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.

Surveillance of Low-Grade Appendiceal Mucinous Neoplasms With Peritoneal Metastases After Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy: Are 5 Years Enough? A Multisite Experience.

BACKGROUND: Low-grade appendiceal mucinous neoplasms (LAMNs) are tumors that often present with widespread mucin in the peritoneal cavity (pseudomyxoma peritonei [PMP]). Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) are effective treatment, but no published recommendations exist regarding surveillance. METHODS: Data from prospective databases of patients who underwent CRS-HIPEC from 2001 to 2017 at two high-volume institutions were retrospectively analyzed. Patients who underwent complete CRS-HIPEC for PMP secondary to LAMN were included in the analysis. Pathologic examination confirmed the diagnosis of LAMN. Cases of mucinous adenocarcinomas and neuroendocrine tumors (goblet cell carcinoids) were excluded. RESULTS: The study enrolled 156 patients. The median peritoneal cancer index (PCI) was 18 (interquartile range IQR1-3, 12-23), and 125 patients (80.1%) had a CC0 cytoreduction. According to American Joint Committee on Cancer (AJCC) grading, 152 patients (97.4%) presented with acellular mucin or G1 implants, 2 patients (1.3%) presented with G2 disease, and 2 patients (1.3%) presented with G3 disease. During the follow-up period (median, 45 months; IQR1-3 23-76 months), 23 patients (14.7%) experienced recurrence. All the recurrences were peritoneal and occurred within 5 years. The 1-, 3-, and 5-year disease-free survival (DFS) rates were respectively 95.5%, 83.4%, and 78.3%. Univariate Cox regression analysis showed that higher PCI scores (p < 0.001), a CC1 cytoreduction (p = 0.005), and higher preoperative levels of carcinoembryonic antigen (CEA) (p = 0.012) and CA-125 (p = 0.032) correlated with a shorter DFS. Only higher PCI scores independently predicted earlier recurrences (p < 0.001). CONCLUSION: Most patients had recurrence within 3 years after CRS-HIPEC, and none after 5 years. High PCI was the only independently significant variable. The study findings support intensive surveillance (every 3-6 months) with tumor markers and imaging methods during the first 3 years, and annual surveillance thereafter, with follow-up assessment after 5 years yielding limited benefit.

Correction to: Surveillance of Low-Grade Appendiceal Mucinous Neoplasms With Peritoneal Metastases After Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy: Are 5 Years Enough? A Multisite Experience.

In the original version of the article, Margaret Hofstedt's last name was misspelled.

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.

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.

Are Clinical Guidelines for the Management of Intraductal Papillary Mucinous Neoplasms Followed?: A Single-Center Analysis.

OBJECTIVES: This study aimed to determine how frequently guidelines for the management of intraductal papillary mucinous neoplasms (IPMNs) are followed and establish factors associated with failure. METHODS: Four hundred forty-five patients with radiographic diagnosis of IPMN 1 cm or greater between January 1, 2003 and January 1, 2013 were included. We defined failure of guideline adherence if the following occurred: (a) failure of acknowledgment of IPMN, (b) failure to undergo endoscopic ultrasound, (c) failure to undergo resection, or (d) failure to undergo at least 1 surveillance image within 2 years after diagnosis. RESULTS: Failure of guideline adherence was observed in 58% of patients and evident across all the respective criteria (A: 38%, B: 25%, C: 29%, D: 33%). Age older than 68 years (P < 0.01), American Society of Anesthesiologists score of 3 or higher (P < 0.0001), benign findings on imaging (P < 0.0001), and major comorbid conditions (P < 0.01) were factors associated with higher rate of failure to compliance. On multivariate logistic regression, American Society of Anesthesiologists score of 3 or higher and benign features were associated with 4.0 times (95% confidence interval, 2.02-8.06) and 2.6 times (95% confidence interval, 1.60-4.07) higher odds of failure to compliance with guidelines, respectively. CONCLUSIONS: Compliance with clinical guidelines for the management of IPMN is poor. Socioeconomic factors do not seem to create a disparity to care. However, many patients with IPMN have other medical diagnoses that take priority over IPMN surveillance and treatment.

Extrahepatic metastasectomy for hepatocellular carcinoma: Predictors of long-term survival.

INTRODUCTION: We report our institutional experience with extrahepatic metastasectomy (EM) in a cohort of hepatocellular carcinoma (HCC) patients with focus on predictors of survival. METHODS: All patients diagnosed with metastatic HCC from 2001 to 2014 were retrospectively reviewed to identify those who underwent EM with therapeutic intent. Associations among multiple clinicopathological variables and survival after EM were analyzed by univariate and multivariate analyses. RESULTS: Out of 440 metastatic HCC cases, we identified 85 patients (mean age 58.8 ± 11.7 years, 81.2% males) who underwent lung (n = 36), peritoneal (n = 22), lymph node (n = 19), musculoskeletal (n = 18), and adrenal (n = 9) metastasectomy. Most patients (84.7%) underwent metachronous EM following primary liver resection or transplantation. The median follow-up period was 20.9 months, during which 55 patients (64.7%) died. The 1-/2-/5-year overall survival rates after EM were 77.4, 53.1, and 25.1%, respectively. On multivariate analysis, number of metastases resected >2 correlated independently with poor survival (HR = 2.058, P = 0.0099). EM patients had superior median survival compared to all (n = 194) metastatic HCC patients treated with sorafenib without EM during the study period (27.2 vs. 7.4 months, P < 0.001). CONCLUSION: Long-term survival may be achieved in highly selected HCC patients following EM. The presence of greater than two extrahepatic lesions correlates independently with poor survival. J. Surg. Oncol. 2016;114:469-474. © 2016 Wiley Periodicals, Inc.

The effect of locoregional therapies in patients with advanced hepatocellular carcinoma treated with sorafenib.

BACKGROUND & AIMS: It is unknown whether the addition of locoregional therapies (LRTx) to sorafenib improves prognosis over sorafenib alone in patients with advanced hepatocellular carcinoma (HCC). The aim of this study was to assess the effect of LRTx in this population. METHODS: A retrospective analysis was performed of patients with advanced HCC as defined by extrahepatic metastasis, lymphadenopathy >2 cm, or gross vascular invasion. Sorafenib therapy was required for inclusion. Survival of patients who received LRTx after progression to advanced stage was compared to those who did not receive LRTx. RESULTS: Using an intention to treat analysis of 312 eligible patients, a propensity weighted proportional hazards model demonstrated LRTx as a predictor of survival (HR = 0.505, 95% CI: 0.407-0.628; P < 0.001). The greatest benefit was seen in patients with the largest tumor burden (HR = 0.305, 95% CI: 0.236-0.393; P < 0.01). Median survival in the sorafenib arm was 143 days (95% CI: 118-161) vs. 247 days (95% CI: 220-289) in the sorafenib plus LRTx arm (P < 0.001). CONCLUSIONS: These results demonstrate a survival benefit with the addition of LRTx to sorafenib for patients with advanced HCC. These findings should prompt a prospective clinical trial to further assess the role of LRTx in patients with advanced HCC.

Prophylactic hyperthermic intraperitoneal chemotherapy in patients with epithelial appendiceal neoplasms.

Background Prophylactic hyperthermic intraperitoneal chemotherapy (HIPEC) is a promising approach for preventing peritoneal carcinomatosis in high-risk patients. We report our initial experience with prophylactic HIPEC in a series of patients with appendiceal neoplasms. Methods We retrospectively reviewed our prospectively maintained database to identify patients who underwent HIPEC in the absence of peritoneal disease. Patients with previously documented peritoneal surface disease were excluded. Data regarding clinical, operative and pathological features were analysed. Results Out of 322 HIPEC procedures performed between March 2007and August 2015, we identified 16 patients who underwent surgery with prophylactic intent. Primary diagnoses included high-grade and low-grade appendiceal neoplasms. Most patients presented originally with appendiceal perforation; all patients underwent initial surgery during which the appendix or right colon were resected. Following a median time interval of 2.2 months, a second surgery performed at our institution consisted of completion of omentectomy, partial colectomy and oophorectomy, with administration of prophylactic HIPEC (using mitomycin C). A totally laparoscopic approach was attempted and achieved in 11 patients in whom the median duration of surgery, estimated intraoperative blood loss and length of hospitalisation were 251 min, 100 cm(3) and 4 days, respectively. There were no cases of major perioperative morbidity or mortality. Conclusions Prophylactic HIPEC for appendiceal neoplasms is feasible, safe and may be performed laparoscopically. Larger studies with long-term follow-up are needed to determine whether a survival benefit is associated with this treatment.

Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in patients with liver involvement.

BACKGROUND: We examined outcomes of patients undergoing cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) combined with liver resection. METHODS: All patients undergoing CRS/HIPEC between 2007 and 2014 were retrospectively reviewed: patients who underwent synchronous liver resection (group 1) were compared with those who did not (group 2) in terms of perioperative and long-term results. RESULTS: Group 1 included 103 patients with colorectal cancer (CRC, n = 28), appendiceal cancer (n = 34), and other malignancies. Compared with group 2 (n = 166), group 1 had higher number of organs resected, increased intraoperative blood loss, and longer hospital stay (all P ≤ 0.004) but similar major morbidity (24.3% vs. 18.1%, P = 0.22) and perioperative mortality rates. Two patients from group 1 developed liver resection-related complications. A comparison between patients who underwent parenchymal liver resection (n = 42) and matched pairs from group 2 with similar extent of cytoreduction did not yield significant differences in morbidity/mortality. CRC patients from group 1 had poorer median overall survival (45.1 vs. 73.5 months from stage IV diagnosis, P = 0.009). CONCLUSIONS: Liver involvement denotes high peritoneal carcinomatosis burden, which often requires resection of multiple organs in order to achieve optimal cytoreduction. However, liver resection-related morbidity is low and overall morbidity/mortality rates are comparable to other extensive CRS/HIPEC procedures. J. Surg. Oncol. 2016;113:432-437. © 2016 Wiley Periodicals, Inc.

Extreme cytoreductive surgery and hyperthermic intraperitoneal chemotherapy: Outcomes from a single tertiary center.

BACKGROUND: Multivisceral resection as part of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) may be required in order to achieve optimal debulking. This study aimed to assess perioperative and long-term outcomes of the most extensive CRS/HIPEC procedures. METHODS: All patients who underwent CRS/HIPEC at our institution between March 2007 and July 2014 were retrospectively reviewed. Patients undergoing extreme cytoreduction (n = 50), defined as a resection of ≥5 organs or ≥3 bowel anastomoses, were compared with patients who underwent less extensive procedures (n = 219). RESULTS: Complete cytoreduction (CC score ≤1) was achieved in 76% of the extreme CRS/HIPEC group, which included patients with colorectal cancer (CRC, n = 17), appendiceal adenocarcinoma (n = 20), gastric cancer (n = 6), and low-grade appendiceal neoplasm (n = 3). When compared with other patients undergoing CRS/HIPEC, the extreme CRS/HIPEC group had higher median PCI score, increased intraoperative blood loss, longer duration of surgery and longer hospital stay (all p values < 0.001). Major 30-day morbidity was significantly higher among the extreme CRS/HIPEC group (34% vs. 17.4%, p = 0.008) and there was also a trend towards higher 90-day mortality (12% vs. 5.1%, p = 0.07). Median disease free survival and overall survival in CRC patients undergoing extreme CRS/HIPEC was poorer (4.1 vs. 14.3 months, p = 0.01 and 10.1 vs. 43.8 months, p < 0.001, respectively). Extreme CRS/HIPEC was found to independently predict decreased overall survival in CRC patients. CONCLUSIONS: Extreme multivisceral resection as part of CRS/HIPEC is associated with higher major morbidity and inferior oncologic outcomes; therefore CRS/HIPEC provides the best outcomes in patients with fewer organs involved.

Incorporation of diagnostic laparoscopy in the management algorithm for patients with peritoneal metastases: A multi-institutional analysis.

INTRODUCTION: Diagnostic laparoscopy (DL), which can predict complete cytoreduction (CC), is often considered unfeasible in patients with Peritoneal metastases (PM) due to a hostile abdomen, prior surgeries, incomplete assessment or risk of port site recurrence. We hypothesized that DL can be successfully incorporated into the management of patients with PM. METHODS: Retrospective review and data analysis of prospectively maintained databases from two high volume institutions was performed between 2007 and 2013. RESULTS: DL was successfully completed in 211/217 (92.6%) patients with PM. The technique for entry was the Hasson in 57%, optical trocar in 38% and Veress needle in 5%. Serosal injury from DL occurred in one patient (0.4%). Predominant histology included appendiceal (40%) and colorectal primaries (34%). Exclusion from cytoreduction by DL occurred in 68 (31.3%). Among those excluded, 7 (of 68, 10.3%) subsequently underwent CRS + HIPEC after receiving systemic chemotherapy. Overall survival (from laparoscopy) for those that underwent CRS + HIPEC at the original operation was 36 versus 12.7 months among those who were excluded by laparoscopy. There were no cases of port site recurrence. CONCLUSION: Diagnostic laparoscopy can be safely incorporated in the management of patients with peritoneal metastases, and can be especially beneficial in excluding patients from attempted incomplete cytoreduction.