Preoperative CA 19-9 Predicts Disease Progression in Colorectal Peritoneal Metastases Treated with Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy: An Analysis from the US HIPEC Collaborative.

INTRODUCTION: Patients with colorectal peritoneal metastases (CRPM) are increasingly treated with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS/HIPEC). Unfortunately, data identifying preoperative risk factors for poor oncologic outcomes after this procedure are limited. We aimed to determine the prognostic value of preoperative CEA, CA 125, and CA 19-9 on disease progression after CRS/HIPEC. METHODS: Patients with CRPM treated with curative intent CRS/HIPEC from 12 participating sites in the United States from 2000 to 2017 were identified. Progression-free survival (PFS), defined as disease progression or recurrence, was the primary outcome. RESULTS: In 279 patients who met inclusion criteria, the rate of disease progression was 63.8%, with a median PFS of 11 months (interquartile range [IQR] 5-20). Elevated CA 19-9 was associated with dismal PFS at 2 years (8.9% elevated vs. 30% not elevated, p < 0.01). In 113 patients who underwent upfront CRS/HIPEC, CA 19-9 emerged as the sole tumor marker independently predictive of worse PFS (hazard ratio [HR] 2.88, p = 0.048). In the subgroup of patients who had received neoadjuvant therapy (NAT), no variable was independently predictive of PFS. CA 19-9 levels over 37 U/ml were highly specific for accelerated disease progression after CRS/HIPEC. Lastly, there was no association between PFS and elevated CEA or CA 125. CONCLUSIONS: Elevated CA 19-9 is associated with decreased PFS in patients with CRPM. While traditionally CEA is the main tumor marker assessed in colon cancer, we found that CA 19-9 may better inform preoperative risk stratification for poor oncologic outcomes in patients with CRPM. However, prospective studies are required to confirm this association.

Validation of the AJCC 8th Edition Staging System for Disseminated Appendiceal Cancer Patients Treated with Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy: A Multi-institutional Analysis.

BACKGROUND: The AJCC 8th edition stratifies stage IV disseminated appendiceal cancer (dAC) patients based on grade and pathology. This study was designed to externally validate the staging system and to identify predictors of long-term survival. METHODS: A 12-institution cohort of dAC patients treated with CRS ± HIPEC was retrospectively analyzed. Overall survival (OS) and recurrence-free survival (RFS) were analyzed by using Kaplan-Meier and log-rank tests. Univariate and multivariate cox-regression was performed to assess factors associated with OS and RFS. RESULTS: Among 1009 patients, 708 had stage IVA and 301 had stage IVB disease. Median OS (120.4 mo vs. 47.2 mo) and RFS (79.3 mo vs. 19.8 mo) was significantly higher in stage IVA compared with IVB patients (p < 0.0001). RFS was greater among IVA-M1a (acellular mucin only) than IV M1b/G1 (well-differentiated cellular dissemination) patients (NR vs. 64 mo, p = 0.0004). Survival significantly differed between mucinous and nonmucinous tumors (OS 106.1 mo vs. 41.0 mo; RFS 46.7 mo vs. 21.2 mo, p < 0.05), and OS differed between well, moderate, and poorly differentiated (120.4 mo vs. 56.3 mo vs. 32.9 mo, p < 0.05). Both stage and grade were independent predictors of OS and RFS on multivariate analysis. Acellular mucin and mucinous histology were associated with better OS and RFS on univariate analysis only. CONCLUSIONS: AJCC 8th edition performed well in predicting outcomes in this large cohort of dAC patients treated with CRS ± HIPEC. Separation of stage IVA patients based on the presence of acellular mucin improved prognostication, which may inform treatment and long-term, follow-up strategies.

Implementation of a Hepatocellular Carcinoma Screening Program for At-risk Patients Safety-Net Hospital: A Model for National Dissemination.

OBJECTIVE: This study aimed to enhance hepatocellular carcinoma (HCC) screening to achieve earlier diagnosis of patients with hepatitis C (HCV) cirrhosis in our Safety-Net population. BACKGROUND: Adherence to HCC screening guidelines at Safety-Net hospitals is poor. Only 23% of patients with HCC at our health system had a screening exam within 1-year of diagnosis and 46% presented with stage IV disease. HCV-induced cirrhosis remains the most common etiology of HCC (75%) in our patients. METHODS: In the setting of an established HCV treatment clinic, an HCC screening quality improvement initiative was initiated for patients with stage 3 fibrosis or cirrhosis by transient elastography. The program consisted of semiannual imaging. Navigators scheduled imaging appointments and tracked compliance. RESULTS: From April 2018 to April 2021, 318 patients were enrolled (mean age 61 years, 81% Black race, 38% uninsured). Adherence to screening was higher than previously reported: 94%, 75%, and 74% of patients completed their first, second, and third imaging tests. Twenty-two patients (7%) were diagnosed with HCC; 55% stage I and 14% stage IV. All patients were referred and 13 (59%) received treatment. Median time to receipt of treatment was 77 days (range, 32-282). Median overall survival for treated patients was 32 months. CONCLUSIONS: Implementation of an HCC screening program at a safety-net hospital is feasible and facilitated earlier diagnosis in this study. Patient navigation and tracking completion of imaging tests were key components of the program's success. Next steps include expanding the program to additional at-risk populations.

The Impact of Carbohydrate Antigen 19-9 on Survival in Patients with Clinical Stage I and II Pancreatic Cancer.

BACKGROUND: Carbohydrate antigen (CA) 19-9 is a biomarker to monitor treatment effect. A threshold to predict prognostic significance remains undefined. We evaluated the impact of CA19-9 on overall survival (OS) in patients with early-stage pancreatic cancer (PC) utilizing the National Cancer Database (NCDB). METHODS: The NCDB was queried from 2010 to 2014 to identify patients with clinical stage I-II PC. Patients who had undocumented pretreatment CA19-9 were excluded. Patients were stratified into two cohorts: CA19-9 < 98 U/mL and CA19-9 ≥ 98 U/mL, and further categorized into surgery versus no surgery. Twelve- and 24-month OS rates are reported. RESULTS: Overall, 32,382 patients (stage I: 12,173; stage II: 20,209) were included. The majority of stage I (52.1%) and II (60%) patients had CA19-9 ≥ 98 U/mL. Stage I-II patients with CA19-9 < 98 U/mL had improved OS rates (stage I: 67.5%, 42.6%; stage II: 59.8%, 32.8%) compared with stage I and II patients with CA19-9 ≥ 98 U/mL (stage I: 50.7%, 26.9%; stage II: 48.1%, 22%). Among resected stage I patients, CA19-9 <98 U/mL was associated with improved OS (< 98: 80.5%, 56%; ≥ 98: 70.2%, 42.8%), and a similar trend was seen in resected stage II patients (< 98: 77.6%, 49.9%; ≥ 98: 71%, 39.2%). Unresected stage I patients with lower CA19-9 had improved OS (< 98: 42.1%, 17.5; ≥ 98: 29.9%, 10%), with similar findings in unresected stage II patients (< 98: 41.1%, 15.3%; ≥ 98: 33.4%, 10.6%). CONCLUSIONS: Our study demonstrated the prognostic value of CA19-9 in patients with clinical stage I-II PC, with a value < 98 U/mL demonstrating improved survival. Surgery significantly improved survival at 12 and 24 months irrespective of CA19-9.

Is Cytoreductive Surgery-Hyperthermic Intraperitoneal Chemotherapy Still Indicated in Patients With Extraperitoneal Disease?

INTRODUCTION: The role of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) in patients with extraperitoneal disease (EPD) is controversial. METHODS: Among patients with peritoneal metastases from appendiceal cancer (AC) and colorectal cancer (CRC) who underwent CRS-HIPEC, those with EPD (liver, lung, or retroperitoneal lymph nodes [RP LN]) were retrospectively compared to those without EPD. Overall (OS) and recurrence-free survival (RFS) analyses were performed before/after propensity score matching (PSM). RESULTS: Among 1341 patients with AC (64%) or CRC (36%) who underwent CRS ± HIPEC, 134 (10%) had EPD whereas 1207 (90%) did not. EPD was located in the lungs (47%), RP LN (28%), liver (18%), or multiple (6%). Patients with EPD experienced worse median OS (34 versus 63 mo; P = 0.002) and RFS (12 versus 19 mo; P < 0.001). On a multivariable analysis, EPD was associated with worse RFS (P = 0.003), but not OS (P = 0.071). After PSM, the association of EPD with OS (P = 0.204) and RFS (P = 0.056) was no longer significant. In the multivariable analysis of the PSM cohort, EPD was not associated with OS (P = 0.157) or RFS (P = 0.110). CONCLUSIONS: The findings of this large retrospective multi-institutional study suggest that EPD alone, while a negative prognostic indicator, should not be considered an absolute contraindication to CRS ± HIPEC for otherwise well-selected patients with peritoneal surface malignancies. Further research is needed to delineate whether location of EPD influences OS and RFS following CRS-HIPEC.

Implications of leukocytosis following distal pancreatectomy splenectomy (DPS) and association with postoperative complications.

BACKGROUND: Early identification of complications after distal pancreatectomy splenectomy (DPS) poses challenges, as white blood cell count (WBC) is confounded by physiologic leukocytosis. We examined WBC patterns associated with complications after DPS. METHODS: Clinicopathologic data were collected for patients who underwent DPS in our system from 2009 to 2016. We examined WBC, temperature, platelet count (PC), and ratios of these variables as potential early indicators of patients at risk of infections or major complications (MCs). RESULTS: 348 patients met study inclusion, of whom 206 (59%) were women and the median patient age was 59 ± 15 years. Infectious and MC rates were 11% and 16%, respectively, with <1% 30-day mortality. Postoperative WBC peaks were higher in patients with infections and MCs compared with no complication (23 vs. 17, p < 0.0001). WBC peak timing occurred postoperative day (POD) 2-3 for uncomplicated cases while peaks occurred POD9 for patients with infections and MCs. DISCUSSION: These data define patterns of leukocytosis following DPS. Although differences in infection markers were identified for patients with and without complications, no obvious thresholds were identified. Clinical suspicion for complications after DPS remains our best tool for early identification.

Should Signet Ring Cell Histology Alter the Treatment Approach for Clinical Stage I Gastric Cancer?

BACKGROUND: Surgery alone is standard-of-care for stage I gastric adenocarcinoma; however, clinicians can offer preoperative therapy for clinical stage I disease with signet ring cell histology, given its presumed aggressive biology. We aimed to assess the validity of this practice. METHODS: The National Cancer Database (2004-2015) was reviewed for patients with clinical stage I signet ring cell gastric adenocarcinoma who underwent treatment with surgery alone, perioperative chemotherapy, neoadjuvant therapy, or adjuvant therapy. Analysis was stratified by preoperative clinical/pathologic stage. Primary outcome was overall survival (OS). RESULTS: Of 1018 patients, median age was 60 years (±14); 53% received surgery alone (n = 542), 5% received perioperative chemotherapy (n = 47), 12% received neoadjuvant therapy (n = 125), and 30% received adjuvant therapy (n = 304). For clinical stage I disease, surgery alone was associated with an improved 5-year OS rate (71%) versus perioperative chemotherapy (58%), neoadjuvant therapy (38%), or adjuvant therapy (52%) [overall p < 0.01]. For pathologic stage I, surgery alone had equivalent or improved survival compared with perioperative, neoadjuvant, and adjuvant therapy (5-year OS: 78% vs. 89% [p = 0.77] vs. 64% [p = 0.04] vs. 84% [p = 0.99]). Adjuvant therapy was associated with improved 5-year OS compared with pretreatment for those patients upstaged (37%) to pathologic stage II/III (55% vs. 36% and 34% vs. 7%; all p < 0.01). CONCLUSIONS: This stage-specific study demonstrates improved survival with surgery alone for clinical stage I signet ring cell gastric adenocarcinoma. Despite 37% of clinical stage I patients being upstaged to pathologic stage II/III, adjuvant therapy offers a favorable rescue strategy, with improved outcomes compared with those treated preoperatively. Surgery alone also affords similar or improved survival for pathologic stage I disease versus multimodality therapy. This study challenges the bias to overtreat stage I signet ring cell gastric adenocarcinoma.

Impact of Perioperative Blood Transfusions on Outcomes After Hyperthermic Intraperitoneal Chemotherapy: A Propensity-Matched Analysis.

BACKGROUND: Cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) is a major operation frequently necessitating red blood cell transfusion. Using multi-institutional data from the U.S. HIPEC Collaborative, this study sought to determine the association of perioperative allogenic blood transfusion (PABT) with perioperative outcomes after CRS/HIPEC. METHODS: This retrospective cohort study analyzed patients who underwent CRS/HIPEC for peritoneal surface malignancy between 2000 and 2017. Propensity score-matching was performed to mitigate bias. Univariate analysis was used to compare demographic, preoperative, intraoperative, and postoperative variables. Factors independently associated with PABT were identified using multivariate analysis. RESULTS: The inclusion criteria were met by 1717 patients, 510 (29.7%) of whom required PABT. The mean Peritoneal Cancer Index (PCI) of our cohort was 14.8 ± 9.3. Propensity score-matching showed an independent association between PABT and postoperative risk of pleural effusion, hemorrhage, pulmonary embolism, enteric fistula formation, Clavien-Dindo grades 3 and 4 morbidity, longer hospital stay, and reoperation (all P < 0.05 in the multivariate analysis). Compared with the patients who received 1 to 5 red blood cell (RBC) units, the patients who received more than 5 units had a greater risk of renal impairment, a longer intensive care unit (ICU) stay, and more postoperative infections. Finally, PABT was an independent predictor of worse survival for patients with appendiceal and colorectal primaries. CONCLUSION: Even low levels of PABT for patients undergoing CRS/HIPEC are independently associated with a greater risk of infectious and non-infectious postoperative complications, and this risk is increased for patients receiving more than 5 RBC units. Worse survival was independently predicted by PABT for patients with peritoneal carcinomatosis of an appendiceal or colorectal origin.

Elderly Patients Benefit From Enhanced Recovery Protocols After Colorectal Surgery.

BACKGROUND: Enhanced recovery protocols (ERAS) aim to decrease physiological stress response to surgery and maintain postoperative physiological function. Proponents of ERAS state these protocols decrease lengths of stay (LOS) and complication rates. Our aim was to assess whether elderly patients receive the same benefit as younger patients using ERAS protocols. METHODS: We queried patients from 2015 to 2017 at our institution with Enhanced Recovery in Surgery (ERIN) variables from the targeted colectomy NSQIP database. The patients were divided into sextiles and analyzed for readmission, LOS, return of bowel function, tolerating diet, mobilization, and multimodal pain management comparing the youngest sextile to the oldest sextile. RESULTS: Two hundred sixty-two patients (73% colectomies) were enrolled in ERAS. When compared with the youngest sextile (age 19-43.8), the oldest sextile (age 71.4-92.5) had similar readmission rates at 9.8% versus 9.5% (P-value = 0.87), quicker return of bowel function, average 1.9 d versus 3.7 d (P-value < 0.01), and tolerated diet quicker, average POD 2.4 d versus 5.1 d (P-value < 0.01). There was a slight decrease in the use of multimodal pain management 88% versus 100% (P-value = 0.07), but mobilization on POD1 was slightly better in the elderly at 80% versus 78% (P-value = 0.76). Elderly patients enrolled in ERAS had an average LOS of 4.9 days versus 7.8 in the younger patients (P-value = 0.08). Among elderly non-ERAS patients average LOS was 14.6 days. CONCLUSION: Overall, elderly patients fared better or the same on the ERIN variables analyzed than the younger cohort. ERAS protocols are beneficial and applicable to elderly patients undergoing colorectal surgery.

Fertility after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy: A call to action.

INTRODUCTION: Cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) is increasingly accepted as the best therapeutic option in primary and some secondary peritoneal malignancies. The ramifications of this procedure on fertility are unknown. The aim of this study was to assess the current association of CRS/HIPEC with fertility following surgery. METHODS: A review of patients who underwent CRS/HIPEC between 2009 and 2018 was performed. Female patients were included if they were between ages 18-50 at the time of surgery. Gynecologic and obstetric history before and following CRS/HIPEC was collected by phone interview. RESULTS: Of 48 eligible participants, 21 completed the survey. Sixty-five percent of women underwent a total abdominal hysterectomy before or during CRS. Twenty-nine percent of these women recall fertility counseling before CRS/HIPEC, while 14.3% saw a fertility specialist for consultation, and only one patient proceeded with oocyte cryopreservation before treatment. There were no pregnancies reported following treatment with CRS/HIPEC. CONCLUSION: Few patients after CRS/HIPEC retain child-bearing potential, partly due to the high rate of hysterectomy and oophorectomy at time of surgery. Efforts towards improved preoperative counseling, increased oocyte cryopreservation, and evaluating the safety of preserving reproductive organs at the time of surgery are needed.

A novel preoperative risk score to optimize patient selection for performing concomitant liver resection with cytoreductive surgery/HIPEC.

BACKGROUND: While parenchymal hepatic metastases were previously considered a contraindication to cytoreductive surgery (CRS) and heated intraperitoneal chemotherapy (HIPEC), liver resection (LR) is increasingly performed with CRS/HIPEC. METHODS: Patients from the US HIPEC Collaborative (2000-2017) with invasive appendiceal or colorectal adenocarcinoma undergoing primary, curative intent CRS/HIPEC with CC0-1 resection were included. LR was defined as a formal parenchymal resection. Primary endpoints were postoperative complications and overall survival (OS). RESULTS: A total of 658 patients were included. About 83 (15%) underwent LR of colorectal (58%) or invasive appendiceal (42%) metastases. LR patients had more complications (81% vs. 60%; p = .001), greater number of complications (2.3 vs. 1.5; p < .001) per patient and required more reoperations (22% vs. 11%; p = .007) and readmissions (39% vs. 25%; p = .014) than non-LR patients. LR patients had decreased OS (2-year OS 62% vs. 79%, p < .001), even when accounting for peritoneal carcinomatosis index and histology type. Preoperative factors associated with decreased OS on multivariable analysis in LR patients included age < 60 years (HR, 3.61; 95% CI, 1.10-11.81), colorectal histology (HR, 3.84; 95% CI, 1.69-12.65), and multiple liver tumors (HR, 3.45; 95% CI, 1.21-9.85) (all p < .05). When assigning one point for each factor, there was an incremental decrease in 2-year survival as the risk score increased from 0 to 3 (0: 100%; 1: 91%; 2: 58%; 3: 0%). CONCLUSIONS: As CRS/HIPEC + LR has become more common, we created a simple risk score to stratify patients considered for CRS/HIPEC + LR. These data aid in striking the balance between an increased perioperative complication profile with the potential for improvement in OS.

Blood-Based Next-Generation Sequencing Analysis of Appendiceal Cancers.

BACKGROUND: Appendiceal cancers (ACs) are rare. The genomic landscape of ACs has not been well studied. The aim of this study was to confirm the feasibility of next-generation sequencing (NGS) using circulating tumor DNA (ctDNA) in ACs and characterize common genomic alterations. MATERIALS AND METHODS: Molecular alterations in 372 plasma samples from 303 patients with AC using clinical-grade NGS of ctDNA (Guardant360) across multiple institutions were evaluated. Test detects single nucleotide variants in 54-73 genes, copy number amplifications, fusions, and indels in selected genes. RESULTS: A total of 303 patients with AC were evaluated, of which 169 (56%) were female. Median age was 56.8 (25-83) years. ctDNA NGS testing was performed on 372 plasma samples; 48 patients had testing performed twice, 9 patients had testing performed three times, and 1 patient had testing performed four times. Genomic alterations were defined in 207 (n = 207/372, 55.6%) samples, and 288 alterations were identified excluding variants of uncertain significance and synonymous mutations. Alterations were identified in at least one sample from 184 patients; TP53-associated genes (n = 71, 38.6%), KRAS (n = 33, 17.9%), APC (n = 14, 7.6%), EGFR (n = 12, 6.5%), BRAF (n = 11, 5.9%), NF1 (n = 10, 5.4%), MYC (n = 9, 4.9%), GNAS (n = 8, 4.3%), MET (n = 6, 3.3%), PIK3CA (n = 5, 2.7%), and ATM (n = 5, 2.7%). Other low-frequency but clinically relevant genomic alterations were as follows: AR (n = 4, 2.2%), TERT (n = 4, 2.2%), ERBB2 (n = 4, 2.2%), SMAD4 (n = 3, 1.6%), CDK4 (n = 2, 1.1%), NRAS (n = 2, 1.1%), FGFR1 (n = 2, 1.1%), FGFR2 (n = 2, 1.1%), PTEN (n = 2, 1.1%), RB1 (n = 2, 1.1%), and CDK6, CDKN2A, BRCA1, BRCA2, JAK2, IDH2, MAPK, NTRK1, CDH1, ARID1A, and PDGFRA (n = 1, 0.5%). CONCLUSION: Evaluation of ctDNA is feasible among patients with AC. The frequency of genomic alterations is similar to that previously reported in tissue NGS. Liquid biopsies are not invasive and can provide personalized options for targeted therapies in patients with AC. IMPLICATIONS FOR PRACTICE: The complexity of appendiceal cancer and its unique genomic characteristics suggest that customized combination therapy may be required for many patients. Theoretically, as more oncogenic pathways are discovered and more targeted therapies are approved, customized treatment based on the patient's unique molecular profile will lead to personalized care and improve patient outcomes. Liquid biopsies are noninvasive, cost-effective, and promising methods that provide patients with access to personalized treatment.

Phase II Study of Preoperative Chemoradiotherapy with Oxaliplatin, Infusional 5-Fluorouracil, and Cetuximab Followed by Postoperative Docetaxel and Cetuximab in Patients with Adenocarcinoma of the Esophagus: A Trial of the ECOG-ACRIN Cancer Research Group (E2205).

BACKGROUND: A standard approach to treating resectable esophageal adenocarcinoma is chemoradiotherapy (CRT) followed by surgery; however, recurrence is common. To improve this, we designed a single-arm, phase II trial that added an epidermal growth factor receptor (EGFR) inhibitor, cetuximab (C), to CRT, with the hypothesis that EGFR inhibition would improve pathologic complete response (pCR) rate. MATERIALS AND METHODS: We aimed to increase the pCR rate from 25% to 45%. A Simon two-stage design (α and ß of 0.10) required pCR/enrolled 5/18 for stage 1 and 14/40 total. CRT: oxaliplatin 85 mg/m2 days 1, 15, and 29; infusional 5-fluorouracil 180 mg/m2 /24 hours × 35 days; C 400 mg/m2 day 1 then 250 mg/m2 days 8, 15, 22, and 29 and radiation (intensity modulated radiotherapy [IMRT] allowed) 180 cGy/day × 25 fractions (Monday through Friday). Following esophagectomy, adjuvant chemotherapy (CT): weekly docetaxel 35 mg/m2 and C 250 mg/m2 5 out of 6 weeks for two cycles. RESULTS: Of 21 eligible patients enrolled, 17 had surgery; 4 died before operation (due to pulmonary embolism 4 days after CRT, G3 diarrhea, progressive disease during CRT, sepsis/hypoxia during CRT, and acute respiratory distress syndrome [ARDS]). pCR = 7/17. Three postoperative deaths due to ARDS resulted in seven total study-related deaths. Of the 14 remaining patients, 12 started and completed adjuvant CT. Two of seven patients with pCR died, both of ARDS. Out of the 21 eligible subjects in this study, 13 have died and 8 remain alive. The use of IMRT did not correlate with ARDS. CONCLUSION: This regimen demonstrated promising activity. Toxicity was significant, with seven study-related deaths leading to closure after stage 1. All postoperative deaths were due to ARDS. This regimen is not recommended. IMPLICATIONS FOR PRACTICE: Esophageal cancer is a disease with a high death rate. The current treatment involves giving chemotherapy plus radiation followed by surgery, but this cures only a quarter of patients. In order to improve survival, better treatments are needed. This trial evaluated the addition of a novel drug, cetuximab, to chemotherapy plus radiation. Unfortunately, the side effects were too great and the study was stopped early.

CRS/HIPEC with Major Organ Resection in Peritoneal Mesothelioma Does not Impact Major Complications or Overall Survival: A Retrospective Cohort Study of the US HIPEC Collaborative.

INTRODUCTION: CRS/HIPEC is thought to confer a survival advantage for patients with malignant peritoneal mesothelioma (MPM). However, the impact of nonperitoneal organ resection is not clearly defined. We evaluated the impact of major organ resection (MOR) on postoperative outcomes and overall survival (OS). PATIENTS AND METHODS: The US HIPEC collaborative database (2000-2017) was reviewed for MPM patients who underwent CRS/HIPEC. MOR was defined as total or partial resection of diaphragm, stomach, spleen, pancreas, small bowel, colon, rectum, kidney, ureter, bladder, and/or uterus. MOR was categorized as 0, 1, or 2+ organs. RESULTS: A total of 174 patients were identified. Median PCI was 16 (3-39). The distribution of patients with MOR-0, MOR-1, and MOR-2+ was 94, 45, and 35 patients, respectively. MOR-1 and MOR-2+ groups had a higher frequency of any complication compared with MOR-0 (57.8%, 74.3%, and 48.9%, respectively, p = 0.035), but Clavien 3/4 complications were similar. Median length of stay was slightly higher in the MOR-1 and MOR-2+ groups (10 and 11 days) compared with the MOR-0 cohort (9 days, p = 0.005). Incomplete cytoreduction, ASA class 4, and male gender were associated with increased mortality on unadjusted analysis; however, their impact on OS was attenuated on multivariable analysis. MOR was not associated with OS based on these data (MOR-1: HR 1.67, 95% CI 0.59-4.74; MOR-2+ : HR 0.77, 95% CI 0.22-2.69). CONCLUSIONS: MOR was not associated with an increase in major complications or worse OS in patients undergoing CRS/HIPEC for MPM and should be considered, if necessary, to achieve complete cytoreduction for MPM patients.

Repeat Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy Is Not Associated with Prohibitive Complications: Results of a Multiinstitutional Retrospective Study.

BACKGROUND: Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) is offered to select patients with peritoneal metastases. In instances of recurrence/progression, a repeat CRS/HIPEC may be considered. The perioperative morbidity and the potential oncologic benefits are not well described. PATIENTS AND METHODS: We performed a retrospective analysis of a multiinstitutional database to assess the perioperative outcomes following repeat CRS/HIPEC (repeat). Kaplan-Meier and Cox estimates were used to assess survival. RESULTS: In the entire cohort, 2157 patients were analyzed, with 158 (7.3%) in the repeat cohort. The rate of complete cytoreduction was 89.8% versus 83.0% in initial versus repeat groups. The overall incidence of major complications was similar (26.3% vs. 30.7%); however, reoperation was more common in the repeat group. Perioperative outcomes such as length of stay and nonhome discharge were not significantly different. For the entire cohort, 5-year overall survival (OS) was 56.0% in the initial group and 59.5% in the repeat group. In patients with only appendiceal cancer, we observed a 5-year OS of 64.0% in the initial group compared with 67.3% in the repeat cohort. For patients with appendiceal cancer who developed a recurrence/progression, median OS was 36 months in the no repeat operation group compared with 73 months for those that did. Multivariable regression demonstrated that completeness of cytoreduction and tumor grade were associated with OS, but repeat operation was not. CONCLUSIONS: Repeat CRS/HIPEC is not associated with prohibitive risk. Survival is possibly improved, and therefore, repeat operation should be considered in selected patients with recurrent or progressive disease.

The Intersection of Age and Tumor Biology with Postoperative Outcomes in Patients After Cytoreductive Surgery and HIPEC.

BACKGROUND: Patient age is a significant factor in preoperative selection for major abdominal surgery. The association of age, tumor biology, and postoperative outcomes in patients undergoing cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) remains ill-defined. METHODS: Retrospective analysis was performed for patients who underwent a CCR0/1 CRS/HIPEC from the US HIPEC Collaborative Database (2000-2017). Age was categorized into < 65 or ≥ 65 years. Primary outcome was postoperative major complications. Secondary outcomes were non-home discharge (NHD) and readmission. Analysis was stratified by disease histology: non-invasive (appendiceal LAMN/HAMN), and invasive (appendiceal/colorectal adenocarcinoma). RESULTS: Of 1090 patients identified, 22% were ≥ 65 (n = 240), 59% were female (n = 646), 25% had non-invasive (n = 276) and 51% had invasive (n = 555) histology. Median PCI was 13 (IQR 7-20). Patients ≥ 65 had a higher rate of major complications (37 vs 26%, p = 0.02), NHD (12 vs 5%, p < 0.01), and readmission (28 vs 22%, p = 0.05), compared to those < 65. For non-invasive histology, age ≥ 65 was not associated with major complications or NHD on multivariable analysis. For invasive histology, when accounting for PCI and CCR, age ≥ 65 was associated with major complications (OR 2.04, 95% CI 1.16-3.59, p = 0.01). When accounting for major complications, age ≥ 65 was associated with NHD (OR 2.54, 95% CI 1.08-5.98, p = 0.03). Age ≥ 65 was not predictive of readmission for any histology when accounting for major complications. CONCLUSIONS: Age ≥ 65 years is an independent predictor for postoperative major complications and non-home discharge for invasive histology, but not non-invasive histology. These data inform preoperative counseling, risk stratification, and early discharge planning.

Implications of Postoperative Complications for Survival After Cytoreductive Surgery and HIPEC: A Multi-Institutional Analysis of the US HIPEC Collaborative.

BACKGROUND: Postoperative complications (POCs) are associated with worse oncologic outcomes in various cancer histologies. The impact of POCs on the survival of patients with appendiceal or colorectal cancer after cytoreductive surgery (CRS) and heated intraperitoneal chemotherapy (HIPEC) is unknown. METHODS: The US HIPEC Collaborative (2000-2017) was reviewed for patients who underwent CCR0/1 CRS/HIPEC for appendiceal/colorectal cancer. The analysis was stratified by noninvasive appendiceal neoplasm versus invasive appendiceal/colorectal adenocarcinoma. The POCs were grouped into infectious, cardiopulmonary, thromboembolic, and intestinal dysmotility. The primary outcomes were overall survival (OS) and recurrence-free survival (RFS). RESULTS: Of the 1304 patients, 33% had noninvasive appendiceal neoplasm (n = 426), and 67% had invasive appendiceal/colorectal adenocarcinoma (n = 878). In the noninvasive appendiceal cohort, POCs were identified in 55% of the patients (n = 233). The 3-year OS and RFS did not differ between the patients who experienced a complication and those who did not (OS, 94% vs 94%, p = 0.26; RFS, 68% vs 60%, p = 0.15). In the invasive appendiceal/colorectal adenocarcinoma cohort, however, POCs (63%; n = 555) were associated with decreased 3-year OS (59% vs 74%; p < 0.001) and RFS (32% vs 42%; p < 0.001). Infectious POCs were the most common (35%; n = 196). In Multivariable analysis accounting for gender, peritoneal cancer index (PCI), and incomplete resection (CCR1), infectious POCs in particular were associated with decreased OS compared with no complication (hazard ratio [HR] 2.08; p < 0.01) or other types of complications (HR, 1.6; p < 0.01). Similarly, infectious POCs were independently associated with worse RFS (HR 1.61; p < 0.01). CONCLUSION: Postoperative complications are associated with decreased OS and RFS after CRS/HIPEC for invasive histology, but not for an indolent disease such as noninvasive appendiceal neoplasm, and this association is largely driven by infectious complications. The exact mechanism is unknown, but may be immunologic. Efforts must target best practices and standardized prevention strategies to minimize infectious postoperative complications.

Optimal Surveillance Frequency After CRS/HIPEC for Appendiceal and Colorectal Neoplasms: A Multi-institutional Analysis of the US HIPEC Collaborative.

BACKGROUND: No guidelines exist for surveillance following cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) for appendiceal and colorectal cancer. The primary objective was to define the optimal surveillance frequency after CRS/HIPEC. METHODS: The U.S. HIPEC Collaborative database (2000-2017) was reviewed for patients who underwent a CCR0/1 CRS/HIPEC for appendiceal or colorectal cancer. Radiologic surveillance frequency was divided into two categories: low-frequency surveillance (LFS) at q6-12mos or high-frequency surveillance (HFS) at q2-4mos. Primary outcome was overall survival (OS). RESULTS: Among 975 patients, the median age was 55 year, 41% were male: 31% had non-invasive appendiceal (n = 301), 45% invasive appendiceal (n = 435), and 24% colorectal cancer (CRC; n = 239). With a median follow-up time of 25 mos, the median time to recurrence was 12 mos. Despite less surveillance, LFS patients had no decrease in median OS (non-invasive appendiceal: 106 vs. 65 mos, p < 0.01; invasive appendiceal: 120 vs. 73 mos, p = 0.02; colorectal cancer [CRC]: 35 vs. 30 mos, p = 0.8). LFS patients had lower median PCI scores compared with HFS (non-invasive appendiceal: 10 vs. 19; invasive appendiceal: 10 vs. 14; CRC: 8 vs. 11; all p < 0.01). However, on multivariable analysis, accounting for PCI score, LFS was still not associated with decreased OS for any histologic type (non-invasive appendiceal: hazard ratio [HR]: 0.28, p = 0.1; invasive appendiceal: HR: 0.73, p = 0.42; CRC: HR: 1.14, p = 0.59). When estimating annual incident cases of CRS/HIPEC at 375 for non-invasive appendiceal, 375 invasive appendiceal and 4410 colorectal, LFS compared with HFS for the initial two post-operative years would potentially save $13-19 M/year to the U.S. healthcare system. CONCLUSIONS: Low-frequency surveillance after CRS/HIPEC for appendiceal or colorectal cancer is not associated with decreased survival, and when considering decreased costs, may optimize resource utilization.

Predictors of Anastomotic Failure After Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy: Does Technique Matter?

BACKGROUND: Anastomotic failure (AF) after cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) remains a dreaded complication. Whether specific factors, including anastomotic technique, are associated with AF is poorly understood. METHODS: Patients who underwent CRS-HIPEC including at least one bowel resection between 2000 and 2017 from 12 academic institutions were reviewed to determine factors associated with AF (anastomotic leak or enteric fistula). RESULTS: Among 1020 patients who met the inclusion criteria, the median age was 55 years, 43.9% were male, and the most common histology was appendiceal neoplasm (62.3%). The median Peritoneal Cancer Index was 14, and 93.2% of the patients underwent CC0/1 resection. Overall, 82 of the patients (8%) experienced an AF, whereas 938 (92.0%) did not. In the multivariable analysis, the factors associated with AF included male gender (odds ratio [OR], 2.2; p < 0.01), left-sided colorectal resection (OR 10.0; p = 0.03), and preoperative albumin (OR 1.8 per g/dL; p = 0.02).Technical factors such as method (stapled vs hand-sewn), timing of anastomosis, and chemotherapy regimen used were not associated with AF (all p > 0.05). Anastomotic failure was associated with longer hospital stay (23 vs 10 days; p < 0.01), higher complication rate (90% vs 59%; p < 0.01), higher reoperation rate (41% vs 9%; p < 0.01), more 30-day readmissions (59% vs 22%; p < 0.01), greater 30-day mortality (9% vs 1%; p < 0.01), and greater 90-day mortality (16% vs 8%; p = 0.02) as well as shorter median overall survival (25.6 vs 66.0 months; p < 0.01). CONCLUSIONS: Among patients undergoing CRS-HIPEC, AF is independently associated with postoperative morbidity and worse long-term outcomes. Because patient- and tumor-related, but not technical, factors are associated with AF, operative technique may be individualized based on patient considerations and surgeon preference.

Preoperative Risk Score for Predicting Incomplete Cytoreduction: A 12-Institution Study from the US HIPEC Collaborative.

BACKGROUND: For patients with peritoneal carcinomatosis undergoing cytoreductive surgery with heated intraperitoneal chemotherapy (CRS/HIPEC), incomplete cytoreduction (CCR2/3) confers morbidity without survival benefit. The aim of this study is to identify preoperative factors which predict CCR2/3. METHODS: All patients who underwent curative-intent CRS/HIPEC of low/high-grade appendiceal, colorectal, or peritoneal mesothelioma cancers in the 12-institution US HIPEC Collaborative from 2000 to 2017 were included (n = 2027). The primary aim is to create an incomplete-cytoreduction risk score (ICRS) to predict CCR2/3 CRS utilizing preoperative data. ICRS was created from a randomly selected cohort of 50% of patients (derivation cohort) and verified on the remaining patients (validation cohort). RESULTS: Within our derivation cohort (n = 998), histology was low-grade appendiceal neoplasms in 30%, high-grade appendiceal tumor in 41%, colorectal tumor in 22%, and peritoneal mesothelioma in 8%. CCR0/1 was achieved in 816 patients and CCR 2/3 in 116 patients. On multivariable analysis, preoperative factors associated with incomplete cytoreduction were male gender [odds ratio (OR) 3.4, p = 0.007], presence of ascites (OR 2.8, p = 0.028), cancer antigen (CA)-125 ≥ 40 U/mL (OR 3.4, p = 0.012), and carcinoembryonic antigen (CEA) ≥ 4.2 ng/mL (OR 3.2, p = 0.029). Each preoperative factor was assigned a score of 0 or 1 to form an ICRS from 0 to 4. Scores were grouped as zero (0), low (1-2), or high (3-4). Incidence of CCR2/3 progressively increased by risk group from 1.6% in zero to 13% in low and 39% in high. When ICRS was applied to the validation cohort (n = 1029), this relationship was maintained. CONCLUSION: The incomplete cytoreduction risk score incorporates preoperative factors to accurately stratify the risk of CCR2/3 resection in CRS/HIPEC. This score should not be used in isolation, however, to exclude patients from surgery.