Increased Morbidity and Mortality After Hepatectomy for Colorectal Liver Metastases in Frail Patients is Largely Driven by Worse Outcomes After Minor Hepatectomy: It's Not "Just a Wedge".

BACKGROUND: Frailty is associated with postoperative mortality, but its significance after hepatectomy for colorectal liver metastases (CRLM) is poorly defined. This study evaluated the impact of frailty after hepatectomy for CRLM. METHODS: The study identified 8477 patients in National Surgical Quality Improvement Program databases from 2014 to 2019 and stratified them by frailty score using the risk analysis index as very frail (>90th percentile), frail (75th-90th percentile), or non-frail (< 75th percentile). Multivariate regression models determined the impact of frailty on perioperative outcomes, including by the extent of hepatectomy. RESULTS: The procedures performed were 2752 major hepatectomies (left hepatectomy, right hepatectomy, trisectionectomy) and 5725 minor hepatectomies (≤2 segments) for 870 (10.3%) very frail, 1680 (19.8%) frail, and 5927 (69.9%) non-frail patients. Postoperatively, the very frail and frail patients experienced more complications (very frail [41.8%], frail [35.1%], non-frail [31.0%]), which resulted in a longer hospital stay (very-frail [5.7 days], frail [5.8 days], non-frail [5.1 days]), a higher 30-day mortality (very-frail [2.2%], frail [1.3%], non-frail [0.5%]), and more discharges to a facility (very frail [6.8%], frail [3.7%], non-frail [2.6%]) (p < 0.05) although they underwent similarly extensive (major vs. minor) hepatectomies. In the multivariate analysis, frailty was independently associated with complications (very-frail [odds ratio {OR}, 1.70], frail [OR, 1.25]) and 30-day mortality (very-frail [OR, 4.24], frail [OR, 2.41]) (p < 0.05). After minor hepatectomy, the very frail and frail patients had significantly higher rates of complications and 30-day mortality than the non-frail patients, and in the multivariate analysis, frailty was independently associated with complications (very frail [OR, 1.97], frail [OR, 1.27]) and 30-day mortality (very frail [OR, 6.76], frail [OR, 3.47]) (p < 0.05) after minor hepatectomy. CONCLUSIONS: Frailty predicted significantly poorer outcomes after hepatectomy for CRLM, even after only a minor hepatectomy.

Cause and outcome of aborting a difficult laparoscopic cholecystectomy due to severe inflammation: a study of operative notes.

BACKGROUND: Upon encountering a difficult cholecystectomy in which, after a reasonable trial of dissection, anatomical identification has not been attained due to severe inflammation, and the risk of additional dissection is deemed to be hazardous, "bail-out" strategies are encouraged safety valves. One strategy is to abort the cholecystectomy and refer the patient to a HPB center for further management. METHODS: A retrospective review was conducted of cholecystectomies performed by HPB surgeons at our center between 2005 and 2019. We identified 63 patients who had an aborted cholecystectomy because of acute or chronic cholecystitis and were referred for additional care. Of these, operative notes and other clinical records were available for 43 patients who were included in this study. RESULTS: 42 cholecystectomies (98%) were started laparoscopically. 25 patients (58%) had chronic cholecystitis, and 18 (42%) had acute cholecystitis. 40 cases (93%) fell into the highest level of difficulty on the Nassar scale (Grade 4). Procedures were aborted at the following stages of dissection: in 10 patients (23%), none of the gallbladder was identified; in another 11 (26%), only the dome of gallbladder was identified; the body of the gallbladder was exposed in 13 (30%); and dissection of the hepatocystic triangle was attempted unsuccessfully in 9 (21%). Following referral to our center, 30 patients (70%) were managed with total cholecystectomy while in 13 cases (30%), subtotal cholecystectomy was performed. CONCLUSION: Aborting cholecystectomy and referring the patient to an HPB center is rarely needed but is an effective bail-out strategy for general surgeons encountering highly difficult operative conditions due to inflammation.

Improved outcomes with minimally invasive pancreaticoduodenectomy in patients with dilated pancreatic ducts: a prospective study.

BACKGROUND: Little is known about what factors predict better outcomes for patients who undergo minimally invasive pancreaticoduodenectomy (MIPD) versus open pancreaticoduodenectomy (OPD). We hypothesized that patients with dilated pancreatic ducts have improved postoperative outcomes with MIPD compared to OPD. METHODS: All patients undergoing pancreaticoduodenectomy were prospectively followed over a time period of 47 months, and perioperative and pathologic covariates and outcomes were compared. Ideal outcome after PD was defined as follows: (1) no complications, (2) postoperative length of stay < 7 days, and (3) negative (R0) margins on pathology. Patients with dilated pancreatic ducts (≥ 3 mm) who underwent MIPD were 1:3 propensity score-matched to patients with dilated ducts who underwent OPD and outcomes compared. Likewise, patients with non-dilated pancreatic ducts (< 3 mm) who underwent MIPD were 1:3 propensity score-matched to patients with non-dilated ducts who underwent OPD and outcomes were compared. RESULTS: 371 patients underwent PD-74 (19.9%) MIPD and 297 (80.1%) underwent OPD. Overall, patients who underwent MIPD had significantly less intraoperative blood loss. After 1:3 propensity score matching, patients with dilated pancreatic ducts who underwent MIPD (n = 45) had significantly lower overall complication and 90-day readmission rates compared to matched OPD patients (n = 135) with dilated ducts. Patients with dilated duct who underwent MIPD were more likely to have an ideal outcome than patients with OPD (29 vs 15%, p = 0.035). There were no significant differences in postoperative outcomes among propensity score-matched patients with non-dilated pancreatic ducts who underwent MIPD (n = 29) compared to matched patients undergoing OPD (n = 87) with non-dilated ducts. CONCLUSIONS: MIPD is safe with comparable perioperative outcomes to OPD. Patients with pancreatic ducts ≥ 3 mm appear to derive the most benefit from MIPD in terms of fewer complications, lower readmission rates, and higher likelihood of ideal outcome.

Enhanced recovery pathway after open pancreaticoduodenectomy reduces postoperative length of hospital stay without reducing composite length of stay.

BACKGROUND/PURPOSE: There is no data regarding the impact of enhanced recovery pathways (ERP) on composite length of stay (CLOS) after procedures with increased risk of morbidity and mortality, such as pancreaticoduodenectomy. METHODS: Patients undergoing open pancreaticoduodenectomy before and after implementation of ERP were prospectively followed for 90 days after surgery and complications were severity graded using the Modified Accordion Grading System. A retrospective analysis of patient outcomes were compared before and after instituting ERP. 1:1 propensity score matching was used to compare ERP patient outcomes to those of matched pre-ERP patients. CLOS is defined as postoperative length of hospital stay (PLOS) plus readmission length of hospital stay within 90 days after surgery. RESULTS: 494 patients underwent open pancreaticoduodenectomy - 359 pre-ERP and 135 ERP. In a 1:1 propensity-score-matched analysis of 110 matched pairs, ERP patients had significantly decreased superficial surgical site infections (5.5% vs 15.5% p = 0.015) and significantly increased rates of urinary retention (29.1% vs 7.3% p < 0.0001) compared to matched pre-ERP patients. However, overall complication rate and 90-day readmission rate were not significantly different between matched groups. Propensity score-matched ERP patients had significantly decreased PLOS (7 days vs 8 days p = 0.046) compared to matched pre-ERP patients, but CLOS was not significantly different (9 days vs 9.5 days p = 0.615). CONCLUSION: ERP may reduce PLOS but might not impact the total postoperative time spent in the hospital (i.e. CLOS) within 90 days after pancreaticoduodenectomy.

Less is more in the difficult gallbladder: recent evolution of subtotal cholecystectomy in a single HPB unit.

INTRODUCTION: Subtotal cholecystectomy (SC) is a technique to manage the difficult gallbladder and avoid hazardous dissection and biliary injury. Until recently it was used infrequently. However, because of reduced exposure to open total cholecystectomy in resident training, we recently adopted subtotal cholecystectomy as the bail-out procedure of choice for resident teaching. This study reports our experience and outcomes with subtotal cholecystectomy in the years immediately preceding adoption and since adoption. METHODS: A retrospective analysis was conducted of patients undergoing SC from July 2010 to June 2019. Outcomes, including bile leak, reoperation and need for additional procedures, were analyzed. Complications were graded by the Modified Accordion Grading Scale (MAGS). RESULTS: 1571 cholecystectomies were performed of which 71 were SC. Subtotal cholecystectomy patients had several indicators of difficulty including prior attempted cholecystectomy and previous cholecystostomy tube insertion. The most common indication for SC was marked inflammation in the hepatocystic triangle (51%). As our experience increased, fewer patients required open conversion to accomplish SC and SC was completed laparoscopically, usually subtotal fenestrating cholecystectomy (SFC). Most patients (85%) had a drain placed and 28% were discharged with a drain. The highest MAGS complication observed was grade 3 (11 patients, 15%). Six patients had a bile leak from the cystic duct resolved by ERCP. At mean follow-up of about 1 year no patient returned with recurrent symptoms. CONCLUSIONS: Subtotal fenestrating cholecystectomy is a useful technique to avoid biliary injury in the difficult gallbladder and can be performed with very satisfactory rates of bile fistula, ERCP, and reoperation.

Feasibility and safety of non-operative management of portal vein aneurysms: a thirty-five year experience.

BACKGROUND: Portal vein aneurysms (PVAs) are rare, though clinically challenging with post-operative mortality approaching 20% and no evidence-based treatment guidelines. We aim to describe our experience with PVAs and recommend optimum management strategies. METHODS: Demographics and clinical details of patients with PVAs admitted to our institution from 1984 to 2019 were reviewed. Clinical presentation, management and outcomes were analysed. RESULTS: PVAs were identified in 18 patients (median age 56 years, range 20-101 years; 13 female); 10 were incidental and 8 diagnosed during abdominal pain work-up. Median aneurysm diameter at diagnosis was 3.4 cm (1.8-5.5 cm), remaining unchanged at 3.5 cm (1.9-4.8 cm) during a 3.2-year follow-up (4 months-31 years). Aneurysm sites were the main portal vein (n = 12), porto-splenic-junction (n = 3), splenic-SMV-junction (n = 2) and right portal vein (n = 1). Thrombosis occurred in 4 patients; 3 developed clinically insignificant cavernous transformation. Two patients underwent surgery for abdominal pain. Postoperatively, one developed PV thrombosis and PVA recurrence occurred in the second. No aneurysm ruptures or mortalities occurred during follow-up. CONCLUSION: PVAs follow a clinically indolent course with structural stability and minimal complications over time. Non-operative management is feasible for most patients. Abdominal pain, large size or thrombosis don't appear to confer additional risks and should not, in isolation, merit surgical intervention.

Safe Cholecystectomy Multi-society Practice Guideline and State of the Art Consensus Conference on Prevention of Bile Duct Injury During Cholecystectomy.

BACKGROUND: BDI is the most common serious complication of laparoscopic cholecystectomy. To address this problem, a multi-society consensus conference was held to develop evidenced-based recommendations for safe cholecystectomy and prevention of BDI. METHODS: Literature reviews were conducted for 18 key questions across 6 broad topics around cholecystectomy directed by a steering group and subject experts from 5 surgical societies (Society of Gastrointestinal and Endoscopic Surgeons, Americas Hepato-Pancreato-Biliary Association, International Hepato-Pancreato-Biliary Association, Society for Surgery of the Alimentary Tract, and European Association for Endoscopic Surgery). Evidence-based recommendations were formulated using the grading of recommendations assessment, development, and evaluation methodology. When evidence-based recommendations could not be made, expert opinion was documented. A number of recommendations for future research were also documented. Recommendations were presented at a consensus meeting in October 2018 and were voted on by an international panel of 25 experts with greater than 80% agreement considered consensus. RESULTS: Consensus was reached on 17 of 18 questions by the guideline development group and expert panel with high concordance from audience participation. Most recommendations were conditional due to low certainty of evidence. Strong recommendations were made for (1) use of intraoperative biliary imaging for uncertainty of anatomy or suspicion of biliary injury; and (2) referral of patients with confirmed or suspected BDI to an experienced surgeon/multispecialty hepatobiliary team. CONCLUSIONS: These consensus recommendations should provide guidance to surgeons, training programs, hospitals, and professional societies for strategies that have the potential to reduce BDIs and positively impact patient outcomes. Development of clinical and educational research initiatives based on these recommendations may drive further improvement in the quality of surgical care for patients undergoing cholecystectomy.

Safe cholecystectomy multi-society practice guideline and state-of-the-art consensus conference on prevention of bile duct injury during cholecystectomy.

BACKGROUND: Bile duct injury (BDI) is the most common serious complication of laparoscopic cholecystectomy. To address this problem, a multi-society consensus conference was held to develop evidenced-based recommendations for safe cholecystectomy and prevention of BDI. METHODS: Literature reviews were conducted for 18 key questions across six broad topics around cholecystectomy directed by a steering group and subject experts from five surgical societies (SAGES, AHPBA IHPBA, SSAT, and EAES). Evidence-based recommendations were formulated using the GRADE methodology. When evidence-based recommendations could not be made, expert opinion was documented. A number of recommendations for future research were also documented. Recommendations were presented at a consensus meeting in October 2018 and were voted on by an international panel of 25 experts with greater than 80% agreement considered consensus. RESULTS: Consensus was reached on 17 of 18 questions by the Guideline Development Group (GDG) and expert panel with high concordance from audience participation. Most recommendations were conditional due to low certainty of evidence. Strong recommendations were made for (1) use of intraoperative biliary imaging for uncertainty of anatomy or suspicion of biliary injury; and (2) referral of patients with confirmed or suspected BDI to an experienced surgeon/multispecialty hepatobiliary team. CONCLUSION: These consensus recommendations should provide guidance to surgeons, training programs, hospitals, and professional societies for strategies that have the potential to reduce BDIs and positively impact patient outcomes. Development of clinical and educational research initiatives based on these recommendations may drive further improvement in the quality of surgical care for patients undergoing cholecystectomy.

A 22-year experience with pancreatic resection for metastatic renal cell carcinoma.

BACKGROUND: The pancreas is a rare site of metastases, although metastatic renal cell carcinoma (mRCC) is the most commonly reported secondary tumor. Pancreatectomy has been described in selected patients with localized metastases, but long-term benefit remains poorly defined. METHODS: A retrospective review of a prospectively maintained database was performed to evaluate the outcomes of patients undergoing pancreatectomy for mRCC at a tertiary care center from 1995-2017. Postoperative complications were evaluated using the Modified Accordion Grading System (MAGS) and Kaplan-Meier curves and log-rank tests were utilized for survival analysis. RESULTS: 29 patients underwent pancreatectomy for mRCC including 15 distal pancreatectomies (DP), 10 pancreaticoduodenectomies (PD) and 4 total-pancreatectomies (TP). The mean age was 67 ± 8 years, and 15 were male. The median time from index nephrectomy to pancreatectomy was 8 (IQR: 3.72-12.2) years. There was no 90 Day post-pancreatectomy mortalities and the morbidity incidence included 13 Minor MAGS and 8 Severe MAGS complications respectively. Post-pancreatectomy disease specific survival at 2- and 4-years were 89% and 80% with 12 patients being alive at last follow up. CONCLUSIONS: Pancreatic resection can be safely performed in select patients with localized mRCC with favorable long-term outcomes.

Thunderbeat™ Integrated Bipolar and Ultrasonic Forceps in the Whipple Procedure: A Prospective Randomized Trial.

Thunderbeat™ is a device that uses both ultrasonic and advanced bipolar energies to achieve hemostasis. It has been evaluated in a variety of clinical contexts, but no literature exists regarding its application to pancreatic surgery. Using a prospective, randomized controlled trial, we evaluated its safety and efficacy in the Whipple procedure. Thirty-two participants were enrolled in the study. The Thunderbeat™ device during the Whipple procedure showed similar safety profile compared to standard of care.

Association of preoperative monocyte-to-lymphocyte and neutrophil-to-lymphocyte ratio with recurrence-free and overall survival after resection of pancreatic neuroendocrine tumors (US-NETSG).

BACKGROUND: Preoperative systemic inflammatory response plays a crucial role in tumorigenesis, progression, and prognosis; and neutrophil, monocyte, and lymphocyte counts serve as important biomarkers. An altered monocyte-to-lymphocyte ratio (MLR) and neutrophil-to-lymphocyte ratio (NLR) has been reported to be associated with a favorable prognosis for certain hematologic malignancies and breast cancer. The aim of this study was to investigate the prognostic significance of MLR, NLR in patients with resectable PNETs. METHODS: Patients undergoing surgery for PNETs between 2000 and 2016 were identified using a large, multi-center database. NLR and MLR were calculated and Contal and O'Quigley analysis was used to determine the optimal cutoff value. RESULTS: A total of 620 patients were included in the analytic cohort. The prognostic implications of blood count parameters were evaluated in both univariate and multivariate analysis. The univariate analysis revealed that low MLR and NLR is associated with significantly improved overall survival (OS; P < .01) and recurrence-free survival (RFS; P < .01). On multivariate analysis, in addition to tumor size and grade, NLR was an independent predictor of improved OS and RFS. CONCLUSION: In addition to established tumor-specific factors, preoperative NLR levels can serve as a valuable biomarker that can be used as a predictor of OS and RFS after resection of PNETs.

Utility of Endoscopic Ultrasound in Evaluating Local Recurrence After Surgery for Pancreatic Cancer.

Pancreatic adenocarcinoma recurrence after surgery (PARaS) is associated with poor outcomes. PARaS is locoregional in 50%-80%, effecting the resection bed and adjacent lymphatics.1-3 Detection of PARaS via endoscopic ultrasound (EUS) is challenging because recurrent malignancy is difficult to distinguish from normal postoperative changes. Diagnosing PARaS is important, because salvage chemotherapy/radiation improves survival.4,5 The purpose of this investigation is to determine the clinical utility of EUS fine-needle aspiration (FNA) in patients with suspected PARaS.

Adjuvant therapy is associated with improved survival after curative resection for hilar cholangiocarcinoma: A multi-institution analysis from the U.S. extrahepatic biliary malignancy consortium.

BACKGROUND: Curative-intent treatment for localized hilar cholangiocarcinoma (HC) requires surgical resection. However, the effect of adjuvant therapy (AT) on survival is unclear. We analyzed the impact of AT on overall (OS) and recurrence free survival (RFS) in patients undergoing curative resection. METHODS: We reviewed patients with resected HC between 2000 and 2015 from the ten institutions participating in the U.S. Extrahepatic Biliary Malignancy Consortium. We analyzed the impact of AT on RFS and OS. The probability of RFS and OS were calculated in the method of Kaplan and Meier and analyzed using multivariate Cox regression analysis. RESULTS: A total of 249 patients underwent curative resection for HC. Patients who received AT and those who did not had similar demographic and preoperative features. In a multivariate Cox regression analysis, AT conferred a significant protective effect on OS (HR 0.58, P = 0.013), and this was maintained in a propensity matched analysis (HR 0.66, P = 0.033). The protective effect of AT remained significant when node negative patients were excluded (HR 0.28, P = 0.001), while it disappeared (HR 0.76, P = 0.260) when node positive patients were excluded. CONCLUSIONS: AT should be strongly considered after curative-intent resection for HC, particularly in patients with node positive disease.

The importance of early recognition in management of ERCP-related perforations.

BACKGROUND: Iatrogenic perforations related to endoscopic retrograde cholangiopancreatography (ERCP) are rare events, carrying with it a mortality of up to 8%. Given the rarity of this adverse event, there remains limited data and continued uncertainties when choosing therapeutic strategies. Our aims were to evaluate the management of ERCP-related perforations and compare outcomes based on timing of recognition. METHODS: The endoscopic databases of two tertiary care centers were interrogated to identify consecutive adult patients who sustained ERCP-related perforation over a 10-year period from 2006 to 2016. Electronic medical records were reviewed to extract demographic data, perforation type, management strategies, clinical data, and patient outcomes. RESULTS: 14,045 ERCP's were performed during our 10-year study period. Sixty-three patients (average age 62.3 ± 2.38 years, 76% female) with ERCP-related perforations were included. Stapfer I perforations were found in 14 (22.2%) patients, Stapfer II in 24 (38.1%), and Stapfer III and IV perforations were identified in 16 (25.4%) and 9 (14.28%), respectively. Forty-seven (74.6%) perforations were recognized immediately during the ERCP, whereas 16 (25.4%) were recognized late. Endoscopic therapy was attempted in 35 patients in whom perforations were identified immediately, and was technically successful in 33 (94.3%). In all, 4 (1 immediate/ 3 delayed) patients required percutaneous drainage and 9 (5 immediate/ 4 delayed) surgery. Length of hospital stay, ICU admission were significantly shorter and incidence of SIRS was significantly lower when perforation was recognized immediately. CONCLUSIONS: Immediate recognition of ERCP-related perforations leads to more favorable patient outcomes; with lower incidence of SIRS, less need for ICU level care, and shorter hospital stay.

Proposed standards for reporting outcomes of treating biliary injuries.

BACKGROUND: There is no standard nor widely accepted way of reporting outcomes of treatment of biliary injuries. This hinders comparison of results among approaches and among centers. This paper presents a proposal to standardize terminology and reporting of results of treating biliary injuries. METHODS: The proposal was developed by an international group of surgeons, biliary endoscopists and interventional radiologists. The method is based on the concept of "patency" and is similar to the approach used to create reporting standards for arteriovenous hemodialysis access. RESULTS: The group considered definitions and gradings under the following headings: Definition of Patency, Definition of Index Treatment Periods, Grading of Severity of Biliary Injury, Grading of Patency, Metrics, Comparison of Surgical to Non Surgical Treatments and Presentation of Case Series. CONCLUSIONS: A standard procedure for reporting outcomes of treating biliary injuries has been produced. It is applicable to presenting results of treatment by surgery, endoscopy, and interventional radiology.

Outcomes after vascular resection during curative-intent resection for hilar cholangiocarcinoma: a multi-institution study from the US extrahepatic biliary malignancy consortium.

BACKGROUND: Surgical resection is the cornerstone of curative-intent therapy for patients with hilar cholangiocarcinoma (HC). The role of vascular resection (VR) in the treatment of HC in western centres is not well defined. METHODS: Utilizing data from the U.S. Extrahepatic Biliary Malignancy Consortium, patients were grouped into those who underwent resection for HC based on VR status: no VR, portal vein resection (PVR), or hepatic artery resection (HAR). Perioperative and long-term survival outcomes were analyzed. RESULTS: Between 1998 and 2015, 201 patients underwent resection for HC, of which 31 (15%) underwent VR: 19 patients (9%) underwent PVR alone and 12 patients (6%) underwent HAR either with (n = 2) or without PVR (n = 10). Patients selected for VR tended to be younger with higher stage disease. Rates of postoperative complications and 30-day mortality were similar when stratified by vascular resection status. On multivariate analysis, receipt of PVR or HAR did not significantly affect OS or RFS. CONCLUSION: In a modern, multi-institutional cohort of patients undergoing curative-intent resection for HC, VR appears to be a safe procedure in a highly selected subset, although long-term survival outcomes appear equivalent. VR should be considered only in select patients based on tumor and patient characteristics.

Interferon-based chemoradiation followed by gemcitabine for resected pancreatic adenocarcinoma: long-term follow-up.

To report long-term follow up of a phase II, single-arm trial of resectable pancreatic ductal adenocarcinoma (PDAC) treated with adjuvant interferon-based chemoradiation followed by gemcitabine to determine survival, recurrence, and complications. METHODS: From 2002 to 2005, 53 patients with PDAC underwent pancreaticoduodenectomy and received adjuvant interferon-based chemoradiation consisting of external-beam irradiation and simultaneous 3-drug chemotherapy of continuous daily 5-fluorouracil infusion, weekly intravenous bolus cisplatin, and subcutaneous interferon-α, followed by two months of weekly intravenous gemcitabine. RESULTS: Actual overall survival for the 5- and 10-year periods were 26% and 10%, respectively, with a median overall survival of 25 months (95% CI: 16.4-38.5). Adverse prognostic factors on multivariate analysis were positive tumor margin (p < 0.035), lymphovascular invasion (p < 0.015), and perineural invasion (p < 0.026). Median time to recurrence was 11 months. Positive tumor margin was associated with lymph node involvement (p < 0.005), portal vein resection (p < 0.038), and metastases (p < 0.018). Late complications were frequent and predominated by gastrointestinal and infectious complications. CONCLUSIONS: Adjuvant interferon-based chemoradiation for PDAC improves long-term survival compared to standard therapy. However, recurrence rates and long-term complications remain high, thus further studies are indicated to assess patient characteristics that indicate a favorable treatment profile.

Targeting tumour-associated macrophages with CCR2 inhibition in combination with FOLFIRINOX in patients with borderline resectable and locally advanced pancreatic cancer: a single-centre, open-label, dose-finding, non-randomised, phase 1b trial.

BACKGROUND: In pancreatic ductal adenocarcinoma, the CCL2-CCR2 chemokine axis is used to recruit tumour-associated macrophages for construction of an immunosuppressive tumour microenvironment. This pathway has prognostic implications in pancreatic cancer, and blockade of CCR2 restores anti-tumour immunity in preclinical models. We aimed to establish the safety, tolerability, and recommended phase 2 oral dose of the CCR2 inhibitor PF-04136309 in combination with FOLFIRINOX chemotherapy (oxaliplatin and irinotecan plus leucovorin and fluorouracil). METHODS: We did this open-label, dose-finding, non-randomised, phase 1b study at one centre in the USA. We enrolled treatment-naive patients aged 18 years or older with borderline resectable or locally advanced biopsy-proven pancreatic ductal adenocarcinoma, an Eastern Cooperative Oncology Group performance status of 1 or less, measurable disease as defined by Response Evaluation Criteria in Solid Tumors version 1.1, and normal end-organ function. Patients were allocated to receive either FOLFIRINOX alone (oxaliplatin 85 mg/m(2), irinotecan 180 mg/m(2), leucovorin 400 mg/m(2), and bolus fluorouracil 400 mg/m(2), followed by 2400 mg/m(2) 46-h continuous infusion), administered every 2 weeks for a total of six treatment cycles, or in combination with oral PF-04136309, administered at a starting dose of 500 mg twice daily in a standard 3 + 3 dose de-escalation design. Both FOLFIRINOX and PF-04136309 were simultaneously initiated with a total treatment duration of 12 weeks. The primary endpoints were the safety, tolerability, and recommended phase 2 dose of PF-04136309 plus FOLFIRINOX, with an expansion phase planned at the recommended dose. We analysed the primary outcome by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01413022. RESULTS: Between April 19, 2012, and Nov 12, 2014, we treated 47 patients with FOLFIRINOX alone (n=8) or with FOLFIRINOX plus PF-04136309 (n=39). One patient had a dose-limiting toxic effect in the dose de-escalation group receiving FOLFIRINOX plus PF-04136309 at 500 mg twice daily (n=6); this dose was established as the recommended phase 2 dose. We pooled patients in the expansion-phase group (n=33) with those in the dose de-escalation group that received PF-04136309 at the recommended phase 2 dose for assessment of treatment-related toxicity. Six (75%) of the eight patients receiving FOLFIRINOX alone were assessed for treatment toxicity, after exclusion of two (25%) patients due to insurance coverage issues. The median duration of follow-up for treatment toxicity was 72·0 days (IQR 49·5-89·0) in the FOLFIRINOX alone group and 77·0 days (70·0-90·5) in the FOLFIRINOX plus PF-04136309 group. No treatment-related deaths occurred. Two (5%) patients in the FOLFIRINOX plus PF-04136309 group stopped treatment earlier than planned due to treatment-related toxic effects. Grade 3 or higher adverse events reported in at least 10% of the patients receiving PF-04136309 included neutropenia (n=27), febrile neutropenia (n=7), lymphopenia (n=4), diarrhoea (n=6), and hypokalaemia (n=7). Grade 3 or higher adverse events reported in at least 10% of patients receiving FOLFIRINOX alone were neutropenia (n=6), febrile neutropenia (n=1), anaemia (n=2), lymphopenia (n=1), diarrhoea (n=2), hypoalbuminaemia (n=1), and hypokalaemia (n=3). Therapy was terminated because of treatment-related toxicity in one (17%) of the six patients receiving FOLFIRINOX alone. 16 (49%) of 33 patients receiving FOLFIRINOX plus PF-04136309 who had undergone repeat imaging achieved an objective tumour response, with local tumour control achieved in 32 (97%) patients. In the FOLFIRINOX alone group, none of the five patients with repeat imaging achieved an objective response, although four (80%) of those patients achieved stable disease. INTERPRETATION: CCR2-targeted therapy with PF-04136309 in combination with FOLFIRINOX is safe and tolerable. FUNDING: Washington University-Pfizer Biomedical Collaborative.

Randomized controlled trial of irinotecan drug-eluting beads with simultaneous FOLFOX and bevacizumab for patients with unresectable colorectal liver-limited metastasis.

BACKGROUND: Reports have demonstrated the superior activity of combining both irinotecan and oxaliplatin (FOLFOXIRI) therapy. An option for gaining similar benefits with less toxicity would be the administration of irinotecan through a hepatic artery approach. The aim of this study was to assess the response and adverse event rates for irinotecan drug-eluting beads (DEBIRI) with folinic acid, 5-fluorouracil, and oxaliplatin (FOLFOX) and bevacizumab as a first-line treatment for unresectable colorectal liver metastasis. METHODS: Patients with colorectal liver metastases were randomly assigned to modified FOLFOX (mFOLFOX) and bevacizumab or mFOLFOX6, bevacizumab, and DEBIRI (FOLFOX-DEBIRI). The primary endpoint was the response rate. The secondary endpoints were adverse events, the rate of conversion to resection, and progression-free survival. RESULTS: The intention-to-treat population comprised 70 patients: 10 patients in the pilot and then 30 patients randomly assigned to the FOLFOX-DEBIRI arm and 30 patients randomly assigned to the FOLFOX/bevacizumab arm. The 2 groups were similar with respect to the extent of liver involvement (30% vs 30%), but a greater percentage of patients in the FOLFOX-DEBIRI arm had an Eastern Cooperative Oncology Group performance status of 1 or 2 (57% vs 31%) and extrahepatic disease (56% vs 32%, P = .02). The median numbers of chemotherapy cycles were similar (10 vs 9), and there were similar rates of grade 3/4 adverse events (54% for the FOLFOX-DEBIRI group vs 46% for the FOLFOX/bevacizumab group). The overall response rate was significantly greater in the FOLFOX-DEBIRI arm versus the FOLFOX/bevacizumab arm at 2 (78% vs 54%, P = .02), 4 (95% vs 70%, P = .03), and 6 months (76% vs 60%, P = .05). There was significantly more downsizing to resection in the FOLFOX-DEBIRI arm versus the FOLFOX/bevacizumab arm (35% vs 16%, P = .05), and there was improved median progression-free survival (15.3 vs 7.6 months). CONCLUSIONS: The simultaneous administration of mFOLFOX6 (with or without bevacizumab) and DEBIRI through the hepatic artery (FOLFOX-DEBIRI) is safe and does not cause treatment delays or increase the systemic toxicity of chemotherapy. This strategy leads to improved overall response rates, improved hepatic progression-free survival, and more durable overall progression-free survival in patients downsized to resection.