Development of a predictive model for risk stratification of acute kidney injury in patients undergoing cytoreductive surgery with hyperthermic intraperitoneal chemotherapy.

Acute kidney injury (AKI) following hyperthermic intraperitoneal chemotherapy (HIPEC) is common. Identifying patients at risk could have implications for surgical and anesthetic management. We aimed to develop a predictive model that could predict AKI based on patients' preoperative characteristics and intraperitoneal chemotherapy regimen. We retrospectively gathered data of adult patients undergoing HIPEC at our health system between November 2013 and April 2022. Next, we developed a model predicting postoperative AKI using multivariable logistic regression and calculated the performance of the model (area under the receiver operating characteristics curve [AUC]) via tenfold cross-validation. A total of 412 patients were included, of which 36 (8.7%) developed postoperative AKI. Based on our multivariable logistic regression model, multiple preoperative and intraoperative characteristics were associated with AKI. We included the total intraoperative cisplatin dose, body mass index, male sex, and preoperative hemoglobin level in the final model. The mean area under the receiver operating characteristics curve value was 0.82 (95% confidence interval 0.71-0.93). Our risk model predicted AKI with high accuracy in patients undergoing HIPEC in our institution. The external validity of our model should now be tested in independent and prospective patient cohorts.

Laparoscopic cytoreductive surgery and hyperthermic intraperitoneal chemotherapy: a prospective clinical trial and comparative analysis.

BACKGROUND: Open cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) is associated with high morbidity, which limits the degree to which patients may benefit from this therapy. This study aimed to determine the feasibility of laparoscopic CRS/HIPEC. METHODS: This was a single institution prospective clinical trial and comparative study using historical controls. Patients with histologically confirmed peritoneal surface malignancy (PSM) of appendiceal, colorectal, ovarian, or primary peritoneal origin, peritoneal carcinomatosis index (PCI) [Formula: see text] 10 were eligible. RESULTS: Clinical trial: 18 patients (median age 57 years, 39% female) with appendiceal (15) or colorectal (3) primary PSM underwent laparoscopic CRS/HIPEC. Median and range outcomes were: operative time 219 min (134-378), EBL 10 mL (0-100), time to return to bowel function 3 days (1-7), duration IV narcotic use 3 days (1-8), length of stay 6 days (3-11). All patients had a complete cytoreduction (CC-score 0). Three (17%) experienced minor morbidity, with no major morbidity or mortality. Median DFS and OS were not reached with median follow-up of 48 months. Comparative analysis: Laparoscopic approach associated with reduced time to return of bowel function (3 versus 4 days, p = 0.001), length of stay (8 versus 5 days, p < 0.001), and morbidity (16% versus 42%, p = 0.008). Independent predictors of DFS included prior chemotherapy (HR 5.07, 95% CI 1.85, 13.89; p = 0.002), and CC-score > 0 (HR 3.31, 95% CI 1.19, 9.41; p = 0.025), but not surgical approach. CC-score > 0 was the only independent predictor of OS (HR 10.12, 95% CI 2.16, 47.30, p = 0.003). CONCLUSIONS AND RELEVANCE: Laparoscopic CRS/HIPEC should be considered for patients with PSM with low-volume disease, including those with adenocarcinoma histology. TRIAL REGISTRATION: Clinicaltrials.gov; NCT02463877.

Is Routine Omentectomy a Necessary Component of Cytoreductive Surgery and HIPEC?

BACKGROUND: Cytoreductive surgery (CRS) with or without hyperthermic intraperitoneal chemotherapy (HIPEC) for peritoneal metastases traditionally includes omentectomy, even in the absence of visible omental metastases. We sought to determine the rate of occult histologic omental metastasis (OHOM), evaluate morbidity with omentectomy, and examine the rate of omental recurrence among patients undergoing CRS-HIPEC. METHODS: All CRS-HIPEC procedures from August 2007 to August 2020 were included in this single-center, retrospective, cohort study. Procedures were divided into those that included greater omentectomy (OM) and those that did not (NOM). The incidence of OHOM was evaluated specifically among the OM group with a grossly normal omentum. Multivariate regression analyses were performed to evaluate return of bowel function, ileus, and morbidity in the OM and NOM groups. RESULTS: Among 683 CRS-HIPEC procedures, 578 (84.6%) included omentectomy and 105 (15.4%) did not. The OM group had higher operative time, blood loss, peritoneal cancer index, number of visceral resections, and length of stay. In the OM group, 72 (12.5%) patients had a grossly normal omentum, and 23 (31.9%) of these had OHOM. Risk-adjusted return of bowel function, ileus, and 60-day complications were no different in the OM and NOM groups. Among 43 patients with residual omentum, 24 (55.8%) recurred, including 9 (20.9%) with omental recurrence. CONCLUSIONS: Histologically occult metastasis was present in one-third of patients undergoing omentectomy during CRS-HIPEC. Omentectomy did not increase the rate of overall morbidity, and one-fifth of patients with residual omentum later developed omental recurrence. Thus, omentectomy is warranted in the absence of gross metastases during CRS-HIPEC.

Efficacy of Perioperative Chemotherapy for Resectable Pancreatic Adenocarcinoma: A Phase 2 Randomized Clinical Trial.

Importance: Clinical outcomes after curative treatment of resectable pancreatic ductal adenocarcinoma (PDA) remain suboptimal. To assess the potential of early control of systemic disease with multiagent perioperative chemotherapy, we conducted a prospective trial. Objective: To determine 2-year overall survival (OS) using perioperative chemotherapy for resectable PDA. Design, Setting, and Participants: This was a randomized phase 2 trial of perioperative chemotherapy with a pick-the-winner design. It was conducted across the National Clinical Trials Network, including academic and community centers all across the US. Eligibility required patients with Zubrod Performance Score of 0 or 1, confirmed tissue diagnosis of PDA, and resectable disease per Intergroup criteria. Interventions: Perioperative (12 weeks preoperative, 12 weeks postoperative) chemotherapy with either fluorouracil, irinotecan, and oxaliplatin (mFOLFIRINOX, arm 1) or gemcitabine/nab-paclitaxel (arm 2). Main Outcomes and Measures: The primary outcome was 2-year overall survival (OS), using a pick-the-winner design; for 100 eligible patients, accrual up to 150 patients was planned to account for cases deemed ineligible at central radiology review. Results: From 2015 to 2018, 147 patients were enrolled; 43 patients (29%) had ineligible disease, beyond resectability criteria, at central radiology review. There were 102 eligible and evaluable patients, 55 in arm 1 and 47 in arm 2, of whom the median (range) age was 66 (44-76) and 64 (46-76) years, respectively; 36 patients (65%) in arm 1 and 24 (51%) in arm 2 were men. In arm 1, 34 (62%) had Zubrod Performance Score of 0, while in arm 2, 31 (66%) did; and 44 (80%) in arm 1 and 39 (83%) in arm 2 had head tumors. Of 102 patients, 84% and 85% completed preoperative chemotherapy, 73% and 70% underwent resection, and 49% and 40% completed all treatment. Adverse events were expected hematologic toxic effects, fatigue, and gastrointestinal toxicities. Two-year OS was 47% (95% CI, 31%-61%) for arm 1 and 48% (95% CI, 31%-63%) for arm 2; median OS was 23.2 months (95% CI, 17.6-45.9 months) and 23.6 months (95% CI, 17.8-31.7 months). Neither arm's 2-year OS estimate was significantly higher than the a priori threshold of 40%. Median disease-free survival after resection was 10.9 months in arm 1 and 14.2 months in arm 2. Conclusions and Relevance: This phase 2 randomized clinical trial did not demonstrate an improved OS with perioperative chemotherapy, compared with historical data from adjuvant trials in resectable pancreatic cancer. Two-year OS was 47% with mFOLFIRINOX and 48% with gemcitabine/nab-paclitaxel for all eligible patients starting treatment for resectable PDA. The trial also demonstrated adequate safety and high resectability rates with perioperative chemotherapy, and challenges in quality control for resectability criteria. Trial Registration: ClinicalTrials.gov Identifier: NCT02562716.

Preoperative bevacizumab does not increase complications following cytoreductive surgery and hyperthermic intraperitoneal chemotherapy.

BACKGROUND: Preoperative bevacizumab has been reported to increase postoperative complication risk following cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS/HIPEC). We sought to review our experience with preoperative bevacizumab in patients undergoing CRS/HIPEC for peritoneal surface malignancy. METHODS: This is a retrospective review of patients who received neoadjuvant systemic therapy with or without bevacizumab prior to CRS/HIPEC at a high-volume academic center from 2007-2018. RESULTS: Of 499 patients, a total of 88 patients received neoadjuvant chemotherapy alone (n = 34) or in combination with bevacizumab (n = 54) within 3 months prior to CRS/HIPEC. No differences existed in 60-day major morbidity (17.6 vs. 16.7%, p = 0.81) or 60-day mortality (0 vs. 0%) between the two cohorts, and neoadjuvant bevacizumab was not associated with increased odds of overall complications (OR 0.86, 95% CI 0.35-2.09, p = 0.73) or major morbidity (OR 0.86, 95% CI 0.24-3.00, p = 0.81). Stratifying patients by primary tumor origin and post-operative complications did not reveal any significant differences between the two treatment groups. In addition, progression-free survival (PFS) and overall survival (OS) were similar in both cohorts. CONCLUSIONS: Preoperative bevacizumab is not associated with increased morbidity or mortality following CRS/HIPEC. Neoadjuvant therapy employing this biologic agent is safe and should not be a deterrent for aggressive cytoreduction with curative intent.

Surgical Outcome Results From SWOG S1505: A Randomized Clinical Trial of mFOLFIRINOX Versus Gemcitabine/Nab-paclitaxel for Perioperative Treatment of Resectable Pancreatic Ductal Adenocarcinoma.

OBJECTIVE: The optimal neoadjuvant therapy for resectable pancreatic ductal adenocarcinoma (PDA) and the impact on surgical outcomes remains unclear. METHODS: S1505 (NCT02562716) was a randomized phase II study of perioperative chemotherapy with mFOLFIRINOX (Arm 1) or gemcitabine/nab-paclitaxel (Arm 2). Measured parameters included resection rate, margin positivity, pathologic response, and toxicity. RESULTS: Between 2015 and 2018, 147 patients were randomized. Of these, 44 (30%) were deemed ineligible (43 by central review). Of the 103 eligible patients, 77 (76%) completed preoperative therapy and underwent surgery; reasons patients did not undergo surgery included toxicity related to preoperative therapy (n = 9), progression (n = 9), or other (n = 7). Of the 77, 73 (95%) underwent successful resection; 21 (29%) required vascular reconstruction, 62 (85%) had negative (R0) margins, and 24 (33%) had a complete or major pathologic response to therapy. The grade 3-5 postoperative complication rate was 16%. Of the 73 patients completing surgery, 57 (78%) started and 46 (63%) completed postoperative therapy. This study represents the first prospective trial evaluating modern systemic therapy delivered in a neoadjuvant/perioperative format for resectable PDA. CONCLUSIONS: We have demonstrated: (1) Based on the high percentage of enrolled, but ineligible patients, it is clear that adherence to strict definitions of resectable PDA is challenging; (2) Patients can tolerate modern systemic therapy and undergo successful surgical resection without prohibitive perioperative complications; (3) Completion of adjuvant therapy in the perioperative format is difficult; (4) Major pathologic response rate of 33% is encouraging.

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.

Detection and Quantification of GPCR mRNA: An Assessment and Implications of Data from High-Content Methods.

G protein-coupled receptors (GPCRs) are the largest family of membrane receptors and targets for approved drugs. The analysis of GPCR expression is, thus, important for drug discovery and typically involves messenger RNA (mRNA)-based methods. We compared transcriptomic complementary DNA (cDNA) (Affymetrix) microarrays, RNA sequencing (RNA-seq), and quantitative polymerase chain reaction (qPCR)-based TaqMan arrays for their ability to detect and quantify expression of endoGPCRs (nonchemosensory GPCRs with endogenous agonists). In human pancreatic cancer-associated fibroblasts, RNA-seq and TaqMan arrays yielded closely correlated values for GPCR number (∼100) and expression levels, as validated by independent qPCR. By contrast, the microarrays failed to identify ∼30 such GPCRs and generated data poorly correlated with results from those methods. RNA-seq and TaqMan arrays also yielded comparable results for GPCRs in human cardiac fibroblasts, pancreatic stellate cells, cancer cell lines, and pulmonary arterial smooth muscle cells. The magnitude of mRNA expression for several Gq/11-coupled GPCRs predicted cytosolic calcium increase and cell migration by cognate agonists. RNA-seq also revealed splice variants for endoGPCRs. Thus, RNA-seq and qPCR-based arrays are much better suited than transcriptomic cDNA microarrays for assessing GPCR expression and can yield results predictive of functional responses, findings that have implications for GPCR biology and drug discovery.

Incidence, Risk Factors, and Prevention Strategies for Venous Thromboembolism after Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy.

BACKGROUND: The risk factors and incidence of venous thromboembolism (VTE) are not well defined in patients undergoing cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS/HIPEC). We sought to characterize the incidence, risk factors, and pharmacothromboprophylaxis strategies for VTE after CRS/HIPEC. PATIENTS AND METHODS: We performed a retrospective study of CRS/HIPEC procedures at our institution from 8/2007 to 11/2017, examining the 60-day VTE incidence. Baseline, potential risk factor, and prevention strategy data were collected. Univariate and multivariate regression analysis was used to determine risk factors associated with 60-day VTEs. RESULTS: We identified 25 60-day VTEs among 447 CRS/HIPEC procedures (5.6%). VTEs were discovered on median postoperative day 20 (range 2-59); pulmonary emboli (68%) were the most common type of VTE. The 60-day VTE rate was 10.2% before versus 4.9% after initiation of a policy to discharge patients on pharmacothromboprophylaxis (p = 0.10). Patients with 60-day VTEs had longer average length of stay (14 vs. 11 days, p = 0.01) and higher 60-day mortality rate (4% vs. 0.2%, p = 0.02) than those without VTEs. Caprini score (odds ratio [OR] 1.53, 95% confidence interval [CI] 1.10-2.15, p = 0.01), preoperative serum albumin level (OR 0.40, 95% CI 0.16-1.00, p = 0.05), and 60-day non-VTE serious morbidity (OR 3.45, 95% CI 1.25-9.51, p = 0.02) were risk factors associated with 60-day VTEs on multivariate analysis. CONCLUSIONS: VTEs are relatively common after CRS/HIPEC and are associated with high Caprini scores, low serum albumin levels, and additional inpatient comorbidities. They result in longer length of stay and higher mortality rate. Compliance with current guidelines for extended postoperative thromboprophylaxis was likely associated with reduced VTE rate.

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.

Does Primary Tumor Side Matter in Patients with Metastatic Colon Cancer Treated with Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy?

BACKGROUND: Primary tumor location has been shown to be prognostic of overall survival (OS) in patients with both locally advanced and metastatic colorectal cancer. The impact of sidedness on prognosis has not been evaluated in the setting of peritoneal-only metastases treated with cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). METHODS: A retrospective review of prospectively maintained databases of patients with peritoneal surface malignancy undergoing CRS/HIPEC from three high-volume centers was performed. RESULTS: A total of 115 patients with metastatic colon cancer to the peritoneum who underwent CRS/HIPEC with mitomycin C were identified. Fifty-one patients (45%) had left-sided primary tumors, and 64 (55%) had right-sided primary tumors. Patients with right-sided tumors were more likely to be older (median age 56 vs. 49 years, p = 0.007) and to have signet ring cell histology (17% vs. 4%, p = 0.026). Patients with right-sided tumors had median disease-free survival (DFS) and OS of 14 months (95% confidence interval [CI] 10.5-17.5) and 36 months (95% CI 27.4-44.6), respectively, versus 16 months (95% CI 11.0-21.0) and 69 months (95% CI 24.3-113.7) for those patients with left-sided tumors. On multivariate analysis, primary tumor side was an independent predictor of both DFS and OS. CONCLUSIONS: In this study, there was a dramatic, clinically significant difference in OS between patients with right- and left-sided tumors, and primary tumor side was an independent predictor of DFS and OS. Primary tumor side should be considered in patient selection for CRS with or without HIPEC.

Cirrhosis is not a contraindication to cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in highly selected patients.

BACKGROUND: Patient selection for cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) is critically important to optimizing outcomes. There is currently no literature regarding the safety of CRS/HIPEC in patients with cirrhosis. The aim of this case series is to report the outcomes of three patients with well-compensated cirrhosis who underwent CRS/HIPEC. METHODS: Patients were identified from a prospectively maintained peritoneal surface malignancy database. Patient, tumor, and operative-related details were recorded as short-term postoperative outcomes. Results were analyzed using descriptive statistics. RESULTS: All patients had well-compensated (Child-Pugh Class A) cirrhosis and Eastern Cooperative Oncology Group (ECOG) performance status of 0. One patient had preoperative evidence of portal hypertension. All safely underwent CRS/HIPEC with completeness of cytoreduction (CC) scores of 0. The postoperative morbidity profile was unique, but all complications were manageable and resulted in full recovery to preoperative baseline status. CONCLUSIONS: Patient selection for CRS/HIPEC is critical for optimization of short- and long-term outcomes. This small series suggests that well-compensated cirrhosis should not be an absolute contraindication to CRS/HIPEC.

Factors Associated with 60-Day Readmission Following Cytoreduction and Hyperthermic Intraperitoneal Chemotherapy.

INTRODUCTION: Readmission rates following surgery are subject to scrutiny in efforts to control health care costs. This study was designed to define the 60-day readmission rate following cytoreduction and HIPEC at a high-volume center and to identify factors associated with readmission. METHODS: Patients who underwent complete cytoreduction and HIPEC at a single institution from August 2007 through June 2014 were identified from a prospectively maintained database. Multiple preoperative and operative factors were analyzed for their ability to predict 60-day readmission following surgery. RESULTS: A total of 250 patients were identified. Forty patients (17%) experienced readmission within 60 days of surgery. The most common reasons for readmission were ileus/dehydration (12, 31%), deep space infection (8, 21%), and DVT/PE (6, 15%). Initial postoperative length of stay was longer for patients readmitted within 60 days (median 12 vs. 9 days, p = 0.013). Of categorical variables analyzed, including gender, histology, HIPEC agent, intraoperative transfusion, and individual procedures performed during cytoreduction, adjuvant systemic therapy, and postoperative morbidity, only Charlson comorbidity index CCI (odds ratio (OR) = 3.80 [1.68-8.60]) and stoma creation (OR = 6.04 [1.56-12.14]) were associated with 60-day readmission. CONCLUSIONS: Few measurable variables are associated with readmission following cytoreduction and HIPEC. Patients with high CCI and those with stomas created at the time of CRS/HIPEC may be at increased risk of readmission within 60 days. Earlier or more frequent follow-up for high-risk patients should be considered as a strategy to reduce readmissions.

Histologic Predictors of Recurrence in Mucinous Appendiceal Tumors with Peritoneal Dissemination after HIPEC.

BACKGROUND: Mucinous appendiceal tumors (MAT) are rare neoplasms that can metastasize to the peritoneum and often are treated with cytoreductive surgery (CRS) and HIPEC. Pathologic classification and outcomes vary, but standardized histologic definitions are emerging. We sought to evaluate outcomes in this disease after CRS/HIPEC using standardized pathologic criteria. METHOD: Outcomes of MAT with peritoneal metastases (PM) after CRS/HIPEC from 2007 to 2015 were reviewed at our institution. Standardized histologic categories per WHO and consensus definitions were used: low-grade appendiceal mucinous neoplasm (LAMN), low-grade adenocarcinoma (LGAC), or high-grade adenocarcinoma (HGAC) primary tumors; and acellular mucin (AM), low-grade mucinous carcinoma peritonei (LGMCP), or high-grade mucinous carcinoma peritonei (HGMCP) peritoneal metastases. Cox proportional hazards model was used identify predictors of progression-free survival (PFS) by univariate and multivariate analyses. RESULTS: A total of 183 patients undergoing 197 CRS/HIPECs were included. Among 75 patients with primary histology review, there were 33 (44.0%) LAMNs, 28 (37.3%) LGACs, and 14 (18.7%) HGACs. Peritoneal histology was benign in 6 (3.0%), AM in 33 (16.8%), LGMCP in 114 (57.9%), and HGMCP in 44 (22.3%). PFS was not reached for AM, 34.3 months for LGMCP, and 16.8 months for HGMCP (p < 0.001). Peritoneal histology predicted PFS on multivariate analysis (hazard ratio 9.82 and 24.60 for LGMCP and HGMCP, respectively, vs. AM, p < 0.001). Among the LGMCP group, CEA and completeness of cytoreduction (CC score) predicted PFS on multivariate analysis. CONCLUSIONS: Standardized peritoneal histology in patients with PM from MAT predicts PFS and patients with low-grade histology can be further discriminated by CEA and CC score.

Laparoscopy is Safe and Accurate to Evaluate Peritoneal Surface Metastasis Prior to Cytoreductive Surgery.

BACKGROUND: Completeness of cytoreduction is a significant predictor of long-term outcome after cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). Imaging has limited sensitivity to identify peritoneal metastases and therefore predict whether complete cytoreduction is possible. We reviewed our experience using laparoscopy to determine candidates for complete cytoreduction and HIPEC. METHODS: This single-center, retrospective study examined patients from 2007 to 2014 who underwent laparoscopy to determine complete cytoreduction (CC-0/1)/HIPEC candidacy. Preoperative, intraoperative, and postoperative data were collected. RESULTS: A total of 145 laparoscopies were performed on 141 patients, 72 (51.1 %) of whom were female, with a median age of 53 years (range 20-79). The primary site was appendiceal in 67 (47.5 %) patients, colorectal in 43 (30.5 %), mesothelioma in 17 (12.1 %), unknown in 9 (6.4 %), small bowel in 3 (2.1 %), gastric in 1, and ovarian in 1 (0.7 % each). Overall, 115 (81.6 %) patients had prior abdominal surgery, 111 (76.6 %) had evidence of disease on imaging, and 117 (80.7 %) underwent prior chemotherapy, with a median of 5.9 weeks between the last treatment and laparoscopy (0.9-498.9 weeks). Four (2.8 %) intraoperative complications were observed (one liver laceration, two enterotomies, and one air embolus), and nine (6.2 %) postoperative complications [four (2.8 %) Clavien grade (CG) I, three (2.8 %) CG II, one (0.7 %) CG III (return to operating room) and one (0.7 %) CG IV (transient ischemic attack)]. Forty-eight patients deemed candidates by laparoscopy underwent CRS/HIPEC (positive predictive value 82.8 %). CONCLUSION: Diagnostic laparoscopy is a safe, feasible, and accurate staging tool in patients with suspected peritoneal metastases being considered for CRS.

A Novel Tool for Predicting Major Complications After Cytoreductive Surgery with Hyperthermic Intraperitoneal Chemotherapy.

BACKGROUND: Cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) has an emerging role in the treatment of peritoneal malignancies. The CRS-HIPEC approach has known treatment-related toxicities. This study sought to determine the predictors of major postoperative complications after CRS-HIPEC in a high-volume center. METHODS: From a single-institution database, this study investigated complications experienced by patients undergoing CRS-HIPEC. Multiple preoperative and operative factors were analyzed for their ability to predict 60-day Clavien grade 3 and greater (major) complications by logistic regression. A predictive model was created from preoperative factors using multivariate logistic regression. The model was tested by Akaike's information criterion, the Hosmer and Lemeshow Goodness-of-Fit Test, the receiver operating characteristic, and the Youden Index. RESULTS: The study evaluated 247 patients undergoing CRS-HIPEC. The primary tumor site was the appendix in 166 cases (67.2 %), the colorectal area in 51 cases (20.6 %), the peritoneum (mesothelioma) in 22 cases (8.9 %), the ovary in 5 cases (2 %), and the small bowel in 3 cases (1.2 %). The median peritoneal cancer index was 14 (range 0-29), and 235 patients (95.1 %) had a complete (CC-0/1) cytoreduction. Major complications occurred for 41 patients (16.6 %), classified as grade 3 in 33 cases (13.4 %), grade 4 in 5 cases (2 %), and grade 5 (deaths) in 3 cases (1.2 %). The factors predictive of major complications in the multivariate analysis were a Charlson Comorbidity Index (CCI) score higher than 0 [odds ratio (OR), 2.505; p = 0.035], presence of preoperative symptoms (OR 1.951; p = 0.064), and prior resection status [no resection or prior CRS-HIPEC (OR 2.087) vs. prior resection without CRS-HIPEC (OR 3.209); p = 0.046]. These variables were used to create a tool predictive of postoperative complications. CONCLUSION: Presence of symptoms, CCI, and prior resection status predict major complications and define a low-risk population after CRS-HIPEC.

SWOG S0809: A Phase II Intergroup Trial of Adjuvant Capecitabine and Gemcitabine Followed by Radiotherapy and Concurrent Capecitabine in Extrahepatic Cholangiocarcinoma and Gallbladder Carcinoma.

PURPOSE: The role of postoperative therapy in extrahepatic cholangiocarcinoma (EHCC) or gallbladder carcinoma (GBCA) is unknown. S0809 was designed to estimate 2-year survival (overall and after R0 or R1 resection), pattern of relapse, and toxicity in patients treated with this adjuvant regimen. PATIENTS AND METHODS: Eligibility criteria included diagnosis of EHCC or GBCA after radical resection, stage pT2-4 or N+ or positive resection margins, M0, and performance status 0 to 1. Patients received four cycles of gemcitabine (1,000 mg/m(2) intravenously on days 1 and 8) and capecitabine (1,500 mg/m(2) per day on days 1 to 14) every 21 days followed by concurrent capecitabine (1,330 mg/m(2) per day) and radiotherapy (45 Gy to regional lymphatics; 54 to 59.4 Gy to tumor bed). With 80 evaluable patients, results would be promising if 2-year survival 95% CI were > 45% and R0 and R1 survival estimates were ≥ 65% and 45%, respectively. RESULTS: A total of 79 eligible patients (R0, n = 54; R1, n = 25; EHCC, 68%; GBCA, 32%) were treated (86% completed). For all patients, 2-year survival was 65% (95% CI, 53% to 74%); it was 67% and 60% in R0 and R1 patients, respectively. Median overall survival was 35 months (R0, 34 months; R1, 35 months). Local, distant, and combined relapse occurred in 14, 24, and nine patients. Grade 3 and 4 adverse effects were observed in 52% and 11% of patients, respectively. The most common grade 3 to 4 adverse effects were neutropenia (44%), hand-foot syndrome (11%), diarrhea (8%), lymphopenia (8%), and leukopenia (6%). There was one death resulting from GI hemorrhage. CONCLUSION: This combination was well tolerated, has promising efficacy, and provides clinicians with a well-supported regimen. Our trial establishes the feasibility of conducting national adjuvant trials in EHCC and GBCA and provides baseline data for planning future phase III trials.

Approach to patients with pancreatic cancer without detectable metastases.

The poors outcomes associated with pancreatic cancer clearly reflect the advanced stage of disease at diagnosis for most patients. Through this lens, it is easy to lose sight of the fact that roughly 50% of patients with pancreatic cancer have no clinically detectable metastases at presentation. Herein, we discuss how patients with localized pancreatic cancer are currently managed. The primary goal of care for patients with resectable and borderline-resectable tumors is cure, facilitated by achieving margin-negative resection of the primary disease and delivering effective adjuvant and/or neoadjuvant therapy. For patients with locally advanced disease, the focus is on limiting local progression and outgrowth of metastatic disease and maintaining quality of life. Although it was once a centerpiece of therapy for localized pancreatic cancer, the value and place of radiation therapy in the treatment algorithm is now under increased scrutiny. In contrast, given its value as demonstrated in multiple prospective trials, chemotherapy is an established part of the treatment paradigm for all patients. With the demonstration that cytotoxic combinations such as fluorouracil, leucovorin, irinotecan, and oxaliplatin as well as gemcitabine/nab-paclitaxel are active in the metastatic setting, these agents are now being studied in patients with localized disease. The neoadjuvant setting provides a particularly favorable setting for evaluating new systemic strategies. Given the array of new targets, including immunomodulatory approaches, there is reason for optimism that we can markedly improve survival for all patients with pancreatic cancer and enter an era in which surgery with curative intent actually fulfills this goal on a much more regular basis.

Predictors of progression in high-grade appendiceal or colorectal peritoneal carcinomatosis after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy.

BACKGROUND: Long-term survival of patients with appendiceal or colorectal peritoneal carcinomatosis (PC) may be achieved by combining cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS/HIPEC). Unfortunately, such favorable outcomes are realized in a minority of patients. Given the morbidity of the CRS/HIPEC and the uncertain role of postresection systemic therapy, it is important that prognostic factors in high-grade PC be clearly defined. METHODS: This single center, retrospective, cohort study examined the outcomes of CRS/HIPEC performed on patients with high-grade PC secondary to appendiceal or colorectal adenocarcinoma between 2007 and 2013. Cox regression analysis was utilized to evaluate the association between potential prognostic factors [age, sex, primary site, lymph node (LN) status, peritoneal cancer index (PCI) score, completeness of cytoreduction score (CC score), number of visceral resections, and systemic chemotherapy] and progression-free survival (PFS). RESULTS: A total of 70 patients with high-grade appendiceal or colorectal PC underwent CRS/HIPEC during the study period; 82.9 % underwent complete (CC-0) cytoreduction with a median PFS of 9.7 months. Positive LNs at the time of CRS/HIPEC were predictors of worse PFS on univariate and multivariate analysis. No association was demonstrated between pre- or post-HIPEC systemic chemotherapy and PFS. CONCLUSIONS: High-grade PC secondary to appendiceal or colorectal adenocarcinoma can be managed with CRS/HIPEC. The number of LN metastases at the time of CRS/HIPEC is the strongest predictor of progression and must be considered when determining patient eligibility for this aggressive treatment.

The American Society of Peritoneal Surface Malignancies evaluation of HIPEC with Mitomycin C versus Oxaliplatin in 539 patients with colon cancer undergoing a complete cytoreductive surgery.

BACKGROUND: Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) are gaining acceptance as treatment for selected patients with colorectal cancer with peritoneal carcinomatosis (CRCPC). Tremendous variations exist in the HIPEC delivery. METHODS: The American Society of Peritoneal Surface Malignancies (ASPSM) examined the overall survival in patients with CRCPC who underwent a complete cytoreduction and HIPEC with Oxaliplatin vs. Mitomycin C (MMC), stratifying them by the Peritoneal Surface Disease Severity Score (PSDSS). RESULTS: Median overall survival (OS) of 539 patients with complete cytoreduction was 32.6 months, 32.7 months for the MMC group and 31.4 months for the Oxaliplatin group (P = 0.925). However, when stratified by PSDSS, median OS rates in PSDSS I/II patients were 54.3 months in those receiving MMC vs. 28.2 months in those receiving oxaliplatin (P = 0.012), whereas in PSDSS III/IV patients, median OS rates were 19.4 months in those receiving MMC vs. 30.4 months in those receiving Oxaliplatin (P = 0.427). CONCLUSION: These data suggest that MMC might be a better agent for HIPEC delivery than Oxaliplatin in patients with CRCPC, favorable histologies and low burden of disease (PSDSS I/II) undergoing complete cytoreduction. Prospective studies are warranted, which stratify patients by their PSDSS and randomize them to HIPEC with MMC vs. Oxaliplatin.