The role of molecular biomarkers in outcomes and patient selection for cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for peritoneal metastases of colorectal origin.

BACKGROUND: Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) is effective in select patients with peritoneal metastases of colorectal (CRC) origin. The impact of different biomarkers in predicting recurrence after CRS/HIPEC is unclear. METHODS: Retrospective review of patients who underwent CRS/HIPEC for PC of CRC origin from 03/2007-08/2017. Molecular profile of the primary tumor was obtained from pathology reports, whenever available. RESULTS: Overall, 100 patients underwent CRS/HIPEC for peritoneal metastases of CRC origin. Most patients presented high grade tumor histology (G2/G3, n = 97, 97%), and a majority showed mucinous features (n = 61, 61%). At a median follow-up of 18 months, median DFS for the overall population was 13 months (95% CI 9.6, 16.4). Data reporting at least one mutational analysis was available in 64 patients. Microsatellite stability was detected in 42/50 (84%) patients, mKRAS in 25/51 (49%), and mBRAF in 5/35 (14.3%). On Kaplan-Meier analysis, BRAF was the only mutation associated with poor DFS (16 months, CI 95% 11.7-43.3 vs. 7 months, CI 95% 2.1-11.9, p = .008). On multivariate analysis, mBRAF independently predicted earlier recurrence (p = .032). CONCLUSIONS: In this analysis, mBRAF was independently associated with earlier recurrence in patients undergoing CRS/HIPEC for CRC, leading to dismal median DFS (7 months). Strict patient selection is advisable in these patients.

Improved Survival with Experience: A 10-Year Learning Curve in Hyperthermic Intraperitoneal Chemotherapy and Cytoreductive Surgery.

BACKGROUND: Cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) is an aggressive locoregional treatment for peritoneal carcinomatosis (PC). Studies demonstrate improved perioperative and oncologic outcomes at high-volume centers. METHODS: This study retrospectively analyzed all patients with PC from various malignancies who underwent attempted CRS/HIPEC at the authors' institution from 2007 to 2017. Clinicopathologic, perioperative, and oncologic outcomes of early (2007-2012) and late (2012-2017) experience were compared, and multivariate analyses for factors predictive of perioperative and oncologic outcomes were performed. RESULTS: The study enrolled 388 patients (157 early and 231 late). The late experience contained more appendiceal low-grade mucinous neoplasms (LGMNs; 21% vs 9%) and had a lower Peritoneal Cancer Index (PCI; 10 vs 16). Moreover, achieving a similar rate of CC-0/1 required fewer organ resections, involved shorter operations (298 vs 347 min), and had lower estimated blood loss (EBL) (400 vs 200 ml) (p < 0.05). More procedures were aborted (20% vs 3%; p < 0.01). The late experience had fewer ICU admissions (13% vs. 55%) and a lower perioperative mortality rate (0% vs 3%) (p < 0.05). In the multivariate analyses, PCI and number of organ resections were independent predictors of multiple perioperative outcomes [EBL, operating room time, intensive care unit (ICU) admission, ICU length of stay (LOS), overall LOS]. Survival was significantly longer in the late cohort (median overall survival: NR vs 31 months; progression-free survival: 22 vs 11 months; p < 0.01), even after control for tumor histology. CONCLUSIONS: At the authors' high-volume center, with increased surgeon and institutional experience over time, perioperative and oncologic outcomes have improved significantly for patients undergoing CRS/HIPEC for PC.

Assessing the Implementation of American College of Surgeons Quality Indicators for Pancreatic Cancer Across an Integrated Health System.

PURPOSE: The American College of Surgeons (ACS) recently published quality assurance (QA) indicators for pancreatic cancer care. Implementing quality indicators in a newly formed health system may lead to better patient selection and standardized cancer care. METHODS: Select ACS and internal quality indicators were implemented system wide in 2014. We compared compliance with these measures before and after their implementation at the main hospital and two new affiliate institutions. RESULTS: A total of 506 patients with pancreatic cancer were included. At the main hospital in the pre-QA period, 11 (12.6%) of 87 patients were discussed at our institutional multidisciplinary tumor board meeting; this number rose to 89 (49.7%) of 179 patients (P < .001) after the implementation. Clinical TNM stage was documented in the electronic medical record in 75 patients (86.2%) in the pre-QA group; this number rose to 170 (94.9%; P = .026) in the post-QA era. External imaging of patients undergoing resection was uploaded in 10 (66.7%) of 15 patient cases in the pre-QA period; this number rose to 33 (93.4%) of 35 (P = .020). Rates of time from diagnosis to treatment initiation shorter than 60 days were similar between eras (n = 26, 96.3% v n = 57, 95%). Implementation of QA measures at the affiliate institutions did not result in measurable differences. There were no differences in margin-negative resection rate, lymph node yield, or perioperative mortality after QA implementation at any site. CONCLUSION: The implementation of ACS quality indicators at our main hospital was feasible and effective for several measures, without delaying treatment. Instituting these indicators at lower-volume affiliates was more challenging.

Staging gallbladder cancer with lymphadenectomy: the practical application of new AHPBA and AJCC guidelines.

BACKGROUND: Current guidelines recommend harvesting a total lymph node count (TLNC) ≥6 from portal lymphadenectomy in ≥pT1b gallbladder cancers (GBC) for accurate staging and prognostication. This study aimed to determine nodal yields from portal lymphadenectomy and identify measures to maximize TLNC. METHODS: We retrospectively reviewed all ≥pT1b GBC which underwent resection with curative intent including portal lymphadenectomy at our specialized HPB center from 2007 to 2017. We compared outcomes of TLNC < 6 and TLNC ≥ 6 cohorts and determined factors predictive of TLNC. RESULTS: Of 92 patients, 20% had a TLNC ≥ 6 (IQR 7-11) and 9% had no nodes found on pathology. Malignant lymphadenopathy was twice as common in TLNC ≥ 6 as TLNC < 6 (p = 0.003) most frequently from portal, cystic and pericholedochal stations. On logistic regression analysis, concomitant liver resection was an independent predictor of higher TLNC [4b/5 wedge resection (OR 0.166, CI 0.057-0.486, p = 0.001) extended hepatectomy (OR 0.065, CI 0.012-0.340, p = 0.001)]; biliary resection and en bloc adjacent organ resection were not. CONCLUSION: At our center, prior to current guidelines, a TLNC≥6 was not met in 80% undergoing portal lymphadenectomy for ≥ pT1b GBC. To increase nodal yield, future guidelines should consider including additional lymph node stations and incorporation of frozen section analysis.

More Synchronous Peritoneal Disease but Longer Survival in Younger Patients with Carcinomatosis from Colorectal Cancer Undergoing Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy.

BACKGROUND: Colonoscopy to detect colorectal cancer (CRC) is recommended starting at age 50 years; however, CRC rates are increasing in the prescreening population. Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) has been proven effective in select patients with peritoneal carcinomatosis (PC) from CRC, although it has not been evaluated specifically in patients < 50 years. METHODS: CRC patients aged < 50 years at diagnosis undergoing CRS/HIPEC 2007-2017 were compared with those aged ≥ 50 years. Age distribution was analyzed in patients undergoing colectomy alone versus CRS/HIPEC for CRC 1993-2013. RESULTS: A total of 98 patients underwent CRS/HIPEC, of which 44% were < 50 years. Younger patients were more likely to present with synchronous peritoneal metastases (p = 0.050). Receipt of perioperative chemotherapy was comparable (p = not significant [NS]). Charlson Comorbidity Index and ECOG score were similar (p = NS). Tumor grade was similar (p = NS). Peritoneal Carcinomatosis Index, total organs resected, and anastomoses created were comparable (p = NS). Major Clavien-Dindo morbidity and LOS were similar (p = NS). Younger patients survived longer after CRS/HIPEC (p = 0.011). Demographic data from patients undergoing colectomy (n = 225) and CRS/HIPEC (n = 98) showed that age < 50 years was increasingly common with the more aggressive procedure (9% and 44% respectively, p < 0.001). CONCLUSIONS: Younger patients with PC from CRC presented more often with peritoneal metastases at the time of diagnosis. Yet despite similar perioperative features at CRS/HIPEC, they survived longer than older patients. Patients undergoing CRS/HIPEC are overall younger than those undergoing index colectomy.

Signet ring cell features with peritoneal carcinomatosis in patients undergoing cytoreductive surgery and hyperthermic intraperitoneal chemotherapy are associated with poor overall survival.

BACKGROUND: Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) is effective in select patients with peritoneal carcinomatosis (PC). Signet ring cell (SRC) pathology is associated with poor prognosis. The role of CRS/HIPEC in this population is unclear. METHODS: Patients diagnosed with PC due to appendiceal (AC), colorectal (CRC), and gastric cancer (GC) undergoing CRS/HIPEC 2007-2016 were included. RESULTS: A total of 268 patients were referred for CRS/HIPEC. Of the 204 patients who underwent complete CRS/HIPEC, 101 (49.5%) had AC, 85 (41.7%) CRC, and 18 (8.8%) GC. Patients with GC had higher rates of SRC pathology than AC and CRC: 12 (66.7%) vs 16 (15.8%) and 10 (11.7%). The 3-year survival rate after CRS/HIPEC was 5.7% for the SRC group and 66.1% for the non-SRC group (P < 0.001). This was true for both AC and CRC subgroups (P < 0.001 for both). Overall, patients with SRC were more likely to have a peritoneal carcinomatosis index (PCI) score > 15 (P = 0.046). Upon multivariate analysis of the SRC population, PCI > 20 (P = 0.007) and GC (P = 0.008) were found to be independent predictors of poor overall survival. CONCLUSIONS: Performing CRS/HIPEC for PC from gastrointestinal malignancies presenting SRC features is recommended on patients with select diseases of appendiceal and colorectal origins.

Sites of Recurrence After Complete Cytoreduction and Hyperthermic Intraperitoneal Chemotherapy for Patients with Peritoneal Carcinomatosis from Colorectal and Appendiceal Adenocarcinoma: A Tertiary Center Experience.

BACKGROUND: This report describes patterns of disease recurrence after optimal cytoreduction (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) for peritoneal carcinomatosis (PC) of colorectal (CRC) and appendiceal adenocarcinoma (AC) origin. METHODS: Patients undergoing optimal CRS/HIPEC (2007-2016) at the authors' institution were retrospectively reviewed from a prospectively maintained database. Data regarding disease recurrence were analyzed. RESULTS: Of 74 patients who underwent CRS/HIPEC for PC from CRC (n = 46) or AC (n = 28), 49 (66%) had recurrence during a median follow-up period of 39.5 months. The sites of recurrence were peritoneal-only (n = 34, 69%), hematogenous-only (n = 6, 12%), and combined peritoneal and hematogenous (n = 9, 19%) sites. No patients with AC had hematogenous-only recurrence. The median disease-free survival (DFS) time for all the patients was 15 months (95% confidence interval [CI] 12.5-17.5 months). The recurrence rate after CRS/HIPEC was 41% at 1 year, 73% at 3 years, and 76% at 5 years. All the patients with hematogenous-only metastases experienced recurrence within 12 months after CRS/HIPEC. Mucinous or signet ring features predicted peritoneal recurrence (p = 0.041), whereas a complete cytoreduction of 1 was a predictor of early recurrence (p = 0.040). Patients who underwent repeat cytoreduction survived longer than those who received systemic chemotherapy alone. The median survival time after peritoneal-only recurrence was 33 months (95% CI 27.8-38.9 months). CONCLUSION: Recurrence for patients with PC is common, even after optimal CRS/HIPEC. Hematogenous-only recurrence occurs early after CRS/HIPEC, suggesting occult disease at the time of treatment and highlighting the need for methods to identify micro-metastases and improve patient selection. Patients experiencing peritoneal-only recurrence had long survival period after CRS/HIPEC, suggesting its effectiveness at controlling peritoneal disease for a time.

Conflicting Data on the Incidence of Leukopenia and Neutropenia After Heated Intraperitoneal Chemotherapy with Mitomycin C.

BACKGROUND: During heated intraperitoneal chemotherapy (HIPEC), neutropenia rates of 20 to 40% have been reported when mitomycin C (MMC) is dosed by weight or body surface area (BSA). This study investigated the authors' HIPEC experience using a fixed 40-mg dose of MMC, per consensus guidelines, and analyzed predictors for severe leukopenia and neutropenia. METHODS: Patients who underwent MMC-HIPEC from 2007 to 2016 at a single tertiary care center were retrospectively reviewed. RESULTS: Among 314 MMC-HIPEC cases, 72 patients in the early era of the authors' program received routine prophylactic postoperative granulocyte-colony-stimulating factor (GCSF). This early cohort had five severe leukopenic reactions and one neutropenic reaction. In the subsequent 242 cases without GCSF prophylaxis, severe leukopenia developed in 16 patients (7%), with neutropenia occurring in 11 (4.5%) of these cases. A history of prior systemic chemotherapy was noted in 9 (56%) of the 16 leukopenic patients compared with 112 (46%) of the patients who had no leukopenia (nonsignificant difference). The median nadir of leukopenia was 5 days (range 1-11 days). Of the 11 neutropenic patients, 6 received therapeutic GCSF, and 5 recovered without intervention. The 30-day postoperative mortality of the patients with leukopenia was 0%. CONCLUSION: In this study, the incidence of neutropenia after HIPEC with 40 mg of MMC was markedly lower than reported in the literature for doses adjusted by BSA or weight. The authors report that GCSF is not necessary for routine prophylaxis of all MMC-HIPEC patients. The findings suggest that a fixed 40-mg dose of MMC allows HIPEC to be performed with less risk of immunosuppression.