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.

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.

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.

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.

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.

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.

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.