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.

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.

Conditional Survival Following Cytoreductive Surgery with Hyperthermic Intraperitoneal Chemotherapy for Peritoneal Surface Malignancies: An Analysis from the US HIPEC Collaborative.

INTRODUCTION: The long-term prognosis of patients who undergo cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) for peritoneal surface malignancies (PSM) varies considerably on the basis of histological and operative factors. While overall survival (OS) estimates are used to inform adjuvant therapy and surveillance strategies, conditional survival may provide more clinically relevant estimates of prognosis by accounting for disease-free time elapsed. PATIENTS AND METHODS: All patients from 12 academic institutions who underwent CRS ± HIPEC for PSM from 2000 to 2017 were retrospectively analyzed. OS and disease-free survival (DFS) rates were calculated using the Kaplan-Meier method while conditional overall (COS) and conditional disease-free survival (CDFS) rates were calculated at 1, 2, or 3 years from surgery for different tumor histologies. RESULTS: Overall, 1610 patients underwent CRS ± HIPEC. Among patients with benign appendiceal mucinous tumors (N = 460), 5-year OS and COS at 3 years were 92.1% and 96.3% (Δ4.2%), respectively. For patients with well-differentiated appendiceal cancers (N = 400), 5-year OS and COS at 3 years were 76.3% and 88.3% (Δ12.0%), respectively. For patients with high-grade appendiceal cancers (N = 258), 5-year OS and COS at 3 years were 43.8% and 75.4% (Δ31.6%), respectively. For patients with colorectal cancers (N = 362), 5-year OS and COS at 3 years were 31.8% and 67.3% (Δ35.5%), respectively. For patients with peritoneal mesothelioma (N = 130), 5-year OS and COS at 3 years were 67.6% and 89.7% (Δ22.1%), respectively. Similar trends were observed for DFS/CDFS. CONCLUSION: The conditional survival of patients undergoing CRS ± HIPEC for PSM is associated with tumor histology. COS and CDFS provide a more accurate, dynamic estimate of survival than OS and DFS, especially for patients with more aggressive histologies.

Do Lymph Node Metastases Matter in Appendiceal Cancer with Peritoneal Carcinomatosis? A US HIPEC Collaborative Study.

BACKGROUND: Whether formal regional lymph node (LN) evaluation is necessary for patients with appendiceal adenocarcinoma (AA) who have peritoneal metastases is unclear. The aim of this study was to evaluate the prognostic value of LN metastases on survival in patients treated with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS-HIPEC). METHODS: A retrospective analysis of the US HIPEC collaborative, a multi-institutional consortium comprising 12 high-volume centers, was performed to identify patients with AA who underwent CRS-HIPEC with adequate LN sampling (≥ 12 LNs). RESULTS: Two hundred-fifty patients with AA who underwent CRS-HIPEC were included. Outcomes were compared between LN - and LN + disease. Baseline patient characteristics between groups were similar, with most patients undergoing complete cytoreduction (0/1: 86.0% vs. 76.8%, p = 0.08), respectively. More adverse tumor factors were found in patients with LN + disease, including poor differentiation, signet ring cells, and lymphovascular invasion. Multivariate analysis of overall survival (OS) found LN + disease was independently associated with worse OS (HR: 2.82 95%CI: 1.25-6.34, p = 0.01), even after correction for receipt of systemic therapy. On Kaplan-Meier analysis, median OS was lower in patients with LN + disease (25.9 months vs. 91.4 months, p < 0.01). LN + disease remained associated with poor OS following propensity score matching (HR: 4.98 95%CI: 1.72-14.40, p < 0.01) and in patients with PCI ≥ 20 (HR: 3.68 95%CI: 1.54-8.80, p < 0.01). CONCLUSIONS: In this large multi-institutional study of patients with AA undergoing CRS-HIPEC, LN status remained associated with worse OS even in the setting of advanced peritoneal carcinomatosis. Formal LN evaluation should be performed for most patients with AA undergoing CRS-HIPEC.

Prognostic Significance of Preoperative Tumor Markers in Pseudomyxoma Peritonei from Low-Grade Appendiceal Mucinous Neoplasm: a Study from the US HIPEC Collaborative.

BACKGROUND: Tumor markers are commonly utilized in the diagnostic evaluation, treatment decision making, and surveillance of appendiceal tumors. In this study, we aimed to determine the prognostic significance of elevated preoperative tumor markers in patients with pseudomyxoma peritonei secondary to low-grade appendiceal mucinous neoplasm who underwent cytoreductive surgery and hyperthermic intraperitoneal chemotherapy. METHODS: Using a multi-institutional database, eligible patients with measured preoperative tumor markers [carcinoembryonic antigen (CEA), carbohydrate antigen 19-9 (CA 19-9), or cancer antigen 125 (CA-125)] were identified. Univariate and multivariate Cox-proportional hazards regression analysis assessed relationships between normal and elevated serum tumor markers with progression-free and overall survival in the context of multiple clinicopathologic variables. RESULTS: zTwo hundred and sixty-four patients met criteria. CEA was the most commonly measured tumor marker (97%). Patients who had any elevated tumor marker had a higher peritoneal carcinomatosis index (PCI) as compared to those with normal range markers. Elevated CEA and CA 19-9 levels were individually associated with longer inpatient length of stay, requirement for intraoperative transfusion, and incomplete cytoreduction. Utilization of neoadjuvant chemotherapy, increased PCI score, elevated CA 19-9 (p = 0.007), and CA-125 levels (p = 0.01) were predictive of decreased progression-free survival on univariate analysis. However, in a multivariate model, only elevated PCI was a statistically significant predictor of progression-free survival. CONCLUSION: Elevated preoperative tumor markers indicate a higher burden of disease but are not independently associated with survival in this retrospective multi-institutional cohort. Further prospective studies are needed to clarify the utility of these markers in this patient population.

The Utility of Preoperative Tumor Markers in Peritoneal Carcinomatosis from Primary Appendiceal Adenocarcinoma: an Analysis from the US HIPEC Collaborative.

BACKGROUND: Prognostication based on preoperative clinical factors is lacking in patients undergoing cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS/HIPEC). This study aims to determine the value of preoperative tumor markers as predictors of progression-free survival (PFS) and overall survival (OS) for patients with peritoneal carcinomatosis from a primary mucinous adenocarcinoma of the appendix (MACA). METHODS: We queried the United States HIPEC Collaborative, a database of patients with peritoneal carcinomatosis treated with CRS/HIPEC at twelve institutions between 2000 and 2017, identifying 409 patients with MACA. Multivariate analysis was used to identify independent predictors of disease progression. Subgroup analysis was conducted to evaluate the impact of tumor grade on the predictive value of tumor markers. RESULTS: CA19-9 [HR 2.44, CI 1.2-3.4] emerged as an independent predictor of PFS while CEA [HR 4.98, CI 1.06-23.46] was independently predictive of OS (p <0.01). Tumor differentiation was the most potent predictor of both PFS (poorly differentiated vs well, [HR 4.5 CI 2.01-9.94]) and OS ([poorly differentiated vs well-differentiated: [HR 13.5, CI 3.16-57.78]), p <0.05. Among patients with combined CA19-9 elevation and poorly differentiated histology, 86% recurred within a year of CRS/HIPEC (p < 0.01). Similarly, the coexistence of CEA elevation and unfavorable histology led to the lowest survival rate at two years [36%, p < 0.01]. CA-125 was not predictive of PFS or OS. CONCLUSION: Elevated preoperative CA19-9 portends worse PFS, while elevated CEA predicts worse OS after CRS/HIPEC in patients with MACA. This study provides additional evidence that CA19-9 and CEA levels should be collected during standard preoperative bloodwork, while CA-125 can likely be omitted. Tumor differentiation, when added to preoperative tumor marker levels, provides powerful prognostic information. Prospective studies are required to confirm this association.

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.

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.

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.

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.

Trends in the indications for and short-term outcomes of cytoreductive surgery with hyperthermic intraperitoneal chemotherapy.

BACKGROUND: Cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) is an increasingly utilized strategy for patients with peritoneal surface malignancies (PSM). METHODS: The US HIPEC Collaborative was retrospectively reviewed to compare the indications and perioperative outcomes of patients who underwent CRS ±â€¯HIPEC between 2000 and 2012 (P1) versus 2013-2017 (P2). RESULTS: Among 2,364 patients, 39% were from P1 and 61% from P2. The most common primary site was appendiceal (64%) while the median PCI was 13 and most patients had CCR 0 (60%) or 1 (25%). Over time, median estimated blood loss, need for transfusion, and length of hospital stay decreased. While the incidence of any (55% vs. 57%; p = 0.426) and Clavien III/IV complications did not change over time, there was a decrease in 90-day mortality (5% vs. 3%; p = 0.045). CONCLUSION: CRS-HIPEC is increasingly performed for PSM at high-volume centers. Despite improvements in some perioperative outcomes and a reduction in postoperative mortality, morbidity rates remain high.

Lung Surveillance Strategy for High-Grade Soft Tissue Sarcomas: Chest X-Ray or CT Scan?

BACKGROUND: Given the propensity for lung metastases, National Comprehensive Cancer Network guidelines recommend lung surveillance with either chest x-ray (CXR) or CT in high-grade soft tissue sarcoma. Considering survival, diagnostic sensitivity, and cost, the optimal modality is unknown. METHODS: The US Sarcoma Collaborative database (2000 to 2016) was reviewed for patients who underwent resection of a primary high-grade soft tissue sarcoma. Primary end point was overall survival (OS). Cost analysis was performed. RESULTS: Among 909 patients, 83% had truncal/extremity and 17% had retroperitoneal tumors. Recurrence occurred in 48%, of which 54% were lung metastases. Lung surveillance was performed with CT in 80% and CXR in 20%. Both groups were clinically similar, although CT patients had more retroperitoneal tumors and recurrences. Regardless of modality, 85% to 90% of lung metastases were detected within the first 2 years with a similar re-intervention rate. When considering age, tumor size, location, margin status, and receipt of radiation, lung metastasis was independently associated with worse OS (hazard ratio 4.26; p < 0.01) and imaging modality was not (hazard ratio 1.01; p = 0.97). Chest x-ray patients did not have an inferior 5-year OS rate compared with CT (71% vs 60%; p < 0.01). When analyzing patients in whom no lung metastases were detected, both cohorts had a similar 5-year OS rate (73% vs 74%; p = 0.42), suggesting CXR was not missing clinically relevant lung nodules. When adhering to a guideline-specified protocol for 2018 projected 4,406 cases, surveillance with CXR for 5 years results in savings of $5 million to $8 million/year to the US healthcare system. CONCLUSIONS: In this large multicenter study, lung surveillance with CXR did not result in worse overall survival compared with CT. With considerable savings, a CXR-based protocol can optimize resource use for lung surveillance in high-grade soft tissue sarcoma; prospective trials are needed.

Post-hepatectomy hyperbilirubinemia: The point of no return.

BACKGROUND: Post-hepatectomy hyperbilirubinemia is associated with liver insufficiency and failure. The highest survivable peak total bilirubin (ptbili) is not defined. This study aimed to identify the postop ptbili beyond which survival is improbable or impossible. METHODS: An institutional database of major hepatectomies (≥3 segments, no biliary resections), 2000-2012 was reviewed. Data were analyzed to find ptbili in the first 45 postop days. Factors associated with 90-day mortality (90 DM) and those predictive of ptbili were determined. RESULTS: 603 pts were analyzed with 90DM of 4.5%. 90 DM for a ptbili ≥ 18 (n = 15) was 86.6%, but only 2.5% for a ptbili < 18. All 6 pts with a ptbili ≥ 30 died. On multivariate analysis, postop ptbili ≥ 18 (HR34.95, CI 3.8-324; p = 0.002) and cirrhosis (HR6.4, CI 1.2-33.2; p = 0.027) were associated with 90DM. Factors associated with a ptbili ≥ 18 were age >65 (HR14.24, CI 2.9-70.5; p = 0.001), preop chemotherapy (HR4.77, CI 1.3-18.2; p = 0.02) and postop FFP (HR12.5, CI 2.6-56.2; p = 0.001). CONCLUSION: Postop ptbili ≥ 18 after major hepatectomy has an 86.6% risk of 90DM; there are no survivors for tbili ≥ 30. These values may guide postop counseling for prognosis. Future studies may evaluate tbili ≥ 18 as an indication for hepatic replacement therapy.

A Phase 1 Study of Stereotactic Body Radiation Therapy Dose Escalation for Borderline Resectable Pancreatic Cancer After Modified FOLFIRINOX (NCT01446458).

PURPOSE: A challenge in borderline resectable pancreatic cancer (BRPC) management is the high rate of positive posterior margins (PM). Stereotactic body radiation therapy (SBRT) allows for higher radiation delivery dose with conformity. This study evaluated the maximal tolerated dose with a dose escalation plan level up to 45 Gy using SBRT in BRPC. METHODS AND MATERIALS: A single-institution, 3 + 3 phase 1 clinical trial design was used to evaluate 4 dose levels of SBRT delivered in 3 fractions to the planning target volume (PTV) with a simultaneous in-field boost (SIB) to the PM. Dose level (DL) 1 was 30 Gy to the PTV, and for dose levels 2 through 4 (DL2-DL4) the dose was 36 Gy. The SIB dose to the PM was 6, 6, 7.5, and 9 Gy for DL-1, DL-2, DL-3, and DL-4, respectively. All patients received 4 treatments of modified FOLFIRINOX (fluorouracil, leucovorin, irinotecan, oxaliplatin) before SBRT. RESULTS: Thirteen patients with a median age of 64 years were enrolled. The median follow-up time was 18 months. The locations of the cancer were head (n=12) and uncinate/neck (n=1). One patient did not undergo SBRT. There were no grade 3 or 4 toxicities. Five patients did not undergo resection because of disease progression (1 local, 4 distant); 8 had R0 resection in the PM, and 5 of 8 had vessel reconstruction. Two patients had disease downstaged to T1 and T2 from T3 disease. Four patients are still alive, and 3 are disease free. The median overall survival for resected patients was not reached (9.3: not reached). CONCLUSION: The SBRT dose of 36 Gy with a 9-Gy SIB to the PM (total 45 Gy) delivered in 3 fractions is safe and well tolerated. The dose-limiting toxicity for a 45-Gy dose was not reached, and further dose escalations are needed in future trials.

Adherence to Guidelines for Adjuvant Imatinib Therapy for GIST: A Multi-institutional Analysis.

BACKGROUND: Gastrointestinal stromal tumors (GIST) are the most common mesenchymal tumors of the gastrointestinal tract. Adjuvant imatinib therapy improves recurrence-free and overall survival following surgery for patients with high-risk GIST; however, the factors associated with use of adjuvant imatinib therapy are unclear, and adherence to adjuvant imatinib has not been investigated. We sought to determine the clinicopathologic predictors of therapy with adjuvant imatinib following surgical resection for GIST and to determine the utilization of adjuvant imatinib in patients who underwent surgical resection of primary GIST in 2009 or later as recommended by National Comprehensive Cancer network (NCCN) guidelines. METHODS: A multi-institutional cohort including 171 patients who underwent surgery for primary GIST at seven high-volume cancer centers in the USA and Canada between January 2009-December 2012 was used in this study. Receipt of adjuvant imatinib therapy was ascertained, and factors associated with imatinib therapy were analyzed. RESULTS: Following surgery for primary GIST, tumor size (<5.0 cm: ref; 5.0-9.9 cm: odds ratio (OR) 2.36, 95 % confidence interval (CI) 0.74-7.55; >10.0 cm: OR 9.15, 95 % CI 2.28-36.75; p = 0.007), mitotic rate (≤5/50 mitoses per 50 high powered field [HPF]: ref; 6-10/50 HPF: OR 24.91, 95 % CI 3.64-170.35; >10/50 HPF: OR 5.80, 95 % CI 3.64-170.35; p < 0.001), and neoadjuvant therapy (OR 9.52; 95 % CI 2.51-36.14; p = 0.001) were associated with receipt of adjuvant imatinib therapy. Overall, 75 % of patients received appropriate treatment, 23 % of patients were undertreated, and 2 % of patients were overtreated as compared to NCCN guidelines. Adjuvant imatinib therapy was administered in only 53 % of patients for which the NCCN guidelines recommended adjuvant therapy. CONCLUSION: The clinicopathologic factors associated with use of adjuvant imatinib therapy in patients following resection of primary GIST are consistent with established risk factors for recurrence. Adjuvant imatinib therapy remains underutilized in patients with intermediate and high-risk GIST and in patients who receive neoadjuvant therapy. Barriers to adjuvant imatinib therapy in this group of patients needs to be further explored.

Association between hospital finances, payer mix, and complications after hyperthermic intraperitoneal chemotherapy: deficiencies in the current healthcare reimbursement system and future implications.

BACKGROUND: Despite increasing implementation of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC), there are little data on its financial implications. We analyzed hospital cost and reimbursement data within the context of insurance provider type and postoperative complications. METHODS: Clinicopathologic variables, hospital costs, and reimbursement for all patients undergoing CRS/HIPEC at a single institution from 2009 to 2013 were analyzed. RESULTS: A total of 64 patients underwent CRS/HIPEC. Median PCI score was 19, and average operative time was 550 min. Tumor histology included appendiceal (n = 40; 62 %), colorectal (n = 16; 25 %), goblet cell (n = 5; 8 %), and mesothelioma (n = 3; 5 %). Median length-of-stay was 13 days. Complications occurred in 42 patients (66 %), including 13 (20 %) with major (Clavien grade III-IV) complications. Payer mix included 42 private insurance and 22 Medicare/Medicaid. Financial data was available for 56 patients: average total hospital cost was $49,248 and reimbursement was $63,771, for a hospital profit of $14,523/patient. Despite similar costs between Medicare/Medicaid and private-insurance patients, Medicare/Medicaid reimbursed much less ($30,713 vs $80,747; p < 0.001), resulting in a net loss of $17,342 per patient. For private-insured patients, major complications were associated with increased cost and increased reimbursement, resulting in a net profit of $36,285, compared with a net loss of $54,274 in Medicare/Medicaid patients. CONCLUSIONS: CRS/HIPEC is profitable in privately insured patients, even for those with major complications, but loses money in patients with Medicare/Medicaid. Under a future bundled-reimbursement system, complications will be negatively associated with profit. With these impending changes, hospitals must place emphasis on value, recalculate the reimbursement necessary for financial viability, and focus on decreasing costs and minimizing complications.

Hypophosphataemia after major hepatectomy and the risk of post-operative hepatic insufficiency and mortality: an analysis of 719 patients.

BACKGROUND: Hypophosphataemia after a hepatectomy suggests hepatic regeneration. It was hypothesized that the absence of hypophosphataemia is associated with post-operative hepatic insufficiency (PHI) and complications. METHODS: Patients who underwent a major hepatectomy from 2000-2012 at a single institution were identified. Post-operative serum phosphorus levels were assessed. Primary outcomes were PHI (peak bilirubin >7 mg/dl), major complications, and 30- and 90-day mortality. RESULTS: Seven hundred and nineteen out of 749 patients had post-operative phosphorus levels available. PHI and major complications occurred in 63 (8.8%) and 169 (23.5%) patients, respectively. Thirty- and 90-day mortality were 4.0% and 5.4%, respectively. The median phosphorus level on post-operative-day (POD) 2 was 2.2 mg/dl; 231 patients (32.1%) had phosphorus >2.4 on POD2. Patients with POD2 phosphorus >2.4 had a significantly higher incidence of PHI, major complications and mortality. On multivariate analysis, POD2 phosphorus >2.4 remained a significant risk factor for PHI [(hazard ratio HR):1.78; 95% confidence interval (CI):1.02-3.17; P = 0.048], major complications (HR:1.57; 95%CI:1.02-2.47; P = 0.049), 30-day mortality (HR:2.70; 95%CI:1.08-6.76; P = 0.034) and 90-day mortality (HR:2.51; 95%CI:1.03-6.15; P = 0.044). Similarly, patients whose phosphorus level reached nadir after POD3 had higher PHI, major complications and mortality. CONCLUSION: Elevated POD2 phosphorus levels >2.4 mg/dl and a delayed nadir in phosphorus beyond POD3 are associated with increased post-operative hepatic insufficiency, major complications and early mortality. Failure to develop hypophosphataemia within 72 h after a major hepatectomy may reflect insufficient liver remnant regeneration.

Vein involvement during pancreaticoduodenectomy: is there a need for redefinition of "borderline resectable disease"?

INTRODUCTION: Current National Comprehensive Cancer Network guidelines recommend neoadjuvant therapy for borderline resectable pancreatic adenocarcinoma to increase the likelihood of achieving R0 resection. A consensus has not been reached on the degree of venous involvement that constitutes borderline resectability. This study compares the outcome of patients who underwent pancreaticoduodenectomy with or without vein resection without neoadjuvant therapy. METHODS: A multi-institutional database of patients who underwent pancreaticoduodenectomy was reviewed. Patients who required vein resection due to gross vein involvement by tumor were compared to those without evidence of vein involvement. RESULTS: Of 492 patients undergoing pancreaticoduodenectomy, 70 (14 %) had vein resection and 422 (86 %) did not. There was no difference in R0 resection (66 vs. 75 %, p = NS). On multivariate analysis, vein involvement was not predictive of disease-free or overall survival. CONCLUSION: This is the largest modern series examining patients with or without isolated vein involvement by pancreas cancer, none of whom received neoadjuvant therapy. Oncological outcome was not different between the two groups. These data suggest that up-front surgical resection is an appropriate option and call into question the inclusion of isolated vein involvement in the definition of "borderline resectable disease."

Safety and efficacy of doxorubicin drug-eluting bead transarterial chemoembolization in patients with advanced hepatocellular carcinoma.

PURPOSE: To investigate the safety and efficacy of transarterial chemoembolization using doxorubicin drug-eluting beads (DEBs) in patients with Barcelona Clinic Liver Cancer (BCLC) C stage hepatocellular carcinoma (HCC). METHODS: Consecutive patients with initial staging of BCLC C HCC who received DEB transarterial chemoembolization over the last 5 years were studied. The study included 121 patients (mean age, 61.2 years old). Adverse events (AEs) after DEB transarterial chemoembolization were studied in detail and were recorded as per the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03 criteria. Survivals were analyzed according to parameters from the time of first DEB transarterial chemoembolization. Kaplan-Meier method by log-rank test and Cox proportional hazard model were used for survival analysis. RESULTS: AEs occurred in 30.2% of patients. No AEs were greater than Common Terminology Criteria for Adverse Events grade III. Grade I and II AEs included nausea and vomiting in 7.8% of patients and abdominal pain in 23.8% of patients. Grade III AEs were noted in 1.06% of patients. There were no gastrointestinal or hepatic complications. There were no deaths within 30 days after DEB transarterial chemoembolization. The overall median survival was 13.5 months. Among the Child-Pugh class A patients, those without PVT and metastasis (28.9%) had better survival when treated with DEB transarterial chemoembolization than those with PVT and metastases (9.9%) (18.8 mo versus 4.4 mo, P = .001). Ascites, performance status, Okuda stage HCC, serum alpha fetoprotein levels, and etiologic factor for chronic liver disease predicted survival. CONCLUSIONS: DEB transarterial chemoembolization appears to be a safe and effective treatment option for patients with BCLC C HCC. Patients with Child-Pugh class A without PVT and metastasis benefited most from DEB transarterial chemoembolization.