Normal CEA Levels After Neoadjuvant Chemotherapy and Cytoreduction with Hyperthermic Intraperitoneal Chemoperfusion Predict Improved Survival from Colorectal Peritoneal Metastases.

BACKGROUND: Normal carcinoembryonic antigen (CEA) levels (≤ 2.5 ng/ml) after resection of localized colorectal cancer or liver metastases are associated with improved survival, however, these trends are understudied for colorectal peritoneal metastases (CRPM). PATIENTS AND METHODS: We conducted a retrospective single-institution study of patients with CRPM undergoing cytoreductive surgery with hyperthermic intraperitoneal chemoperfusion (CRS/HIPEC) with and without neoadjuvant chemotherapy (NACT). CEA was measured before and after NACT and within 3 months after CRS/HIPEC. RESULTS: A total of 253 patients (mean age 55.3 years) with CRPM undergoing CRS/HIPEC had complete CEA data and 191 also underwent NACT with complete data. The median peritoneal carcinomatosis index score (PCI) of the overall cohort was 12 and 82.7% of patients had complete cytoreduction (CC0). In total, 64 (33.5%) patients had normal CEA levels after NACT with a median overall survival (OS) of 45.2 months compared with those with an elevated CEA (26.4 months, p = 0.004). Patients with normal CEA after NACT had a lower PCI found at the time of surgery than those with elevated CEA (10 versus 14, p < 0.001), 68 (26.9%) patients with an elevated preoperative CEA level experienced normalization after CRS/HIPEC, and 118 (46.6%) patients had elevated CEA after CRS/HIPEC. Patients who experienced normalization demonstrated similar OS to patients that had normal CEA levels pre- and post-surgery and improved OS compared with those with elevated postop CEA (median 41.9 versus 47 months versus 17.1 months, respectively, p < 0.001). CONCLUSIONS: Normal CEA levels after NACT and/or CRS/HIPEC are associated with improved survival for patients with CRPM. Patients that normalize CEA levels after surgery have similar survival to those with normal preoperative levels.

Impact of Primary Tumor Location and Genomic Alterations on Survival Following Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemoperfusion for Colorectal Peritoneal Metastases.

BACKGROUND: Colorectal cancer leads to peritoneal metastases (CRPM) in 10% of cases. Cytoreductive surgery with hyperthermic intraperitoneal chemoperfusion (CRS-HIPEC) improves survival. Primary tumor location and abnormalities in RAS, BRAF, and mismatch repair/microsatellite stability (MMR/MSI) may affect post-CRS-HIPEC survival, but studies have not been consistent. We estimated the effects of primary tumor site and genomic alterations on post-CRS-HIPEC survival. METHODS: This retrospective cohort study included CRS-HIPEC cases for CRPM at a high-volume center from 2001 to 2020. Next-generation sequencing and microsatellite testing defined the RAS, BRAF, and MMR/MSI genotypes. Adjusted effects of tumor sidedness and genomics on survival were evaluated using a multivariable Cox proportional hazards model. We analyzed these variables' effects on progression-free survival and the effects of immune checkpoint-inhibitors. RESULTS: A total of 250 patients underwent CRS-HIPEC with testing for RAS, BRAF, and MMR/MSI; 50.8% of patients were RAS-mutated, 12.4% were BRAF-mutated, and 6.8% were deficient-MMR/MSI-high (dMMR/MSI-H). Genomic alterations predominated in right-sided cancers. After adjustment for comorbidities and oncological and perioperative variables, rectal origin [hazard ratio (HR) 1.9, p = 0.01], RAS mutation (HR 1.6, p = 0.01), and BRAF mutation (HR 1.7, p = 0.05) were associated with worse survival. RAS mutation was also associated with shorter progression-free survival (HR 1.6, p = 0.01 at 6 months post-operatively), and dMMR/MSI-H status was associated with superior survival (HR 0.3, p = 0.01 at 2 years). dMMR/MSI-H patients receiving immune checkpoint-inhibitors trended toward superior survival. CONCLUSIONS: Rectal origin, RAS mutations, and BRAF mutations are each associated with poorer survival after CRS-HIPEC for CRPM. Patients with CRPM and dMMR/MSI-H status have superior survival. Further research should evaluate benefits of immune checkpoint-inhibitors in this subgroup.

Failure to Thrive Following Cytoreduction and Hyperthermic Intraperitoneal Chemotherapy: Causes and Consequences.

BACKGROUND: Failure to thrive (FTT) is a complex syndrome of nutritional failure and functional decline. Readmission for FTT following cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS HIPEC) is common but underexamined. This study aims to determine features, risk factors, and prognostic significance of FTT following CRS HIPEC. PATIENTS AND METHODS: We reviewed patients who underwent CRS HIPEC from 2010 to 2018 at our institution. Patients were categorized into no readmission, FTT readmission, and other readmission. FTT was determined by coding and chart review. We compared baseline characteristics, oncologic data, perioperative outcomes, and survival among the three cohorts. RESULTS: Of 1068 discharges examined, 379 patients (36%) were readmitted within 90 days, of which 134 (12.5%) were labeled as FTT. Patients with FTT readmission had worse preoperative functional status, higher rates of malnutrition, more complex resections, longer hospital stays, and more postoperative complications (all p < 0.001). Ostomy creation [relative risk ratio (RRR) 4.06], in-hospital venous thromboembolism (VTE), discharge to nursing home (RRR 2.48), pre-CRS HIPEC chemotherapy (RRR 1.98), older age (RRR 1.84), and female gender (RRR 1.69) were all independent predictors for FTT readmission on multinomial regression (all p < 0.01). FTT readmission was associated with worse median overall survival on multivariate analysis [hazard ratio (HR) 1.60, p < 0.001] after controlling for oncologic, perioperative, and baseline factors. CONCLUSIONS: FTT is common following CRS HIPEC and appears to be associated with baseline patient characteristics, operative burden, and postoperative complications. Perioperative strategies for improving nutrition and activity, along with early recognition and intervention in FTT may improve patient outcomes.

Predischarge Prediction of Readmission After Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy: Derivation and Validation of a Risk Prediction Score.

BACKGROUND: Ninety-day hospital readmission rates following cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) range from 20 to 40%. OBJECTIVE: The aim of this study was to develop and validate a simple score to predict readmissions following CRS/HIPEC. STUDY DESIGN: Using a prospectively maintained database, we retrospectively reviewed clinicopathologic, perioperative, and day-of-discharge data for patients undergoing CRS/HIPEC for peritoneal surface malignancies between 2010 and 2018. In-hospital mortalities and discharges to hospice were excluded. Multivariate logistic regression was utilized to identify predictors of unplanned readmission, with three-quarters of the sample randomly selected as the derivation cohort and one-quarter as the validation cohort. Using regression coefficient-based scoring methods, we developed a weighted 7-factor, 10-point predictive score for risk of readmission. RESULTS: Overall, 1068 eligible discharges were analyzed; 379 patients were readmitted within 90 days (35.5%). Seven factors were associated with readmission: stoma creation, Peritoneal Cancer Index score ≥ 15, hyponatremia, in-hospital major complication, preoperative chemotherapy, anemia, and discharge to nursing home. In the validation cohort, 25 patients (9.2%) were categorized as high risk for readmission, with a predicted rate of readmission of 69.3% and an observed rate of 76.0%. The score had fair discrimination (area under the curve 0.70) and good calibration (Hosmer-Lemeshow goodness-of-fit p-value of 0.77). CONCLUSION: Our proposed risk score, easily obtainable on day of discharge, distinguishes patients at high risk for readmission over 90 days following CRS/HIPEC. This score has the potential to target high-risk individuals for intensive follow-up and other interventions.

Definition and Prediction of Early Recurrence and Mortality Following Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy for Colorectal Peritoneal Metastases: Towards Predicting Oncologic Futility Preoperatively.

INTRODUCTION: Early recurrence (ER) is a significant challenge for patients with colorectal peritoneal metastases (CRPM) following cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS HIPEC). Preoperative risk stratification for ER would improve preoperative decision making. METHODS: We conducted a retrospective study examining patients who underwent CRS HIPEC for CRPM from 2000 to 2018. Optimal definition of ER was determined via minimum p-value approach based on differentiation of post-recurrence survival. Risk factors for ER were assessed in a derivation cohort by uni- and multivariate logistic regression. A predictive score for ER was generated using preoperative variables and validated in an independent cohort. RESULTS: 384 patients were analyzed, 316 (82%) had documented recurrence. Optimal length of post-operative RFS to distinguish ER (n = 144, 46%) vs. late recurrence (LR) (n = 172, 63%) was 8 mos (p<0.01). ER patients had shorter median OS post-CRS-HIPEC (13.6 vs. 39.4 mos, p<0.01). Preoperative BMI (OR 1.88), liver lesions (OR 1.89), progression on chemotherapy (OR 2.14), positive lymph nodes (OR 2.47) and PCI score (16-20: OR 1.7; >20: OR 4.37) were significant predictors of ER (all p<0.05). Using this model, patients were assigned risk scores from 0 to 9. Intermediate (scores 4-6) and high-risk patients (score 7-9) had observed rates of ER of 56% and 79% and overall 2-year survival rates of 27% and 0% respectively. The model showed fair discrimination (AUC 0.72) and good calibration (Hosmer-Lemeshow GOF p = 0.68). CONCLUSIONS: ER predicts markedly worse OS following surgery. Preoperative factors can accurately stratify risk for ER and identify patients in whom CRS-HIPEC for CPRM is futile.

Impact of Socioeconomic Status on Presentation and Outcomes in Colorectal Peritoneal Metastases Following Cytoreduction and Chemoperfusion: Persistent Inequalities in Outcomes at a High-Volume Center.

BACKGROUND: Cytoreductive surgery and hyperthermic intraperitoneal chemoperfusion (CRS HIPEC) can offer significant survival advantage for select patients with colorectal peritoneal metastases (CRPM). Low socioeconomic status (SES) is implicated in disparities in access to care. We analyze the impact of SES on postoperative outcomes and survival at a high-volume tertiary CRS HIPEC center. PATIENTS AND METHODS: We conducted a retrospective cohort study examining patients who underwent CRS HIPEC for CRPM from 2000 to 2018. Patients were grouped according to SES. Baseline characteristics, perioperative outcomes, and survival were examined between groups. RESULTS: A total of 226 patients were analyzed, 107 (47%) low-SES and 119 (53%) high-SES patients. High-SES patients were younger (52 vs. 58 years, p = 0.01) and more likely to be White (95.0% vs. 91.6%, p = 0.06) and privately insured (83% vs. 57%, p < 0.001). They traveled significantly further for treatment and had lower burden of comorbidities and frailty (p = 0.01). Low-SES patients more often presented with synchronous peritoneal metastases (48% vs. 35%, p = 0.05). Following CRS HIPEC, low-SES patients had longer length of stay and higher burden of postoperative complications, 90-day readmission, and 30-day mortality. Median overall survival following CRS HIPEC was worse for low-SES patients (17.8 vs. 32.4 months, p = 0.02). This disparity persisted on multivariate survival analysis (low SES: HR = 1.46, p = 0.03). CONCLUSIONS: Despite improving therapies for CRPM, low-SES patients remain at a significant disadvantage. Even patients who overcome barriers to care experience worse short- and long-term outcomes. Improving access and addressing these disparities is crucial to ensure equitable outcomes and improve patient care.

Discrimination of low- and high-grade appendiceal mucinous neoplasms by targeted sequencing of cancer-related variants.

DNA was obtained from matching micro-dissected, primary tumor cells, paired metastases, and peripheral blood mononuclear cells (germline) from patients with appendiceal mucinous neoplasms. We compared specimens from patient cohorts comprising low-grade adenomucinous neoplasm versus high-grade mucinous adenocarcinoma using a targeted, amplicon sequencing panel of 409 cancer related genes (Ion Torrent Comprehensive Cancer Panel, Thermo-Fisher, Waltham, MA). Copy number variants, single nucleotide variants and small insertions/deletions were identified using a multiplex algorithm pipeline (GATK, VarScan2, MuTect2, SIFT, SIFT-INDEL, PolyPhen-2, Provean). There were significantly more damaging variants in high-grade versus low-grade tumor cohorts. Both cohorts contained damaging, heterozygous germline variants (catenin ß1; notch receptor 1 and 4) in pathways associated with cell-lineage specification (WNT, NOTCH). Damaging, somatic KRAS proto-oncogene, GTPase mutations were present in both cohorts, while somatic GNAS complex locus mutations were confined to low-grade neoplasms. Variants predominantly affected transcription factors, kinases, and stem cell signaling molecules in canonical pathways including epithelial to mesenchymal transition, stem cell pluripotency, p53, PTEN, and NF-қB signaling pathways. High-grade tumors demonstrated MYC proto-oncogene, bHLH transcription factor (MYC) and death domain associated protein (DAXX) amplification and damaging somatic variants in tumor protein p53 (TP53), likely to amplify an aggressive phenotype. Damaging APC, WNT signaling pathway regulator (APC) deletions were identified in metastatic tissue of both cohorts suggesting a role in invasive disease. Our data suggest that germline dysregulation of WNT and/or NOTCH pathways predisposes patients toward a secretory cell phenotype (i.e., goblet-like cells) upon acquisition of somatic KRAS mutations. Additional somatically acquired variants activating oncogenes MYC and DAXX and inhibiting the critical tumor suppressor, tumor protein TP53, were consistent with manifestation of a high-grade phenotype. These additional changes within the epithelial to mesenchymal transition signaling network (WNT, NOTCH, RAS/ERK/PI3K, PTEN, NF-қB), produce aggressive high-grade tumor characteristics by actively driving cells towards dedifferentiation, proliferation, and migration.

Correction to: Postoperative Complications Independently Predict Cancer-Related Survival in Peritoneal Malignancies.

In the original article, the Comprehensive Complication Index (CCI) was incorrectly identified as the Comprehensive Comorbidity Index. Wherever CCI appears, it refers to the Comprehensive Complication Index.

Repeat Cytoreductive Surgery-Hyperthermic Intraperitoneal Chemoperfusion is Feasible and Offers Survival Benefit in Select Patients with Peritoneal Metastases.

INTRODUCTION: We hypothesized that repeat cytoreductive surgery-hyperthermic intraperitoneal chemoperfusion (CRS-HIPEC) for peritoneal metastases (PM) may be associated with suboptimal resection, more frequent postoperative complications, and worse oncologic outcomes. METHODS: Using a prospectively maintained database, we compared clinicopathologic, perioperative, and oncologic outcome data in patients undergoing single or repeat CRS-HIPEC procedures. The Kaplan-Meier method was used to estimate survival. Multivariate analyses identified associations with perioperative and oncologic outcomes. RESULTS: Of the 1294 patients undergoing CRS-HIPEC procedures at our institution, only one CRS-HIPEC procedure (single HIPEC cohort) was performed in 1169 patients (90.3%), whereas 125 patients (9.7%) underwent repeat CRS-HIPEC procedures (repeat HIPEC cohort). Of the 1440 CRS-HIPEC procedures at our institution, a first CRS-HIPEC procedure was performed in 1294 patients (89.9%), whereas subsequent second, third, and fourth CRS-HIPEC procedures were performed in 125 patients (8.7%), 18 patients (1.3%), and 3 patients (0.2%), respectively. Progression-free survival (PFS) following the second CRS-HIPEC procedure was negatively impacted by shorter PFS following the first CRS-HIPEC procedure, independent of other significant variables related to the second procedure, including completeness of cytoreduction and postoperative complications. Patients undergoing multiple CRS-HIPEC procedures were not at higher risk for suboptimal resection or postoperative complications and demonstrated equivalent PFS following each successive procedure compared to the first procedure. CONCLUSIONS: Repeat CRS-HIPEC procedures for PM were not associated with suboptimal perioperative and oncologic outcomes. Our data confirmed our ability to select patients appropriately for repeat CRS-HIPEC procedures.

Discordant Diagnostic Terminology and Pathologic Grading of Primary Appendiceal Mucinous Neoplasms Reviewed at a High-Volume Center.

BACKGROUND: Diagnostic terminology and grading of primary appendiceal mucinous neoplasms lacks uniformity. We sought to identify discordance in pathologic reporting by reviewing pathology slides for cases referred to our institution. METHODS: Using guidelines from Peritoneal Surface Oncology Group International (PSOGI) and American Joint Committee on Cancer 8th edition (AJCC8), we compared diagnostic terminology/grading of primary appendiceal mucinous neoplasms (n = 115) between pathology reports from referring institutions and review of slides by pathologists at our high-volume institution. RESULTS: There was discordance in pathologic terminology and grading of primary appendiceal mucinous neoplasms between referring institutions and our institution in 28% and 50% of patients, respectively. In particular, 24% of patients referred with mucinous adenocarcinoma (MACA) had LAMN on our review, and a higher grade MACA was found in 48% of patients referred with low-grade (G1) MACA and 16% of patients referred with high-grade (G2) MACA following our review. Discordance in tumor grade between primary and metastatic disease was seen in 19% of cases based on referred primary tumor grading compared with only 4% following our review. Systemic chemotherapy was unnecessarily administered to four cases of LAMN (6%) and inappropriately not administered to four cases of MACA (6%) before referral due to inaccurate diagnosis/grading by referring institutions. CONCLUSIONS: We found significant discordance in diagnostic terminology/grading of primary appendiceal mucinous neoplasms following review of referred cases. Inaccurate pathologic assessment was associated with overtreatment or undertreatment with chemotherapy. These data highlight the need for pathologic review of such rare cases at high-volume centers.

Pleuropulmonary Recurrence Following Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemoperfusion for Appendiceal Pseudomyxoma Peritonei.

BACKGROUND: The aim of this study was to identify factors associated with pleuropulmonary disease recurrence following cytoreductive surgery with hyperthermic intraperitoneal chemoperfusion (CRS/HIPEC) for appendiceal pseudomyxoma peritonei (PMP) and to evaluate the oncologic impact of pleuropulmonary disease recurrence compared with isolated peritoneal recurrence. METHODS: From a prospective database, we identified patients who developed pleuropulmonary recurrence, isolated peritoneal recurrence, or no recurrence following CRS/HIPEC for appendiceal PMP. Clinicopathologic, perioperative, and oncologic data associated with the index CRS/HIPEC procedure were reviewed. The Kaplan-Meier method was used to estimate survival. Multivariate analyses identified associations with recurrence and survival. RESULTS: Of 382 patients undergoing CRS/HIPEC, 61 (16%) developed pleuropulmonary recurrence. Patients who developed a pleuropulmonary recurrence were more likely to have high-grade (American Joint Committee on Cancer [AJCC] grade 2/3) tumors (74% vs. 56%, p = 0.02) and increased operative blood loss (1651 vs. 1201 ml, p = 0.05) and were more likely to have undergone diaphragm stripping/resection (79% vs. 48%, p < 0.01) compared with patients with an abdominal recurrence. In a multivariate analysis, pleuropulmonary recurrence after CRS/HIPEC was associated with diaphragm stripping/resection, incomplete cytoreduction, and higher AJCC tumor grade. There was a trend towards reduced survival in patients with pleuropulmonary recurrence compared with patients with isolated peritoneal recurrence (median overall survival 45 vs. 53 months, p = 0.87). CONCLUSION: Pleuropulmonary recurrence of appendiceal PMP following CRS/HIPEC is common and may negatively impact survival. Formal protocols for surveillance and therapeutic intervention need to be studied and implemented to improve oncologic outcomes.

Postoperative Complications Independently Predict Cancer-Related Survival in Peritoneal Malignancies.

BACKGROUND: The authors hypothesized that postoperative complications after cytoreductive surgery-hyperthermic intraperitoneal chemoperfusion (CRS-HIPEC) have a negative impact on perioperative and oncologic outcomes and that the novel Comprehensive Comorbidity Index (CCI) would be a better predictor of such outcomes than the traditional Clavien-Dindo classification (CDC). METHODS: The study used a prospective database of 1296 patients with peritoneal metastases (PM) undergoing CRS-HIPEC between 2001 and 2016. The Kaplan-Meier method was used to estimate survival. Multivariate analyses identified associations with perioperative and oncologic outcomes. The Akaike information criterion and the Schwarz (Bayesian information) criterion were used to compare model fitting for CCI versus CDC. RESULTS: In this study, CRS-HIPEC was performed for malignant mesothelioma (12%) and PM from appendix (50%), colorectal (30%), and ovarian (8%) cancers. Major postoperative in-hospital complications (CDC grades 3-4) occurred for 24% of the patients. However, a range of CCI scores was calculated for each CDC grade because 36% of the patients experienced multiple complications. After a median follow-up period of 55 months, the median progression-free survival was 15 months, and the median overall survival was 39 months. In the multivariate Cox proportional hazards models, postoperative in-hospital complications (measured by CDC or CCI) were independent prognostic factors for 30-day post-discharge morbidity and readmission, as well as for survival. The CCI scores demonstrated higher prognostic sensitivity for these outcomes than CDC grades. CONCLUSIONS: Reduction of postoperative complications after CRS-HIPEC is essential for optimal short- and long-term outcomes. For assessing total burden of postoperative complications per patient, CCI is superior to CDC and more sensitive for assessing surgery- and cancer-related outcomes after CRS-HIPEC.

Surgical Resection Does Not Improve Survival in Multifocal Intrahepatic Cholangiocarcinoma: A Comparison of Surgical Resection with Intra-Arterial Therapies.

BACKGROUND: Multifocal intrahepatic cholangiocarcinoma (ICC) has traditionally been treated with surgical resection when amenable. Intra-arterial therapy (IAT) for multifocal ICC has not been directly compared with surgical resection. METHODS: A single-center, retrospective review of consecutive patients treated for multifocal ICC was conducted. Patients with distant metastases or treatment with systemic chemotherapy alone were excluded. Patients were divided into two groups: surgical resection versus IAT; IAT included transarterial chemoembolization (TACE), transarterial radioembolization (TARE), and hepatic arterial infusion (HAI) pump therapy. Subjects were also analyzed by surgical resection, TACE, and HAI pump therapy. RESULTS: Overall, 116 patients with multifocal ICC were studied, 57 in the surgical resection group and 59 in the IAT group (TACE = 41, HAI pump = 16, TARE = 2). The IAT group was characterized by a higher incidence of bilobar disease (88.1% vs. 47.4%, p < 0.001), larger tumors (median 10.6 vs. 7.5 cm, p = 0.004), higher incidence of macrovascular invasion (44.1% vs. 24.6%, p = 0.027), and higher rate of nodal metastases (57.6% vs. 28.6%, p = 0.002). Median overall survival for surgical resection was 20 months versus 16 months for IAT (p = 0.627). Multivariate analysis found that macrovascular invasion [hazard ratio (HR) 2.52, 95% confidence interval (CI) 1.56-4.09] and non-receipt of systemic chemotherapy (HR 3.81, 95% CI 2.23-6.52) were independent poor prognostic risk factors. Surgical resection was not associated with a survival advantage over IAT on multivariate analysis (p = 0.242). CONCLUSION: Despite selection bias for use of surgical resection compared with IAT, no survival advantage was conferred in the treatment of multifocal ICC.

Impact of Cellularity on Oncologic Outcomes Following Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemoperfusion for Pseudomyxoma Peritonei.

BACKGROUND: The Peritoneal Surface Oncology Group International (PSOGI) recommends pathologic reporting of tumor cellularity in patients with pseudomyxoma peritonei (PMP) undergoing cytoreductive surgery and hyperthermic intraperitoneal chemoperfusion (CRS-HIPEC). We investigated the prognostic significance of PMP cellularity, or lack thereof (acellular mucin), following CRS-HIPEC. METHODS: We reviewed clinical data for 310 CRS-HIPEC procedures in low-grade (American Joint Committee on Cancer grade G1) PMP with acellular mucin (n = 19), scant cellularity (n = 30), or moderate cellularity (n = 242). Kaplan-Meier survival curves and multivariate Cox regression models identified prognostic factors affecting oncologic outcomes. RESULTS: Compared with patients with acellular mucin, those with scant and moderate cellularity had higher PCI and less-frequent complete macroscopic resection. After an estimated median follow-up of 49 months, 4 patients (14%) with scant cellularity and 127 patients (56%) with moderate cellularity progressed, while none of the patients with acellular mucin progressed. While the median progression-free survival (PFS) was not reached for patients with acellular mucin or scant cellularity (estimated 5-year PFS probability of 100 and 83%, respectively), patients with moderate cellularity demonstrated a median PFS of 32 months (estimated 5-year PFS probability of 27%). In a multivariate model, degree of disease cellularity, or lack thereof (acellular mucin), was an independent predictor of PFS but not overall survival. CONCLUSIONS: Early disease progression is unlikely in patients with acellular mucin undergoing CRS-HIPEC, as opposed to a 14% recurrence rate with scant cellularity. Thorough pathologic assessment for cellularity, or lack thereof (acellular mucin), is vital for accurate prognostication of disease progression for patients with low-grade PMP undergoing CRS-HIPEC.

Effectiveness of Hepatic Artery Infusion (HAI) Versus Selective Internal Radiation Therapy (Y90) for Pretreated Isolated Unresectable Colorectal Liver Metastases (IU-CRCLM).

BACKGROUND: In the era of modern effective systemic chemotherapy, the comparative effectiveness of hepatic artery infusion (HAI) versus selective internal radiation therapy (yttrium-90 [Y90]) for pretreated patients with isolated unresectable colorectal liver metastasis (IU-CRCLM) remains unknown. This study sought to compare the overall survival (OS) after HAI versus Y90 for IU-CRCLM patients treated with modern chemotherapy and to perform a cost analysis of both regional methods. METHODS: This study retrospectively reviewed patients receiving HAI or Y90 in combination with modern chemotherapy as second-line therapy for IU-CRCLM. Overall survival was calculated from the time of IU-CRCLM diagnosis. Uni- and multivariate models were constructed to identify independent predictors of survival. RESULTS: The inclusion criteria were met by 97 patients (48 HAI patients and 49 Y90 patients). Both groups were similar in terms of age, gender, body mass index (BMI), synchronous disease, carcinoembryonic antigen (CEA), liver tumor burden, and chemotherapy-related characteristics including use of biologics and lines of chemotherapy (all p > 0.05). The HAI group had a better OS than the Y90 group (31.2 vs. 16.3 months; p < 0.001). A trend toward reduced cost favored the HAI group (median, $29,479 vs. $39,092; p = 0.296). The multivariate analysis showed that receipt of HAI (hazard ratio 0.465) and number of chemotherapy lines (HR 0.797) were associated with improved OS from the date of IU-CRCLM diagnosis. CONCLUSIONS: This is the first study to evaluate the comparative effectiveness of HAI versus Y90 in the era of modern chemotherapy, and the findings suggests that HAI is associated with better survival than Y90 for patients with pretreated IU-CRCLM.

Institutional Experience with Ostomies Created During Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemoperfusion.

BACKGROUND: Cytoreductive surgery and hyperthermic intraperitoneal chemoperfusion (CRS-HIPEC) is a complex procedure that often requires ostomy creation to protect high-risk anastomoses. This study aimed to evaluate the authors' institutional experience with CRS-HIPEC-associated ostomies, determine predictors of ostomy creation and reversal, and assess their impact on survival. METHODS: The study analyzed clinicopathologic, perioperative, and oncologic data from a prospective database of 1435 CRS-HIPEC procedures for peritoneal metastases. The Kaplan-Meier method was used to estimate survival. Multivariate analyses identified associations with ostomy creation/reversal and survival. RESULTS: Ostomies were created in 34% of the patients, most commonly loop ileostomies (82%). Loop ileostomies were reversed in the majority of patients (83%), whereas non-loop ileostomies were infrequently reversed (< 10% reversal rate). In a multivariate logistic regression model, intermediate or high tumor grade, colectomy/proctectomy, longer operative time, and lower Charlson comorbidity index were associated with loop ileostomy creation, whereas incomplete macroscopic resection, colorectal histology, and major postoperative complications were associated with non-reversal of loop ileostomy. In a multivariate Cox proportional hazards model, intermediate or high tumor grade and non-reversal of loop ileostomy were associated with worse overall survival. CONCLUSIONS: Loop ileostomies were almost always reversed, whereas non-loop ileostomies were almost always permanent. Hospital readmissions for loop ileostomy-related complications were common. Therefore, formal outpatient protocols for prevention and management should be implemented. Non-reversal of loop ileostomy was associated with very poor survival.

Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemoperfusion in Adolescent and Young Adults with Peritoneal Metastases.

BACKGROUND: Several studies suggest that young patients may derive less oncologic benefit from surgical resection of cancers compared with older patients. We hypothesized that young patients may have worse outcomes following cytoreductive surgery with hyperthermic intraperitoneal chemoperfusion (CRS/HIPEC) for peritoneal metastases. METHODS: Perioperative and oncologic outcomes in adolescent and young adults (AYA), defined as younger than age 40 years (n = 135), undergoing CRS/HIPEC between 2001 and 2015 were reviewed and compared with middle-aged adults, defined as aged 40-65 years (n = 684). RESULTS: The two groups were similar with regards to perioperative characteristics except that AYA were more likely to be symptomatic at presentation (65.2 vs. 50.9%, p = 0.003), had lower Charleson comorbidity index (median 6 vs. 8, p < 0.001), were less likely to receive neoadjuvant chemotherapy (32.8 vs. 42.5%, p = 0.042), and had longer operative times (median 543 vs. 493 min, p = 0.010). Postoperative Clavien-Dindo grade 3-4 morbidity was lower in AYA (17 vs. 26%, p = 0.029), and they required fewer reoperations for complications (3.7 vs. 10.4%, p = 0.014). AYA had longer median overall survival (103.6 vs. 73.2 months, p = 0.053). In a multivariate Cox regression analysis, age was an independent predictor of improved overall survival [hazard ratio 0.705; 0.516-0.963, p = 0.028]. CONCLUSIONS: Young patients with peritoneal metastases derive similar benefits from CRS/HIPEC as middle-aged patients. Young age should not be a deterrent to consideration of CRS/HIPEC for peritoneal metastases.

Hepatic Arterial Infusion in Combination with Modern Systemic Chemotherapy is Associated with Improved Survival Compared with Modern Systemic Chemotherapy Alone in Patients with Isolated Unresectable Colorectal Liver Metastases: A Case-Control Study.

BACKGROUND: In the era of effective modern systemic chemotherapy (CT), the role of hepatic arterial infusion of fluoxuridine (HAI-FUDR) in the treatment of isolated unresectable colorectal liver metastasis (IU-CRCLM) remains controversial. This study aimed to compare the overall survival (OS) of HAI-FUDR in combination with modern systemic CT versus modern systemic CT alone in patients with IU-CRCLM. METHODS: This was a case-control study of IU-CRCLM patients who underwent HAI + modern systemic CT or modern systemic CT alone. Modern systemic CT was defined as the use of multidrug regimens containing oxaliplatin and/or irinotecan ± biologics. RESULTS: Overall, 86 patients met the inclusion criteria (n = 40 for the HAI + CT group, and n = 46 for the CT-alone group). Both groups were similar in demographics, primary and stage IV tumor characteristics, and treatment-related variables (carcinoembryonic antigen, use of biologic agents, total number of lines of systemic CT administered) (all p > 0.05). Additionally, both groups were comparable with respect to liver tumor burden [median number of lesions (13.5 vs. 15), percentage of liver tumor replacement (37.5 vs. 40 %), and size of largest lesion] (all p > 0.05). Median OS in the HAI + CT group was 32.8 months compared with 15.3 months in the CT-alone group (p < 0.0001). Multivariate analysis revealed HAI + CT (hazard ratio 0.4, 95 % confidence interval 0.21-0.72; p = 0.003), Eastern Cooperative Oncology Group status, and receipt of increasing number of lines of systemic CT to be independent predictors of survival. CONCLUSIONS: In this case-control study of patients with IU-CRCLM, HAI in combination with CT was associated with improved OS when compared with modern systemic CT alone.

Safety and efficacy of combined resection of colorectal peritoneal and liver metastases.

BACKGROUND: To determine if a select subgroup of patients with combined liver and peritoneal colorectal metastases would derive oncologic benefit from surgical resection as a component of multimodality treatment. MATERIALS AND METHODS: We retrospectively compared 32 patients with combined colorectal peritoneal and liver metastases (CRLM) and 173 patients with peritoneal metastases only (CRPM) undergoing cytoreductive surgery with hyperthermic intraperitoneal chemoperfusion (CRS-HIPEC). Kaplan-Meier survival curves and multivariate Cox-regression models identified prognostic factors affecting survival. RESULTS: Major postoperative complications (Clavien-Dindo grades 3-5) occurred in 32% (CRLM) and 17% (CRPM) of patients (P = 0.08). After an estimated median follow-up from surgery of 57 mo, propensity score-adjusted median progression-free survival was 5.1 mo (CRLM) and 7.6 mo (CRPM), whereas median overall survival was 13 mo (CRLM) and 21 mo (CRPM). Multivariate Cox-regression analysis of the CRLM group identified number of liver metastases to be the only independent predictor of poor survival (hazard ratio: 2.3, P = 0.03), with a dramatic decrease in survival in patients with more than three liver metastases. CONCLUSIONS: Simultaneous resection of colorectal liver metastases at the time of cytoreductive surgery with hyperthermic intraperitoneal chemoperfusion for peritoneal metastases may be associated with worse survival, especially in patients with more than three liver metastases.