymph node metastases (median 14 months, IQR 4–25).  Conclusion: The main reason for CRS-HIPEC ineligibility was extensive PM. The majority of patients received systemic therapy. Patients deemed ineligible due to extra-peritoneal metastases had better survival outcomes than patients deemed ineligible due to extensive PM

Survival Outcomes After Cytoreductive Surgery with Hyperthermic Intraperitoneal Chemotherapy in Patients with Synchronous Versus Metachronous Onset of Peritoneal Metastases of Colorectal Carcinoma

Background: Cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) is a treatment option for peritoneal metastases (PM) from colorectal carcinoma (CRC). Because of considerable morbidity, optimal patient selection is essential. This study was designed to determine the impact of the onset of PM (synchronous vs. metachronous) on survival outcomes after CRS-HIPEC. Methods: Patients undergoing CRS-HIPEC for colorectal PM in two academic centers in the Netherlands between 2010 and 2020 were eligible for inclusion. Patients were classified as synchronous (s-PM, i.e., diagnosis at time of presentation, staging, or primary surgery) or metachronous onset (m-PM, i.e., diagnosis during follow-up) of colorectal PM. Survival outcomes were compared between groups by Kaplan–Meier survival and Cox regression analyses. Results: Of 390 included patients, 179 (45.9%) had synchronous onset of colorectal PM. These patients more often presented with higher TN-stage and poor differentiation/signet cell histology. Treatment with perioperative chemotherapy was more common in s-PM patients. m-PM patients experienced more serious postoperative complications (Clavien-Dindo ≥ III). There was no significant difference in disease-free survival (DFS) between s-PM (median 9 months, interquartile range [IQR] 5–15) and m-PM patients (median 8 months, IQR 5–17). Overall survival (OS) was significantly shorter for s-PM (median 28 months, IQR 11–48) versus m-PM patients (median 33 months, IQR 18–66, p = 0.049). Synchronous onset of PM was not independently associated with OS in a multivariable analysis. Conclusions: Synchronous onset of colorectal PM was associated with poor tumor characteristics and more advanced disease, but was not an independent predictor of survival outcomes after CRS-HIPEC

Intraperitoneal paclitaxel for patients with primary malignant peritoneal mesothelioma: a phase I/II dose escalation and safety study-INTERACT MESO

Introduction Malignant peritoneal mesothelioma (MPM) is a rare, aggressive tumour arising primarily from the peritoneum. The only potentially curative treatment is cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC). However, the majority of patients are not eligible to undergo this treatment. The benefit of systemic treatment for these patients is limited at the cost of considerable morbidity. Hence, there is a need for appropriate palliative treatment options for patients with MPM. As MPM rarely disseminates outside the abdominal cavity, these patients might benefit from local treatment. A higher, more effective dose of chemotherapy can directly be delivered at the site of the disease. Systemic uptake will be limited, likely resulting in less toxicity. The aim of the INTERACT MESO trial is to determine the maximum tolerable dose of intraperitoneal paclitaxel monotherapy in patients with MPM. Secondary endpoints are to assess safety and toxicity, feasibility and the pharmacokinetic profile of this treatment. Methods and analysis The INTERACT MESO trial is a prospective, open-label, single-centre, phase I study with a classic three-plus-three dose escalation design. The study population consists of adult patients with primary MPM, without extra-abdominal disease, who are not eligible to undergo CRS-HIPEC. According to standard of care work-up for CRS-HIPEC, patients will undergo diagnostic laparoscopy to determine the feasibility of CRS-HIPEC. In case CRS-HIPEC is not considered feasible, a peritoneal port-a-cath (PAC) system will be placed. Through this PAC, 8-16 weekly cycles of intraperitoneal chemotherapy will be administered. Ethics and dissemination The Central Committee on Research Involving Human Subjects (CCMO, The Hague, The Netherlands) and the Medical Research Ethics Committee (METC, Rotterdam, The Netherlands) have granted permission to carry out this study protocol. The results of this trial will be submitted for publication in a peer-reviewed scientific journal. Trial registration number NL9718. EudraCT: 2021-003637-11