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Introduction: Preoperative autophagy inhibition with hydroxychloroquine (HCQ) in combination with gemcitabine in pancreatic adenocarcinoma (PDAC) has been shown to be safe and effective in inducing a serum biomarker response and increase resection rates in a previous phase I/II clinical trial. We aimed to analyze the long-term outcomes of preoperative HCQ with gemcitabine for this cohort., Methods: A review of patients enrolled between July 2010 and February 2013 in the completed phase I/II single arm (two doses of fixed-dose gemcitabine (1500 mg/m 2 ) in combination with oral hydroxychloroquine administered for 31 consecutive days until the day of surgery for high-risk pancreatic cancer) was undertaken. Progression-free survival (PFS) and overall survival analysis (OS) using Kaplan-Meier estimates were performed., Results: Of 35 patients initially enrolled, 29 patients underwent surgical resection (median age at diagnosis: 62 years, 45% females). Median duration of follow-up was 7.5 years. There was a median 15% decrease in the serum CA19-9 levels following completion of neoadjuvant therapy and 83% of the cohort underwent a pancreaticoduodenectomy, 7 (24%) patients had a concomitant venous resection. On histopathology, 14 (48%) patients had at least a partial treatment response. The median PFS and OS were 11 months (95% Confidence interval [CI]: 7-28) and 31 months (95% CI: 13-47), respectively, while 9 (31%) patients survived beyond 5 years from diagnosis; a rate that compares very favorably with contemporaneous series., Conclusion: Compared to historical data, neoadjuvant autophagy inhibition with HCQ plus gemcitabine is associated with encouraging long-term survival for patients with PDAC., (© 2021 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Abundant intraperitoneal (IP) accumulation of extracellular mucus in patients with appendiceal mucinous carcinoma peritonei (MCP) causes compressive organ dysfunction and prevents delivery of chemotherapeutic drugs to cancer cells. We hypothesized that reducing extracellular mucus would decrease tumor-related symptoms and improve chemotherapeutic effect in patient-derived models of MCP. Mucolysis was achieved using a combination of bromelain (BRO) and N-acetylcysteine (NAC). Ex vivo experiments of mucolysis and chemotherapeutic drug delivery/effect were conducted with MCP and non-MCP tissue explants. In vivo experiments were performed in mouse and rat patient-derived xenograft (PDX) models of early and late (advanced) MCP. MCP tumor explants were less chemosensitive than non-MCP explants. Chronic IP administration of BRO + NAC in a mouse PDX model of early MCP and a rat PDX model of late (advanced) MCP converted solid mucinous tumors into mucinous ascites (mucolysis) that could be drained via a percutaneous catheter (rat model only), significantly reduced solid mucinous tumor growth and improved the efficacy of chemotherapeutic drugs. Combination of BRO + NAC efficiently lyses extracellular mucus in clinically relevant models of MCP. Conversion of solid mucinous tumors into mucinous ascites decreases tumor bulk and allows for minimally invasive drainage of liquified tumors. Lysis of extracellular mucus removes the protective mucinous coating surrounding cancer cells and improves chemotherapeutic drug delivery/efficacy in cancer cells. Our data provide a preclinical rationale for the clinical evaluation of BRO + NAC as a therapeutic strategy for MCP., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Purpose: We hypothesized that autophagy inhibition would increase response to chemotherapy in the preoperative setting for patients with pancreatic adenocarcinoma. We performed a randomized controlled trial to assess the autophagy inhibitor hydroxychloroquine in combination with gemcitabine and nab-paclitaxel., Patients and Methods: Participants with potentially resectable tumors were randomized to two cycles of nab-paclitaxel and gemcitabine (PG) alone or with hydroxychloroquine (PGH), followed by resection. The primary endpoint was histopathologic response in the resected specimen. Secondary clinical endpoints included serum CA 19-9 biomarker response and margin negative R0 resection. Exploratory endpoints included markers of autophagy, immune infiltrate, and serum cytokines., Results: Thirty-four patients in the PGH arm and 30 in the PG arm were evaluable for the primary endpoint. The PGH arm demonstrated statistically improved Evans grade histopathologic responses ( P = 0.00016), compared with control. In patients with elevated CA 19-9, a return to normal was associated with improved overall and recurrence-free survival ( P < 0.0001). There were no differences in serious adverse events between arms and chemotherapy dose number was equivalent. The PGH arm had greater evidence of autophagy inhibition in their resected specimens (increased SQSTM1, P = 0.027, as well as increased immune cell tumor infiltration, P = 0.033). Overall survival ( P = 0.59) and relapse-free survival ( P = 0.55) did not differ between the two arms., Conclusions: The addition of hydroxychloroquine to preoperative gemcitabine and nab-paclitaxel chemotherapy in patients with resectable pancreatic adenocarcinoma resulted in greater pathologic tumor response, improved serum biomarker response, and evidence of autophagy inhibition and immune activity., (©2020 American Association for Cancer Research.)

Molecular-targeted therapies have demonstrated disappointing results against most advanced solid cancers. This may largey be attributed to irrational drug use against unselected cancers. We investigated the efficacy of dual MEK-PI3K drug therapy against KRAS mutated mucin 2 (MUC2)-secreting LS174T cells and patient-derived ex vivo and in vivo models of KRAS mutated mucinous colon/appendix cancers. These tumors demonstrate unique phenotypic and genotypic features that likely predict sensitivity to this targeted co-therapy. Co-treatment with MEK inhibitor (trametinib) and PI3K inhibitor (pictilisib)-induced synergistic cytotoxicity and intrinsic mitochondrial-mediated apoptosis in LS174T cells and tumor explants in vitro. Dual drug therapy also induced endoplasmic reticulum stress (ERS)-associated proteins (GRP78/BiP, ATF4, and CHOP). However, CHOP knock-down assays demonstrated that mitochondrial-mediated apoptosis in LS174T cells was not ERS-dependent. Dual drug therapy also significantly decreased MUC2 expression, MUC2 post-translational modification (palmitoylation) and secretion in LS174T cells, suggesting a simultaneous cytotoxic and mucin suppressive mechanism of action. We also demonstrated effective mucinous tumor growth suppression in ex vivo epithelial organoid (colonoid) cultures and in in vivo intraperitoneal patient-derived xenograft models derived from mucinous colon/appendix cancer. These promising preclinical data support a role for dual MEK-PI3K inhibitor therapy in mucinous colon/appendix cancers. We postulate that mucinous KRAS mutated cancers are especially vulnerable to this co-treatment based on their unique phenotypic and genotypic characteristics., (© 2020 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Introduction: Appendiceal neoplasms are uncommon tumors. Optimal treatment for patients with perforation or high-grade pathology after initial resection is unknown. This study evaluated patients with increased risk for peritoneal dissemination after primary resection, but no evidence of peritoneal disease, who underwent adjuvant hyperthermic intraperitoneal chemotherapy (HIPEC)., Methods: This multi-institutional cohort study evaluated 56 patients with high-risk (HR) appendiceal neoplasms with a peritoneal carcinomatosis index of 0 who underwent HIPEC. The patients were divided into two groups: perforated low-grade appendiceal (LGA) carcinoma and HR neoplasms, which included perforated high-grade appendiceal carcinoma, positive margins after initial resection, minimal macroscopic peritoneal disease that was previously resected or completely responded to systemic chemotherapy prior to HIPEC, goblet cell carcinoma, and adenocarcinoma with signet ring cell features. Overall survival (OS) and recurrence-free survival (RFS) were estimated by Kaplan-Meier analysis., Results: Thirty-eight percent of patients had perforated LGA and 68% had HR features. Five-year OS probability was 82.1% for the entire cohort, and 100% and 70.1% for patients with perforated LGA and HR features, respectively (p = 0.024). Five-year RFS probability was 79.3% for the entire cohort, and 90.0% and 72.4% for patients with perforated LGA and HR features, respectively (p = 0.025). Eight patients recurred after HIPEC and their OS was significantly worse (p < 0.001)., Conclusion: While adjuvant HIPEC is both safe and feasible, there appears to be little benefit over close surveillance when outcomes are compared with historical and prospective studies, especially for perforated LGA carcinoma.

Purpose: Peritoneal carcinomatosis or pseudomyxoma peritonei from urachus is a rare form of presentation, often diagnosed at an advanced state of tumor burden. Because of its rarity, little is known about its natural history, prognosis, or optimal treatment. We searched a large international multicenter database of peritoneal surface disease to identify cases of peritoneal carcinomatosis of urachus that were treated with cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) at expert centers. The aim is to improve knowledge and understanding of the disease and standardize its treatment., Methods: A prospective multicenter international database was retrospectively searched to identify all patients with urachus tumor and peritoneal metastases who underwent CRS and HIPEC through the Peritoneal Surface Oncology Group International (PSOGI). Postoperative complications, long-term results, and principal prognostic factors were analyzed., Results: The analysis included 36 patients. After median follow-up of 48 months, median overall survival (OS) was 58.5 months. Three- and 5-year OS was 55.4 and 46.2%, respectively. Patients who underwent complete macroscopic CRS had significantly better survival than those treated with incomplete CRS, with median OS not achieved and of 20.1 months, respectively [95% confidence interval (CI) 4.4-30.5, p < 0.001]. There were no postoperative deaths, and 37.9% of patients had major complications., Conclusion: CRS and HIPEC may increase long-term survival in selected patients with peritoneal metastases of urachus origin, especially when complete CRS is achieved.

Background: Cytoreductive surgery and hyperthermic intraperitoneal chemoperfusion (CRS-HIPEC) is a complex procedure that often requires ostomy creation to protect high-risk anastomoses. This study aimed to evaluate the authors' institutional experience with CRS-HIPEC-associated ostomies, determine predictors of ostomy creation and reversal, and assess their impact on survival., Methods: The study analyzed clinicopathologic, perioperative, and oncologic data from a prospective database of 1435 CRS-HIPEC procedures for peritoneal metastases. The Kaplan-Meier method was used to estimate survival. Multivariate analyses identified associations with ostomy creation/reversal and survival., Results: Ostomies were created in 34% of the patients, most commonly loop ileostomies (82%). Loop ileostomies were reversed in the majority of patients (83%), whereas non-loop ileostomies were infrequently reversed (< 10% reversal rate). In a multivariate logistic regression model, intermediate or high tumor grade, colectomy/proctectomy, longer operative time, and lower Charlson comorbidity index were associated with loop ileostomy creation, whereas incomplete macroscopic resection, colorectal histology, and major postoperative complications were associated with non-reversal of loop ileostomy. In a multivariate Cox proportional hazards model, intermediate or high tumor grade and non-reversal of loop ileostomy were associated with worse overall survival., Conclusions: Loop ileostomies were almost always reversed, whereas non-loop ileostomies were almost always permanent. Hospital readmissions for loop ileostomy-related complications were common. Therefore, formal outpatient protocols for prevention and management should be implemented. Non-reversal of loop ileostomy was associated with very poor survival.

Background: In the era of effective modern systemic chemotherapy (CT), the role of hepatic arterial infusion of fluoxuridine (HAI-FUDR) in the treatment of isolated unresectable colorectal liver metastasis (IU-CRCLM) remains controversial. This study aimed to compare the overall survival (OS) of HAI-FUDR in combination with modern systemic CT versus modern systemic CT alone in patients with IU-CRCLM., Methods: This was a case-control study of IU-CRCLM patients who underwent HAI + modern systemic CT or modern systemic CT alone. Modern systemic CT was defined as the use of multidrug regimens containing oxaliplatin and/or irinotecan ± biologics., Results: Overall, 86 patients met the inclusion criteria (n = 40 for the HAI + CT group, and n = 46 for the CT-alone group). Both groups were similar in demographics, primary and stage IV tumor characteristics, and treatment-related variables (carcinoembryonic antigen, use of biologic agents, total number of lines of systemic CT administered) (all p > 0.05). Additionally, both groups were comparable with respect to liver tumor burden [median number of lesions (13.5 vs. 15), percentage of liver tumor replacement (37.5 vs. 40 %), and size of largest lesion] (all p > 0.05). Median OS in the HAI + CT group was 32.8 months compared with 15.3 months in the CT-alone group (p < 0.0001). Multivariate analysis revealed HAI + CT (hazard ratio 0.4, 95 % confidence interval 0.21-0.72; p = 0.003), Eastern Cooperative Oncology Group status, and receipt of increasing number of lines of systemic CT to be independent predictors of survival., Conclusions: In this case-control study of patients with IU-CRCLM, HAI in combination with CT was associated with improved OS when compared with modern systemic CT alone.

Introduction: Patients with peritoneal carcinomatosis (PC) of appendiceal origin demonstrate variable oncologic outcomes, despite aggressive cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS-HIPEC). We sought to devise a prognostic risk stratification system for oncologic outcomes following CRS-HIPEC., Methods: A total of 197 patients undergoing CRS-HIPEC for the treatment of appendiceal PC were reviewed from a prospective database. Kaplan-Meier survival curves and multivariate Cox regression models were used to identify prognostic factors affecting oncologic outcomes. Clinicopathologic variables affecting overall survival (OS) were utilized to develop a prognostic staging system and nomograms., Results: Univariate and multivariate Cox regression analysis indicated that high-grade tumor histology, lymph node metastasis, and incomplete cytoreduction were high-risk features, adversely affecting OS. Patients were stratified on the presence of high-risk features as follows: low-risk patients had no risk factors (n = 102); intermediate-risk patients had one risk factor (n = 49); and high-risk patients had more than one risk factor (n = 46). Median OS for low-risk patients was not reached, and was 43 and 22 months for intermediate-risk and high-risk patients, respectively. Five-year OS was 72, 43, and 13 % for low-, intermediate- and high-risk patients, respectively (p < 0.0003 for low vs. intermediate risk, and p = 0.06 for intermediate vs. high risk)., Conclusions: We propose a three-tier staging system for appendiceal PC following CRS-HIPEC, based on histologic grade, lymph node involvement, and completeness of cytoreduction. The presence of any one or more of these high-risk features significantly decreased survival in our single-institution database and provided the basis for a prognostic staging system and corresponding nomograms.

Background: High-grade (HG) mucinous appendiceal neoplasms (MAN) have a worse prognosis than low-grade histology. Our objective was to assess the safety and efficacy of cytoreductive surgery with hyperthermic intraperitoneal chemoperfusion (CRS/HIPEC) in patients with high-grade, high-volume (HG-HV) peritoneal metastases in whom the utility of this aggressive approach is controversial., Methods: Prospectively collected perioperative data were compared between patients with peritoneal metastases from HG-HV MAN, defined as simplified peritoneal cancer index (SPCI) ≥12, and those with high-grade, low-volume (HG-LV; SPCI <12) disease. Kaplan-Meier curves and multivariate Cox regression models identified prognostic factors affecting oncologic outcomes., Results: Overall, 54 patients with HG-HV and 43 with HG-LV peritoneal metastases underwent CRS/HIPEC. The HG-HV group had longer operative time, increased blood loss/transfusion, and increased intensive care unit length of stay (p < 0.05). Incomplete macroscopic cytoreduction (CC-1/2/3) was higher in the HG-HV group compared with the HG-LV group (68.5 vs. 32.6 %; p = 0.005). Patients with HG-HV disease demonstrated worse survival than those with HG-LV disease (overall survival [OS] 17 vs. 42 m, p = 0.009; time to progression (TTP) 10 vs. 14 m, p = 0.024). However, when complete macroscopic resection (CC-0) was achieved, the OS and progression-free survival of patients with HG-HV disease were comparable with HG-LV disease (OS 56 vs. 52 m, p = 0.728; TTP 20 vs. 19 m, p = 0.393). In a multivariate Cox proportional hazard regression model, CC-0 resection was the only significant predictor of improved survival for patients with HG-HV disease., Conclusions: Although patients with HG-HV peritoneal metastases from MAN have worse prognosis compared with patients with HG-LV disease, their survival is comparable when complete macroscopic cytoreduction is achieved.

Background and Objectives: To evaluate whether urologic procedures during cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) are associated with adverse postoperative outcomes., Methods: We identified patients who underwent CRS-HIPEC at our institution from 2001 to 2012 and compared outcomes between operations that did and did not include a urologic procedure., Results: A total of 938 CRS-HIPEC procedures were performed, 71 of which included a urologic intervention. Urologic interventions were associated with longer operative times (547 vs. 459 min, P < 0.001) and greater length of stay (15 vs. 12 days, P = 0.003). Major complications (Clavien III and IV) were more common in the urologic group (31% vs. 20%, P = 0.028). On multivariable analysis, urologic procedures were associated with a low anterior resection (OR: 2.25, 95%CI 1.07-4.74, P = 0.033) and a greater number of enteric anastomoses (OR: 1.83, 95%CI 1.31-2.56, P < 0.001). At a median follow up of 17 months (IQR 5.6-35 months), addition of a urologic procedure did not significantly impact overall survival for appendiceal or colorectal cancers., Conclusion: Urologic surgery at the time of CRS-HIPEC is associated with longer operative times, length of stay and increased risk of major complications, but not with decreased overall survival. J. Surg. Oncol. 2016;113:218-222. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

Background: Postoperative pancreatic fistulas (POPFs) are potentially morbid complications that often require therapeutic interventions. Distal pancreatectomy performed during cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemoperfusion (HIPEC) puts patients at risk for POPF. The authors hypothesized that POPFs are more severe after CRS/HIPEC than after pancreatectomy alone., Methods: Clinicopathologic and perioperative details, including POPF by International Study Group of Pancreatic Fistula criteria (ISGPF), and oncologic outcomes for patients undergoing distal pancreatectomy during CRS/HIPEC for peritoneal carcinomatosis of appendiceal (n = 31) or colorectal (n = 23) origin (HIPEC group) were compared with those for patients undergoing minimally invasive or open distal pancreatectomy without HIPEC (n = 66) for locally resectable pancreatic adenocarcinoma (non-HIPEC group)., Results: The incidence of POPF was similar between the HIPEC and non-HIPEC groups (26 %). The severity of POPF according to the ISGPF criteria was significantly worse in the HIPEC group. The HIPEC patients had 13 grade B fistulas and 1 grade C fistula compared with 12 grade A fistulas and 4 grade B fistulas in the non-HIPEC group. The HIPEC patients with POPF did not differ in the extent of their CRS, peritoneal cancer index, length of hospital stay, or other postoperative complications from the the HIPEC patients without POPF. The HIPEC patients with colorectal carcinomatosis who experienced POPF had higher disease recurrence in the first year after CRS/HIPEC than those without POPF., Conclusion: The findings showed that POPFs are more severe when distal pancreatectomy is combined with CRS/HIPEC. Moreover, selective use of distal pancreatectomy is important during CRS/HIPEC because POPFs may increase early disease recurrence for patients with colorectal carcinomatosis.

Background: Cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemoperfusion (HIPEC) is routinely used to treat certain peritoneal carcinomatoses (PC), but it can be associated with relatively high complication rates, prolonged hospital length of stay, and potential mortality. Our objective was to determine the learning curve (LC) of CRS/HIPEC in our high-volume institution., Methods: A total of 370 patients with PC from mucinous appendiceal neoplasms (MAN = 282), malignant peritoneal mesothelioma (MPM = 60), and gastric cancer (GC = 24) were studied. Outcomes analyzed included incomplete cytoreduction (IC), severe morbidity (SM), 60-day mortality, progression-free survival (PFS), and overall survival (OS). Risk-adjusted sequential probability ratio test (RA-SPRT) was employed to assess the LC of CRS/HIPEC for IC and SM using prespecified odds ratio (OR) boundaries derived from previously published data. Risk adjusted-cumulative average probability (RA-CAP) was used to analyze 1-year PFS and 2-year OS., Results: Complete cytoreduction, severe morbidity, and 60-day mortality were 84.2, 30, and 1.9 % respectively. Higher simplified peritoneal cancer index was the major independent risk factor for IC, whereas high-grade histology, IC, and diagnosis of MPM and GC (compared with MAN) were predictors of SM after CRS/HIPEC (p < 0.05). RA-SPRT showed that approximately 180 cases are needed to achieve the lowest risk of IC and SM. Ninety cases were needed to achieve a steady 1-year PFS and 2-year OS in RA-CAP plots., Conclusions: The completeness of cytoreduction, morbidity, and mortality rates for CRS/HIPEC at our institution are comparable to previously reported data. Approximately 180 and 90 procedures are required to improve operative and oncologic outcomes respectively.

Background: Baseline carbohydrate antigen 19-9 (CA 19-9) is a useful prognostic marker in pancreatic ductal adenocarcinoma (PDA); however, data on the significance of a change in CA 19-9 following neoadjuvant therapy are lacking., Methods: All patients receiving neoadjuvant therapy for PDA from July 2010 to February 2013 were retrospectively reviewed. Resection rate, R0 resection rate, need for venous resection, and overall survival were correlated to CA 19-9 response. Fisher's exact test, Kaplan-Meier survival analysis, and multivariate analysis using Cox regression were used., Results: A total of 78 patients were studied (21 patients with resectable disease, 40 borderline resectable, and 17 with locally advanced disease). A variety of chemotherapies ± radiation were utilized during the study period. Overall, 56 patients (72 %) had a decrease in CA 19-9 of >50 % with neoadjuvant treatment. In borderline resectable patients, CA 19-9 response of >50 % predicted R0 resection (odds ratio 4.2; p = 0.05). In borderline resectable patients who had an increase in CA 19-9, none of five (0 %) underwent R0 resection compared with 80 % of the remaining cohort (p = 0.001). The complete pathologic response rate was 29 % in patients who had a CA 19-9 response of >90 % versus 0 % in the remaining patients (p < 0.001). A CA 19-9 response of >50 % resulted in improved overall survival (28.0 vs. 11.1 months; p < 0.0001) and was an independent predictor of survival (hazard ratio 0.26; 95 % CI 0.13-0.55; p < 0.0001)., Conclusions: CA 19-9 response to neoadjuvant therapy is associated with R0 resection rate, histopathologic response, and survival. Incorporation of this easily obtainable biomarker into future clinical trials may facilitate more rapid evaluation of novel regimens.

Background: Obesity has been described as a risk factor for surgical complications and may play a prominent role in the progression, recurrence, and survival rates of various cancers. Our objective was to investigate the impact of being overweight or obese on perioperative and oncologic outcomes after cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemoperfusion (HIPEC) for peritoneal carcinomatosis (PC) from mucinous appendiceal neoplasms (MAN)., Methods: From a prospectively maintained database (2001-2010) of CRS/HIPEC for PC from MAN, we evaluated the body mass index (BMI) of patients, categorizing them into normal weight (NW < 25 kg/m(2)), overweight (OW = 25 to 29.9 kg/m(2)), and obese (OB ≥ 30 kg/m(2)). We compared the perioperative and oncologic outcomes among groups., Results: Of the 282 patients in the database, 234 had BMI data available, and 81, 79, and 74 patients were categorized as NW, OW, and OB, respectively. Although there was a trend toward increased risk of overall complications, wound infections, deep vein thrombosis, respiratory and renal complications, and anastomotic leaks in the OW and OB groups, these differences only achieved statistical significance for renal (p = 0.03) and pulmonary (p = 0.02) complications in the OW and OB groups, respectively. The 5-year survival rate for NW, OW, and OB patients was 63.9, 48, and 54.4 %, respectively (p = 0.63). The median time to progression was 21.1 (NW), 21.7 (OW), and 23.9 (OB) months (p = 0.83)., Conclusions: OW and OB patients may have an increased risk of renal and pulmonary complications, respectively. Obesity has no major impact on perioperative mortality and long-term oncologic outcomes in patients undergoing CRS/HIPEC for MAN.

Background: Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemoperfusion (HIPEC) for peritoneal carcinomatosis (PC) of colorectal origin increases survival (OS) compared to systemic chemotherapy alone. Signet ring histology demonstrates aggressive behavior with poor survival. We sought to determine whether CRS/HIPEC increases survival in this subset of patients., Methods: We reviewed 67 patients with PC of appendiceal (AP, n = 37) or colorectal origin (CRC, n = 30) with signet cell histology from a prospective database between May 2001 and August 2011. Survival analysis and multivariate Cox regression were used to determine prognostic factors for survival., Results: Complete CRS (CC-0/1) was achieved in 77 % (CRC) and 73 % (AP) of patients. Progression-free survival (PFS) and OS were 9 and 12 months in CRC and 12 and 21 months in AP patients. In the CRC group, univariate predictors of poor survival included female gender, age, American Society of Anesthesiologists score, preoperative albumin, completeness of cytoreduction, and morbidity. In a multivariate Cox regression model, incomplete cytoreduction (CC-2/3) and female gender were joint significant predictors of poor survival. In the AP group, significant univariate predictors of poor survival included higher EBL and PCI score. In a multivariate Cox regression model, blood loss of >500 ml and a body mass index of <25 kg/m(2) were joint significant predictors of poor survival., Conclusions: AP signet cell tumors demonstrate a more favorable outcome than CRC signet cell tumors after CRC/HIPEC for carcinomatosis, suggesting an underlying difference in biology. CRS/HIPEC does not confer survival benefit in colorectal signet ring carcinomatosis unless complete cytoreduction can be achieved, whereas appendiceal signet ring carcinomatosis may benefit, regardless of resectability.

Background: Peritoneal carcinomatosis from gastric cancer (GPC) responds poorly to systemic chemotherapy. Limited published data demonstrate improved outcomes after aggressive locoregional therapies. We assessed the efficacy of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemoperfusion (HIPEC) in GPC., Methods: We prospectively analyzed 23 patients with GPC undergoing CRS/HIPEC between 2001 and 2010. Kaplan-Meier survival curves and multivariate Cox regression models identified prognostic factors affecting oncologic outcomes., Results: CRS/HIPEC was performed for synchronous GPC in 20 patients and metachronous GPC in 3 patients. Adequate CRS was achieved in 22 patients (CC-0 = 17; CC-1 = 5) and median peritoneal cancer index was 10.5. Most patients received preoperative chemotherapy (83 %) and total gastrectomy (78 %). Pathology revealed diffuse histology (65 %), signet cells (65 %) and LN involvement (64 %). Major postoperative morbidity occurred in 12 patients, with 1 in-hospital mortality at postoperative day 66. With median follow-up of 52 months, median overall survival (OS) was 9.5 months (95 % confidence interval 4.7-17.3), with 1- and 3- year OS rates of 50 and 18 %. Median progression-free survival (PFS) was 6.8 months (95 % confidence interval 3.9-14.6). In a multivariate Cox regression model, male gender [hazard ratio (HR) 6.3], LN involvement (HR 1.2), residual tumor nodules (HR 2.4), and >2 anastomoses (HR 2.8) were joint significant predictors of poor OS (χ (2) = 18.2, p = 0.001), while signet cells (HR 8.9), anastomoses >2 (HR 5.5), and male gender (HR 2.4) were joint significant predictors of poor progression (χ (2) = 16.3, p = 0.001)., Conclusions: Aggressive CRS/HIPEC for GPC may confer a survival benefit in select patients with limited lymph node involvement and completely resectable disease requiring less extensive visceral resections.

Background: Most patients with malignant peritoneal mesothelioma (MPM) present with late-stage, unresectable disease that responds poorly to systemic chemotherapy while, at the same time, effective targeted therapies are lacking. We assessed the efficacy of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemoperfusion (HIPEC) in MPM., Methods: We prospectively analyzed 65 patients with MPM undergoing CRS/HIPEC between 2001 and 2010. Kaplan-Meier survival curves and multivariate Cox-regression models identified prognostic factors affecting oncologic outcomes., Results: Adequate CRS was achieved in 56 patients (CC-0 = 35; CC-1 = 21), and median simplified peritoneal cancer index (SPCI) was 12. Pathologic assessment revealed predominantly epithelioid histology (81 %) and biphasic histology (8 %), while lymph node involvement was uncommon (8 %). Major postoperative morbidity (grade III/IV) occurred in 23 patients (35 %), and 60-day mortality rate was 6 %. With median follow-up of 37 months, median overall survival was 46.2 months, with 1-, 2-, and 5-year overall survival probability of 77, 57, and 39 %, respectively. Median progression-free survival was 13.9 months, with 1-, 2-, and 5-year disease failure probability of 47, 68, and 83 %, respectively. In a multivariate Cox-regression model, age at surgery, SPCI >15, incomplete cytoreduction (CC-2/3), aggressive histology (epithelioid, biphasic), and postoperative sepsis were joint significant predictors of poor survival (chi square = 42.8; p = 0.00001), while age at surgery, SPCI >15, incomplete cytoreduction (CC-2/3), and aggressive histology (epithelioid, biphasic) were joint significant predictors of disease progression (Chi square = 30.6; p = 0.00001)., Conclusions: Tumor histology, disease burden, and the ability to achieve adequate surgical cytoreduction are essential prognostic factors in MPM patients undergoing CRS/HIPEC.

Background: Eighty percent of patients with resected pancreatic ductal carcinoma (PDC) experience treatment failure within 2 years. We hypothesized that preoperative fixed-dose rate (FDR) gemcitabine (GEM) combined with the angiogenesis inhibitor bevacizumab (BEV) and accelerated 30 Gy radiotherapy (RT) would improve outcomes among patients with potentially resectable PDC., Methods: This phase II trial tested induction FDR GEM (1,500 mg/m(2)) plus BEV (10 mg/kg IV) every 2 weeks for three cycles followed by accelerated RT (30 Gy in 10 fractions) plus BEV directed at gross tumor volume plus a 1-2 cm vascular margin. Subjects underwent laparoscopy and resection after day 85. Therapy was considered effective if the complete pathologic response rate exceeded 10 % and the margin-negative resection rate exceeded 80%., Results: Fifty-nine subjects were enrolled; 29 had potential portal vein involvement. Two grade 4 (3.4%) and 19 grade 3 toxicities (32.8%) occurred. Four subjects manifested radiographic progression, and 10 had undetected carcinomatosis. Forty-three pancreatic resections (73%) were performed, including 19 portal vein resections (44%). Margin-negative outcomes were observed in 38 (88%, 95% confidence interval [CI] 75-96), with one complete pathologic response (2.3%; 95% CI 0.1-12). There were seven (6 grade 3; 1 grade 4) wound complications (13%). Median overall survival for the entire cohort was 16.8 months (95% CI 14.9-21.3) and 19.7 months (95% CI 16.5-28.2) after resection., Conclusions: Induction therapy with FDR GEM and BEV, followed by accelerated BEV/RT to 30 Gy, was well tolerated. Although both effectiveness criteria were achieved, survival outcomes were equivalent to published regimens.

Background and Objectives: Peritoneal sarcomatosis responds poorly to systemic chemotherapy and demonstrates high rates of recurrence after resection. We sought to determine perioperative and oncologic outcomes after cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemoperfusion (HIPEC) for recurrent sarcomatosis., Methods: We reviewed 15 patients undergoing 17 CRS/HIPEC for recurrent sarcomatosis from a prospective database., Results: There were four synovial cell sarcomas, five liposarcomas, three leiomyosarcomas, two gastrointestinal stromal tumors (GIST), and three other sarcomas. Adequate cytoreduction (CC-0/1) was achieved in all patients, with a median intra-operative Simplified Peritoneal Carcinomatosis Index of 6 (range: 3-9). Median blood loss and operative time were 1 L (range: 450-5,200) and 402 min (range: 324-680), respectively. Chemoperfusion drug was mitomycin C, cisplatin, or doxorubicin. Significant post-operative complications (Clavien-Dindo III/IV) occurred in four (24%) patients, with no 60-day mortalities and three (18%) 60-day re-admissions. Median intra-abdominal disease-free and overall survival after CRS/HIPEC was 17.2 (95% CI: 2.4-19.7 months) and 22.6 months (95% CI: 6.1-62.6 months), respectively. There was a trend towards delayed recurrence after combined CRS/HIPEC than after prior CRS alone (17.2 months vs. 10.7 months, respectively; P = 0.52)., Conclusion: Cytoreduction combined with HIPEC may improve loco-regional disease control in patients with recurrent sarcomatosis., (Copyright © 2013 Wiley Periodicals, Inc.)

Background: There is currently no consensus about the most effective adjuvant therapy for adenocarcinoma of the pancreas. Both gemcitabine and erlotinib have been demonstrated to improve survival in patients with metastatic disease. This study was designed to evaluate the efficacy of gemcitabine and erlotinib as adjuvant therapy, and to explore potential biomarkers associated with response., Methods: An institutional review board-approved single-center phase II trial of adjuvant biweekly fixed-dose rate gemcitabine (1500 mg/m(2)) and daily erlotinib (150 mg/day) for 4 months followed by maintenance erlotinib (150 mg/day) over 8 months was initiated. Primary end point was recurrence-free survival (RFS). Epidermal growth factor receptor (EGFR) expression in the resected tumors was assessed by fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC)., Results: The study completed planned accrual of 25 patients. Median follow-up was 18.2 (range 11.6-23.5) months. Recurrences were observed in 17 subjects (68%). Median RFS was 14.0 months (95% confidence interval [95% CI], 8.2-24.5) with 1-year and 2-year RFS of 56% (95% CI, 35-73) and 26% (95% CI, 6-52), respectively. Median overall survival was not reached. Estimated 1-year and 2-year overall survival was 84% (95% CI, 63-94) and 53% (95% CI, 22-76), respectively. Nine patients (36%) had a grade 3 event and only 1 (4%) had a grade 4 (neutropenia). Most toxicities were dermatologic, gastrointestinal, and constitutional. There were nonsignificant trends to longer RFS and lower recurrence rates while receiving therapy in subjects with fluorescence in situ hybridization-positive tumors and greater immunohistochemistry expression., Conclusions: Our phase II results suggest that adjuvant gemcitabine and erlotinib is a promising regimen that merits further investigation.

Background: Survival benefit of cytoreductive surgery combined with hyperthermic intraperitoneal chemoperfusion was demonstrated by a prospective randomized trial for colorectal peritoneal carcinomatosis. Because of a recent substantial improvement in chemotherapy, the authors analyzed treatment options of colorectal carcinomatosis in the current era., Methods: Consecutive patients with colorectal carcinomatosis treated by cytoreductive surgery combined with hyperthermic intraperitoneal chemoperfusion from 2001 to 2007 were included. The control group patients with carcinomatosis received contemporary chemotherapy alone. Overall survival was the primary endpoint., Results: All patients underwent systemic chemotherapy. The cytoreductive surgery combined with hyperthermic intraperitoneal chemoperfusion group (n=67) was similar to the control group (n=38) in sex, tumor grade, site of tumor origin, T status, and N status. The control group was, however, older (59 vs 51 years; P<.001). Median survival measured from the diagnosis of peritoneal disease was longer with cytoreductive surgery combined with hyperthermic intraperitoneal chemoperfusion (34.7 months vs 16.8 months; P<.001). Presence of liver metastasis was a significant negative predictor of survival (hazard ratio, 2.13)., Conclusions: The authors concluded that 1) contemporary chemotherapy is associated with prolonged survival among patients with carcinomatosis as compared with historical controls, and 2) addition of cytoreductive surgery combined with hyperthermic intraperitoneal chemoperfusion to modern chemotherapy regimens may significantly prolong survival. Cytoreductive surgery combined with hyperthermic intraperitoneal chemoperfusion and systemic chemotherapy are not competitive therapies, and they both have a role in a multidisciplinary approach to patients with carcinomatosis., (Copyright (c) 2010 American Cancer Society.)

Over the years, a large number of drugs have been used in isolated perfusion of extremities or organs. To interpret the pharmacokinetics of these drugs correctly, the contributions of tissue or organ clearance and chemical degradation, respectively, to overall drug elimination from the circuit need to be identified. In support of a phase I clinical trial of isolated hepatic perfusion (IHP), delivering 5-fluorouracil (5-FU) and oxaliplatin to patients with colorectal cancer hepatic metastases, we aimed to characterize the stability of 5-FU and oxaliplatin in the IHP circuit. Stability of 5-FU and oxaliplatin was assessed in human blood, lactated Ringer infusion (LRI), and in an in vitro IHP circuit consisting of both blood and LRI. Samples were analyzed with liquid chromatography tandem mass spectrometry (5-FU) and atomic absorption spectrophotometry (oxaliplatin). 5-FU was stable under all tested in vitro conditions, but ultrafilterable platinum concentrations decreased slowly with a half-life of 85 minutes in both IHP perfusate and whole blood. The stability of 5-FU in the media containing blood is likely attributable to saturation of dihydropyrimidine dehydrogenase. The decrease of ultrafilterable platinum in blood-containing media with an 85 minutes half-life is in agreement with previous reports on oxaliplatin biotransformation. Oxaliplatin and 5-FU are sufficiently stable in the circuit for the 1-hour perfusion in ongoing and planned clinical trials.

Background: Carcinomatosis of colorectal origin is increasingly treated by cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CS-HIPEC). This procedure commonly involves multivisceral resection (MVR) with potentially high morbidity. We analyzed the effect of MVR on the outcome after CS-HIPEC., Methods: All patients with colorectal carcinomatosis operated between June 2001 and June 2007 were included. MVR was defined as resection of two or more organs (n = 35). Patients without any or with a single visceral resection formed a control group (n = 30)., Results: Sixty-five patients underwent 72 procedures. MVR was not strongly associated with the mortality, morbidity, reoperation, or readmission. Morbidity, but not mortality, was more common in patients requiring bowel anastomosis (36 of 51 vs. 7 of 21, P = .003). Median survival from the diagnosis of carcinomatosis was not significantly different between the MVR and controls (32.8 months vs. 20.0 months, P = .787). Similarly, the median survival from the time of cytoreduction was not significantly different (20.2 vs. 14.3 months; P = .436). Independent predictors of survival in the Cox regression model were presence of residual disease >5 mm (hazard ratio = 4.5, P = .048), evidence of carcinomatosis on preoperative computed tomographic scan (6.1, P = .008), and initial diagnosis of cancer as systemic (2.6, P = .049). MVR had no statistically significant effect on survival (.441, P = .133)., Conclusions: Increased risk of complications is associated with the number of intestinal anastomoses, but not with multivisceral resection in CS-HIPEC. Long-term survival is not affected by the number of resected organs.

Purpose: Malignant mesothelioma (MM) arising in the peritoneal cavity is a rare neoplasm characterized by peritoneal progression and for which there are limited therapeutic options. We evaluated the peritoneal progression-free and overall survival (PFS and OS, respectively) for patients with peritoneal MM after surgical resection and regional chemotherapy., Patients and Methods: Forty-nine patients (28 males, 21 females; median age, 47 years; range, 16 to 76 years) with MM underwent laparotomy, tumor resection, continuous hyperthermic peritoneal perfusion with cisplatin (median dose 250 mg/m2), and a single postoperative intraperitoneal dwell of fluorouracil and paclitaxel (n = 35) on protocols approved by the Institutional Review Board. Standard techniques for actuarial analyses of potential prognostic variables (Kaplan-Meier method with two-tailed log-rank test and Cox proportional hazards model) were performed., Results: At a median potential follow-up of 28.3 months, median actuarial PFS is 17 months and actuarial OS is 92 months. Factors associated with improved PFS and OS by the Cox proportional hazards model were a history of previous debulking surgery, absence of deep tissue invasion, minimal residual disease after surgical resection (OS only), and age younger than 60 years (OS only)., Conclusion: Surgical resection and regional chemotherapy for MM results in durable PFS and OS. Favorable outcome is associated with age, tumor biology (selection of patients with a history of previous debulking), lack of invasive tumor growth, and minimal residual disease after tumor resection.