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.

Influence of insurance status on the postoperative outcomes of cytoreductive surgery and HIPEC.

BACKGROUND: Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) is increasingly performed for peritoneal surface malignancies but remains associated with significant morbidity. Scant research is available regarding the impact of insurance status on postoperative outcomes. METHODS: Patients undergoing CRS/HIPEC between 2000 and 2017 at 12 participating sites in the US HIPEC Collaborative were identified. Univariate and multivariate analyses were used to compare the baseline characteristics, operative variables, and postoperative outcomes of patients with government, private, or no insurance. RESULTS: Among 2268 patients, 699 (30.8%) had government insurance, 1453 (64.0%) had private, and 116 (5.1%) were uninsured. Patients with government insurance were older, more likely to be non-white, and comorbid (p < 0.05). Patients with government (OR: 2.25, CI: 1.50-3.36, p < 0.001) and private (OR: 1.69, CI: 1.15-2.49, p = 0.008) insurance had an increased risk of complications on univariate analysis. There was no independent relationship on multivariate analysis. An American Society of Anesthesiologists score of 3 or 4, peritoneal carcinomatosis index score >15, completeness of cytoreduction score >1, and nonhome discharge were factors independently associated with a postoperative complication. CONCLUSION: While there were differences in postoperative outcomes between the three insurance groups on univariate analysis, there was no independent association between insurance status and postoperative complications after CRS/HIPEC.

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.

Suppressive myeloid cells are expanded by biliary tract cancer-derived cytokines in vitro and associate with aggressive disease.

BACKGROUND: BTC is an aggressive disease exacerbated by inflammation and immune suppression. Expansion of immunosuppressive cells occurs in biliary tract cancer (BTC), yet the role of BTC-derived cytokines in this process is unclear. METHODS: Activated signalling pathways and cytokine production were evaluated in a panel of human BTC cell lines. Human peripheral blood mononuclear cells (PBMCs) were cultured with BTC supernatants, with and without cytokine neutralising antibodies, and analysed by flow cytometry or immunoblot. A human BTC tissue microarray (TMA, n = 69) was stained for IL-6, GM-CSF, and CD33+S100a9+ cells and correlated with clinical outcomes. RESULTS: Immunomodulatory factors (IL-6, GM-CSF, MCP-1) were present in BTC supernatants. BTC supernatants expanded CD33dimCD11b+HLA-DRlow/- myeloid-derived suppressor cells (MDSCs) from human PBMCs. Neutralisation of IL-6 and GM-CSF in BTC supernatants inhibited activation of STAT3/5, respectively, in PBMCs, with heterogeneous effects on MDSC expansion in vitro. Staining of a BTC TMA revealed a positive correlation between IL-6 and GM-CSF, with each cytokine and more CD33+S100a9+ cells. Increased CD33+S100a9+ staining positively correlated with higher tumour grade, differentiation and the presence of satellite lesions. CONCLUSION: BTC-derived factors promote suppressive myeloid cell expansion, and higher numbers of CD33+S100a9+ cells in resectable BTC tumours correlates with more aggressive disease.

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.

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.

Institutional variation in recovery after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy: An opportunity for enhanced recovery pathways.

BACKGROUND: Variations in care have been demonstrated both within and among institutions in many clinical settings. By standardizing perioperative practices, Enhanced Recovery After Surgery (ERAS) pathways reduce variation in perioperative care. We sought to characterize the variation in cytoreductive surgery (CRS)/heated intraperitoneal chemotherapy (HIPEC) perioperative practices among experienced US medical centers. METHODS: Data from the US HIPEC Collaborative represents a retrospective multi-institutional cohort study of CRS and CRS/HIPEC procedures performed from 12 major academic institutions. Patient characteristics and perioperative practices were reported and compared. Institutional variation was analyzed using hierarchical mixed-effects linear (continuous outcomes) or logistic (binary outcomes) regression models. RESULTS: A total of 2372 operations were included. CRS/HIPEC was performed most commonly for appendiceal histologies (64.2%). The rate of complications (overall 56.3%, range: 31.8-70.9) and readmissions (overall 20.6%, range: 8.9-33.3) varied by institution (P < .001). Institution-level variation in perioperative practice patterns existed among measured ERAS pathway process/outcomes (P < .001). The percentages of variation with each process/outcome measure attributable solely to institutional practices ranged from 0.6% to 66.6%. CONCLUSIONS: Significant variation exists in the perioperative care of patients undergoing CRS/HIPEC at major US academic institutions. These findings provide a strong rationale for the investigation of best practices in CRS/HIPEC patients.

The impact of HIPEC vs. EPIC for the treatment of mucinous appendiceal carcinoma: a study from the US HIPEC collaborative.

INTRODUCTION: Mucinous appendiceal carcinoma is a rare malignancy that commonly spreads to the peritoneum leading to peritoneal metastases. Complete cytoreduction with perioperative intraperitoneal chemotherapy (PIC) is the mainstay of treatment, administered as either hyperthermic intra peritoneal chemotherapy (HIPEC) or early post-operative intraperitoneal chemotherapy (EPIC). Our goal was to assess the perioperative and long term survival outcomes associated with these two PIC methods. MATERIALS AND METHODS: Patients with mucinous appendiceal carcinoma were identified in the US HIPEC Collaborative database from 12 academic institutions. Patient demographics, clinical characteristics, and survival outcomes were compared among patients who underwent HIPEC vs. EPIC with inverse probability weighting (IPW) used for adjustment. RESULTS: Among 921 patients with mucinous appendiceal carcinoma, 9% underwent EPIC while 91% underwent HIPEC. There was no difference in Grade III-V complications between the two groups (18.5% for HIPEC vs. 15.0% for EPIC, p=.43) though patients who underwent HIPEC had higher rates of readmissions (21.2% vs. 8.8%, p<.01). Additionally, PIC method was not an independent predictor for overall survival (OS) or recurrence-free survival (RFS) after adjustment on multivariable analysis. CONCLUSIONS: Among patients with mucinous appendiceal carcinoma, both EPIC and HIPEC appear to be associated with similar perioperative and long-term outcomes.

Lending a hand for laparoscopic distal pancreatectomy: the optimal approach?

BACKGROUND: Both minimally invasive surgery (MIS) and open approaches for distal pancreatectomy are acceptable. MIS options include total laparoscopic/robotic (TLR) and hand-assist laparoscopy (HAL). When considering safety profile and specimen quality, the optimal approach is unknown. METHODS: Patients who underwent distal pancreatectomy from 2010-2018 at two major academic institutions were included. Converted procedures were categorized into final approach. Ninety-day perioperative/pathologic outcomes of MIS and open were compared. Subset analyses between TLR vs HAL and HAL vs open were performed. Intent-to-treat analysis was performed. RESULTS: Among 1006 patients, resection was performed by MIS in 35% (n = 352), open in 65% (n = 654). MIS had similar patient comorbidity profile as open but had increased operative time (183 vs 162 min; p < 0.01), lower estimated-blood-loss (EBL; 131 vs 341 mL; p < 0.01), fewer intraoperative blood transfusions (1.4 vs 5%; p < 0.01), shorter LOS (5.2 vs 7.2 days; p < 0.01). Tumor size was smaller (3.2 vs 4.4 cm; p < 0.01) with lower lymph node (LN) yield (14 vs 16; p < 0.01). When comparing HAL (n = 109) to TLR (n = 243), despite increased prior abdominal operations (60 vs 43%; p = 0.008), HAL had shorter operative time (167 vs 191 min; p < 0.01), similar length-of-stay (LOS; 5.4 vs 5.1 days; p = 0.27), and readmission rate (15 vs 13%; p = 0.47). When comparing HAL to open, the advantages of TLR approach persisted including lower EBL (171 vs 342 mL; p < 0.01), and shorter LOS (5.4 vs 7.2 days; p < 0.01). Although HAL had smaller tumors, it had a similar LN yield (16 vs 16; p = 0.80), and higher R0-rate (97 vs 83%; p < 0.01). CONCLUSION: Hand-assist laparoscopy is safe and feasible for distal pancreatectomy as operative time, complication profile, lymph node yield, and R0-rates are similar to open procedures, while maintaining the associated the advantages of a total laparoscopic/robotic approach with reduced blood loss and shorter length-of-stay.

A Novel Validated Recurrence Risk Score to Guide a Pragmatic Surveillance Strategy After Resection of Pancreatic Neuroendocrine Tumors: An International Study of 1006 Patients.

OBJECTIVE: Despite heterogeneous biology, similar surveillance schemas are utilized after resection of all pancreatic neuroendocrine tumors (PanNETs). Given concerns regarding excess radiation exposure and financial burden, our aim was to develop a prognostic score for disease recurrence to guide individually tailored surveillance strategies. METHODS: All patients with primary nonfunctioning, nonmetastatic well/moderately differentiated PanNETs who underwent curative-intent resection at 9-institutions from 2000 to 2016 were included (n = 1006). A Recurrence Risk Score (RRS) was developed from a randomly selected derivation cohort comprised of 67% of patients and verified on the validation-cohort comprised of the remaining 33%. RESULTS: On multivariable analysis, patients within the derivation cohort (n = 681) with symptomatic tumors (jaundice, pain, bleeding), tumors >2 cm, Ki67 >3%, and lymph node (LN) (+) disease had increased recurrence. Each factor was assigned a score based on their weighted odds ratio that formed a RRS of 0 to 10: symptomatic = 1, tumor >2 cm = 2, Ki67 3% to 20% = 1, Ki67 >20% = 6, LN (+) = 1. Patients were grouped into low- (RRS = 0-2; n = 247), intermediate-(RRS = 3-5; n = 204), or high (RRS = 6-10; n = 9)-risk groups. At 24 months, 33% of high RRS recurred, whereas only 2% of low and 14% of intermediate RRS recurred. This persisted in the validation cohort (n = 325). CONCLUSIONS: This international, novel, internally validated RRS accurately stratifies recurrence-free survival for patients with resected PanNETs. Given their unique recurrence patterns, surveillance intervals of 12, 6, and 3 months are proposed for low, intermediate, and high RRS patients, respectively, to minimize radiation exposure and optimize cost/resource utilization.

Assessing the Role of Neoadjuvant Chemotherapy in Primary High-Risk Truncal/Extremity Soft Tissue Sarcomas: An Analysis of the Multi-institutional U.S. Sarcoma Collaborative.

BACKGROUND: The role of neoadjuvant chemotherapy (NCT) for high-risk soft tissue sarcoma (STS) is questioned. This study aimed to define which patients may experience a survival advantage with NCT. METHODS: All the patients from the U.S. Sarcoma Collaborative database (2000-2016) who underwent curative-intent resection of high-grade, primary truncal/extremity STS size 5 cm or larger were included in this study. The primary end points were recurrence-free survival (RFS) and overall survival (OS). RESULTS: Of the 4153 patients, 770 were included in the study. The median tumor size was 10 cm, and 669 of the patients (87%) had extremity tumors. The most common histology was undifferentiated pleomorphic sarcoma (UPS), found in 42% of the patients. Of the 770 patients, 216 (28%) received NCT. The patients who received NCT had deeper, larger tumors (p < 0.001). Of the patients with tumors 5 cm or larger and 8 cm or larger, NCT was not associated with improved RFS or OS. However for the patients with tumors 10 cm or larger, NCT was associated with improved 5-year RFS (51% vs 40%; p = 0.053) and 5-year OS (58% vs 47%; p = 0.043). By location, the patients with extremity tumors 10 cm or larger but not truncal tumors had improved 5-yearr RFS (54% vs 42%; p = 0.042) and 5-year OS (61% vs 47%; p = 0.015) with NCT. According to histology, no subtype had improved RFS or OS with NCT, although the patients with UPS had a trend toward improved 5-year RFS (56% vs 42%; p = 0.092) and 5-year OS (66% vs 52%; p = 0.103) with NCT. CONCLUSION: For the patients with high-grade STS, NCT was associated with improved RFS and OS when tumors were 10 cm or larger and located in the extremity. However, no histiotype-specific advantage was identified. Future studies assessing the efficacy of NCT may consider focusing on these patients, with added focus on histology-specific strategies.

Defining the Role of Lymphadenectomy for Pancreatic Neuroendocrine Tumors: An Eight-Institution Study of 695 Patients from the US Neuroendocrine Tumor Study Group.

BACKGROUND: Preoperative factors that reliably predict lymph node (LN) metastases in pancreatic neuroendocrine tumors (PanNETs) are unclear. The number of LNs needed to accurately stage PanNETs has not been defined. METHODS: Patients who underwent curative-intent resection of non-functional PanNETs at eight institutions from 2000 to 2016 were analyzed. Preoperative factors associated with LN metastases were identified. A procedure-specific target for LN retrieval to accurately stage patients was determined. RESULTS: Of 695 patients who underwent resection, 33% of tumors were proximal (head/uncinate) and 67% were distal (neck/body/tail). Twenty-six percent of patients (n = 158) had LN-positive disease, which was associated with a worse 5-year recurrence-free survival (RFS; 60% vs. 86%; p < 0.001). The increasing number of positive LNs was not associated with worse RFS. Preoperative factors associated with positive LNs included tumor size ≥ 2 cm (odds ratio [OR] 6.6; p < 0.001), proximal location (OR 2.5; p < 0.001), moderate versus well-differentiation (OR 2.1; p = 0.006), and Ki-67 ≥ 3% (OR 3.1; p < 0.001). LN metastases were also present in tumors without these risk factors: < 2 cm (9%), distal location (19%), well-differentiated (23%), and Ki-67 < 3% (16%). Median LN retrieval was 13 for pancreatoduodenectomy (PD), but only 9 for distal pancreatectomy (DP). Given that PD routinely includes a complete regional lymphadenectomy, a minimum number of LNs to accurately stage patients was not identified. However, for DP, removal of less than seven LNs failed to discriminate 5-year RFS between LN-positive and LN-negative patients (less than seven LNs: 72% vs. 83%, p = 0.198; seven or more LNs: 67% vs. 86%; p = 0.002). CONCLUSIONS: Tumor size ≥ 2 cm, proximal location, moderate differentiation, and Ki-67 ≥ 3% are preoperative factors that predict LN positivity in resected non-functional PanNETs. Given the 9-23% incidence of LN metastases in patients without such risk factors, routine regional lymphadenectomy should be considered. PD inherently includes sufficient LN retrieval, while DP should aim to remove seven or more LNs for accurate staging.

Primary Tumor Sidedness is Predictive of Survival in Colon Cancer Patients Treated with Cytoreductive Surgery With or Without Hyperthermic Intraperitoneal Chemotherapy: A US HIPEC Collaborative Study.

INTRODUCTION: The clinical relevance of primary tumor sidedness is not fully understood in colon cancer patients with peritoneal metastasis treated with cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). METHODS: This was a retrospective cohort study of a multi-institutional database of patients with peritoneal surface malignancy at 12 participating high-volume academic centers from the US HIPEC Collaborative. RESULTS: Overall, 336 patients with colon primary tumors who underwent curative-intent CRS with or without HIPEC were identified; 179 (53.3%) patients had right-sided primary tumors and 157 (46.7%) had left-sided primary tumors. Patients with right-sided tumors were more likely to be older, male, have higher Peritoneal Cancer Index (PCI), and have a perforated primary tumor, but were less likely to have extraperitoneal disease. Patients with complete cytoreduction (CC-0/1) had a median disease-free survival (DFS) of 11.5 months (95% confidence interval [CI] 7.6-15.3) versus 13.1 months (95% CI 9.5-16.8) [p = 0.158] and median overall survival (OS) of 30 months (95% CI 23.5-36.6) versus 45.4 months (95% CI 35.9-54.8) [p = 0.028] for right- and left-sided tumors; respectively. Multivariate analysis revealed that right-sided primary tumor was an independent predictor of worse DFS (hazard ratio [HR] 1.75, 95% CI 1.19-2.56; p =0.004) and OS (HR 1.72, 95% CI 1.09-2.73; p = 0.020). CONCLUSION: Right-sided primary tumor was an independent predictor of worse DFS and OS. Relevant clinicopathologic criteria, such as tumor sidedness and PCI, should be considered in patient selection for CRS with or without HIPEC, and guide stratification for clinical trials.

A novel preoperative risk score to predict lymph node positivity for rectal neuroendocrine tumors: An NCDB analysis to guide operative technique.

BACKGROUND/OBJECTIVE: Staging and type of resection for rectal neuroendocrine tumors (R-NETS) relies on preoperative identification of lymph node (LN) involvement. Study objective was to develop a Preoperative Rectal Stratification Score (PReSS) for LN-positivity and to assess the association of PReSS with overall survival (OS). METHODS: All patients in the National Cancer Database (2004-2014) with non-metastatic/nonfunctional R-NETS were included. Tumor size was divided into three categories (<1, 1-2, and ≥2 cm). RESULTS: Among 383 patients, median age was 57 years, 52% were male (n = 200), median tumor size was 1.4 cm, 43% had positive LNs (n = 163). On univariate analysis, age > 60, poorly differentiated grade, depth of invasion past submucosa, and size >1 cm were associated with LN positivity. On multivariable analysis, depth of invasion past submucosa, and increasing tumor size >1 cm remained associated with LN positivity. As these can be determined preoperatively, incidence of LN positivity was determined for each combination of tumor size and depth of invasion. Each variable was assigned a score to create a PReSS of four groups (0-3) associated with an increasing rate of LN-positivity (PReSS group 0: 11%, 1: 38%, 2: 50%, 3: 78%, P < .01). PReSS correlated with 10-year OS (PReSS 0: 90%; 1: 81%; 2: 59%; 3: 41%). CONCLUSION: For R-NETS, depth of invasion and tumor size predict LN positivity and both can be obtained preoperatively. PReSS incorporates both variables and stratifies tumors into four risk groups of progressively increasing LN positivity and should be used to guide surgical approach.

Race, ethnicity, and socioeconomic factors in cholangiocarcinoma: What is driving disparities in receipt of treatment?

BACKGROUND AND OBJECTIVES: Race/ethnicity and socioeconomic factors are associated with worse cancer outcomes. Our aim was to determine the association of these factors with receipt of surgery and multimodality therapy for cholangiocarcinoma. METHODS: Patients with cholangiocarcincoma in the National Cancer Database were identified. Racial/ethnic groups were defined as non-Hispanic White, non-Hispanic Black, Asian, and Hispanic. Socioeconomic factors were insurance status, income, and education. RESULTS: Of 12 095 patients with non-metastatic cholangiocarcinoma, 42% received surgery. Black race was associated with decreased odds of receiving surgery (odds ratio [OR]: 0.66l; P < .001) compared to White patients. Socioeconomic factors accounted for 21% of this disparity. Accounting for socioeconomic and clinicopathologic variables, Black race (OR: 0.73; P < .001), uninsured status (OR: 0.43; P < .001), and Medicaid insurance (OR: 0.63; P < .001) were all associated with decreased receipt of surgery. Of 4808 patients who received surgery, 47% received multimodality therapy. There were no racial/ethnic or socioeconomic differences in receipt of multimodality therapy once patients accessed surgical care. Similar results were seen in patients with advanced disease who received chemotherapy as primary treatment. CONCLUSION: Racial/ethnic and socioeconomic disparities exist in treatment for cholangiocarcinoma, however only for primary treatment. In patients who received surgery or chemotherapy, there were no disparities in receipt of multimodality therapy. This emphasizes the need to improve initial access to health care for minority and socioeconomical disadvantaged patients.

Identifying the barriers to gastric cancer care at safety-net hospitals: A novel comparison of a safety-net hospital to a neighboring quaternary referral academic center in the same healthcare system.

BACKGROUND: The three-delays model describes delays in seeking, reaching, and receiving care for vulnerable populations needing treatment. The dominant delay for patients with gastric adenocarcinoma (GAC) is unknown. We aimed to define patients with GAC who reached and received care at our regional safety-net hospital (Grady Memorial Hospital [GMH]) and our neighboring quaternary referral hospital (Emory University Hospital [EUH]). METHODS: Clinicopathologic data from National Cancer Database (NCDB) participating academic centers were compared with GMH from 2004 to 2014. Outcomes of patients undergoing surgery at GMH were compared to those at EUH. RESULTS: At presentation, compared to NCDB centers (n = 69 662), GMH patients (n = 154) were more often black (85.1 vs 17.2%; P < 0.001), uninsured (30.5 vs 4.7%; P < 0.001), have stage IV disease (43.5 vs 30.1%; P = 0.017), and received no treatment (40.3 vs 18.4%; P < 0.001). When only comparing patients who underwent curative-intent resection at GMH (n = 23) to EUH (n = 137), median overall survival was similar between both groups (GMH: median not reached; EUH: 59.8 mos; P = 0.785). CONCLUSION: Although vulnerable patients with GAC within a safety-net hospital present with later stages of the disease, those who received surgery have acceptable outcomes. Thus, efforts should be made to overcome barriers in seeking care.