Contemporary management of pancreas cancer in older people.

As the population of western countries is aging, the number of patients diagnosed with cancer is growing. Therefore older people, more susceptible to develop pancreatic malignancy, will likely represent the prototype of a pancreatic cancer patient in the near future. Diagnostic modalities utilised for younger patients are also applicable for older individuals. There is accumulative evidence that biological age is not an independent factor predicting poor outcome in elderly patients with resectable disease undergoing surgery, however increased postoperative morbidity and mortality within the elderly group has also been reported. Adjuvant chemotherapy should be offered in all patients with good performance status regardless of their age. Palliative measures for unresectable tumours including relief from biliary and duodenal obstruction as well as chemotherapy should be considered in non-frail patients with reasonable life expectancy. Palliative chemotherapy options are FOLFIRINOX or gemcitabine/nab-paclitaxel for patients with good performance status (0-1) and gemcitabine alone for patients with performance status 2-3. The cornerstone for improving the outcomes of the elderly age group is careful patient selection and perioperative optimization of those who have indication for surgery. Patients and their carers should be involved in the decision making process with emphasis on the expected functional recovery after the proposed treatment modality. The presence of geriatricians in the multidisciplinary team meetings is crucial in order to identify the optimal treatment pathway for elderly patients. Geriatric input regarding peri-habilitation pathways to improve surgical outcomes, to decrease mortality and to expedite patients' functional recovery is highly recommended.

Systemic chemotherapy with or without cetuximab in patients with resectable colorectal liver metastasis (New EPOC): long-term results of a multicentre, randomised, controlled, phase 3 trial.

BACKGROUND: The interim analysis of the multicentre New EPOC trial in patients with resectable colorectal liver metastasis showed a significant reduction in progression-free survival in patients allocated to cetuximab plus chemotherapy compared with those given chemotherapy alone. The focus of the present analysis was to assess the effect on overall survival. METHODS: New EPOC was a multicentre, open-label, randomised, controlled, phase 3 trial. Adult patients (aged ≥18 years) with KRAS wild-type (codons 12, 13, and 61) resectable or suboptimally resectable colorectal liver metastases and a WHO performance status of 0-2 were randomly assigned (1:1) to receive chemotherapy with or without cetuximab before and after liver resection. Randomisation was done centrally with minimisation factors of surgical centre, poor prognosis cancer, and previous adjuvant treatment with oxaliplatin. Chemotherapy consisted of oxaliplatin 85 mg/m2 administered intravenously over 2 h, l-folinic acid (175 mg flat dose administered intravenously over 2 h) or d,l-folinic acid (350 mg flat dose administered intravenously over 2 h), and fluorouracil bolus 400 mg/m2 administered intravenously over 5 min, followed by a 46 h infusion of fluorouracil 2400 mg/m2 repeated every 2 weeks (regimen one), or oxaliplatin 130 mg/m2 administered intravenously over 2 h and oral capecitabine 1000 mg/m2 twice daily on days 1-14 repeated every 3 weeks (regimen two). Patients who had received adjuvant oxaliplatin could receive irinotecan 180 mg/m2 intravenously over 30 min with fluorouracil instead of oxaliplatin (regimen three). Cetuximab was given intravenously, 500 mg/m2 every 2 weeks with regimen one and three or a loading dose of 400 mg/m2 followed by a weekly infusion of 250 mg/m2 with regimen two. The primary endpoint of progression-free survival was published previously. Secondary endpoints were overall survival, preoperative response, pathological resection status, and safety. Trial recruitment was halted prematurely on the advice of the Trial Steering Committee on Nov 1, 2012. All analyses (except safety) were done on the intention-to-treat population. Safety analyses included all randomly assigned patients. This trial is registered with ISRCTN, number 22944367. FINDINGS: Between Feb 26, 2007, and Oct 12, 2012, 257 eligible patients were randomly assigned to chemotherapy with cetuximab (n=129) or without cetuximab (n=128). This analysis was carried out 5 years after the last patient was recruited, as defined in the protocol, at a median follow-up of 66·7 months (IQR 58·0-77·5). Median progression-free survival was 22·2 months (95% CI 18·3-26·8) in the chemotherapy alone group and 15·5 months (13·8-19·0) in the chemotherapy plus cetuximab group (hazard ratio [HR] 1·17, 95% CI 0·87-1·56; p=0·304). Median overall survival was 81·0 months (59·6 to not reached) in the chemotherapy alone group and 55·4 months (43·5-71·5) in the chemotherapy plus cetuximab group (HR 1·45, 1·02-2·05; p=0·036). There was no significant difference in the secondary outcomes of preoperative response or pathological resection status between groups. Five deaths might have been treatment-related (one in the chemotherapy alone group and four in the chemotherapy plus cetuximab group). The most common grade 3-4 adverse events reported were: neutrophil count decreased (26 [19%] of 134 in the chemotherapy alone group vs 21 [15%] of 137 in the chemotherapy plus cetuximab group), diarrhoea (13 [10%] vs 14 [10%]), skin rash (one [1%] vs 22 [16%]), thromboembolic events (ten [7%] vs 11 [8%]), lethargy (ten [7%] vs nine [7%]), oral mucositis (three [2%] vs 14 [10%]), vomiting (seven [5%] vs seven [5%]), peripheral neuropathy (eight [6%] vs five [4%]), and pain (six [4%] vs six [4%]). INTERPRETATION: Although the addition of cetuximab to chemotherapy improves the overall survival in some studies in patients with advanced, inoperable metastatic disease, its use in the perioperative setting in patients with operable disease confers a significant disadvantage in terms of overall survival. Cetuximab should not be used in this setting. FUNDING: Cancer Research UK.

Colorectal cancer with Synchronous liver-limited Metastases: the protocol of an Inception Cohort study (CoSMIC).

INTRODUCTION: Colorectal cancer is the fourth most common cancer in the UK and an important cause of cancer-related death. In 20% of patients, there is metastasis to the liver or beyond at the time of diagnosis. The management of synchronous disease is complex. Conventional surgery removes the colorectal primary first, followed by chemotherapy, with resection of liver metastases as a final step. Advances in the availability and safety of liver surgery, anaesthesia and critical care have made two alternative options feasible. The first is synchronous resection of the primary and liver metastases. The second is resection of the metastatic disease as the first step, termed the reverse or liver-first approach. Currently, evidence is inadequate to inform the selection of care pathway for patients with colorectal cancer and synchronous liver-limited metastases. Specifically, optimal pathways are not defined and there is a dearth of prospectively recorded cohort-defining factors influencing treatment selection or outcome. METHODS AND ANALYSIS: Colorectal cancer with Synchronous liver-limited Metastases: an Inception Cohort (CoSMIC) is an inception cohort study of patients with a new diagnosis of colorectal cancer with synchronous liver-limited metastases. The sequence of treatment received, and factors influencing treatment decisions, will be evaluated against European Society of Medical Oncology guidelines. Clinical data will be collected, and quality of life, morbidity, mortality and long-term outcome compared for different treatment sequences adjusted for prognostic factors. Disease-free survival or progression will be measured at 1, 2 and 5 years. A nested qualitative study will ascertain patient experiences and clinician perspectives on delivery of care. ETHICS AND DISSEMINATION: The full study protocol was independently peer reviewed by Professor Kees de Jong (University of Maastricht, Holland). CoSMIC has ethical approval from the National Health Service Research Ethics Committee (14/NW/1397). Results will be disseminated to healthcare professionals and patient groups, and may be used to design a definitive trial addressing areas of equipoise in treatment pathways, as well as optimising current pathways to improve outcomes and experiences. TRIAL REGISTRATION NUMBER: NCT02456285, pre-results.

Long-term outcome of patients with chronic pancreatitis treated with micronutrient antioxidant therapy.

BACKGROUND: Micronutrient antioxidant therapy did not relieve pain in a European randomized trial of patients with chronic pancreatitis without malnutrition. However, intervention was undertaken only for 6 months leaving unanswered the question of whether long-term antioxidant therapy may modulate chronic pancreatitis. The aim of this study is to assess the outcome of long-term use of micronutrient antioxidant therapy in patients with chronic pancreatitis. METHODS: This is a single center clinical cohort report of patients with chronic pancreatitis prescribed micronutrient antioxidant therapy and followed for up to 10 years. Data were collected on demographic detail, clinic pain assessment, insulin requirements, interventions and outcome. RESULTS: A group of 30 patients with a diagnosis of chronic pancreatitis constitute the study population. Median age at time of diagnosis was 40 years (range 14-66); 19 (63%) were male and the median duration of symptoms was 2 years (range 0-18). Alcohol was the dominant cause in 22 (73%) patients and 16 (53%) patients were Cambridge stage 1. Twenty-four (80%) patients had pain at presentation. During antioxidant treatment of 4 years (range 1-10), pain decreased but the proportion with abdominal pain compared to those who were pain-free remained constant (P=0.16; two-way ANOVA with Bonferroni correction). There was a significant increase in requirement for insulin (P=0.028) with time together with use of both endoscopic and surgical interventions. CONCLUSIONS: This is the first study to report long-term disease-specific outcome in patients with chronic pancreatitis prescribed micronutrient antioxidant therapy. There appears to be no effect of intervention on outcome.

The Plasma Membrane Calcium Pump in Pancreatic Cancer Cells Exhibiting the Warburg Effect Relies on Glycolytic ATP.

Evidence suggests that the plasma membrane Ca(2+)-ATPase (PMCA), which is critical for maintaining a low intracellular Ca(2+) concentration ([Ca(2+)]i), utilizes glycolytically derived ATP in pancreatic ductal adenocarcinoma (PDAC) and that inhibition of glycolysis in PDAC cell lines results in ATP depletion, PMCA inhibition, and an irreversible [Ca(2+)]i overload. We explored whether this is a specific weakness of highly glycolytic PDAC by shifting PDAC cell (MIA PaCa-2 and PANC-1) metabolism from a highly glycolytic phenotype toward mitochondrial metabolism and assessing the effects of mitochondrial versus glycolytic inhibitors on ATP depletion, PMCA inhibition, and [Ca(2+)]i overload. The highly glycolytic phenotype of these cells was first reversed by depriving MIA PaCa-2 and PANC-1 cells of glucose and supplementing with α-ketoisocaproate or galactose. These culture conditions resulted in a significant decrease in both glycolytic flux and proliferation rate, and conferred resistance to ATP depletion by glycolytic inhibition while sensitizing cells to mitochondrial inhibition. Moreover, in direct contrast to cells exhibiting a high glycolytic rate, glycolytic inhibition had no effect on PMCA activity and resting [Ca(2+)]i in α-ketoisocaproate- and galactose-cultured cells, suggesting that the glycolytic dependence of the PMCA is a specific vulnerability of PDAC cells exhibiting the Warburg phenotype.

Contemporary management of perihilar cholangiocarcinoma in a nontransplant hepatopancreatobiliary center.

BACKGROUND: Perihilar cholangiocarcinoma (PHCC) is a rare tumor with a poor prognosis. Outcomes may be optimized by centralization. Recent trends suggest further improvement by localization to transplant centers. This study examines outcomes from the management of PHCC in a nontransplant hepatopancreatobiliary center. METHODS: Data were collected prospectively from patients undergoing treatment for PHCC from October 1999 to May 2011. Twenty-four patients underwent surgery. A further 54 patients had inoperable PHCC. Outcome data are reported. RESULTS: Twenty-two of 24 patients required liver resection with histological R0 status in 12 (50%). In-hospital mortality occurred in two (8%). The mean survival of patients undergoing resection was 39 (95% CI: 16-61) months. The mean survival of nonresected patients was 5 (95% CI: 3-7) months (P<0.0001; log-rank; Mantel-Cox test). CONCLUSION: Currently acceptable standards of holistic care for patients with PHCC can be provided in a nontransplant regional hepatopancreatobiliary center. Further centralization may improve resection volumes and allow more patients to benefit from extended liver resection techniques.

Antioxidant therapy does not reduce pain in patients with chronic pancreatitis: the ANTICIPATE study.

BACKGROUND & AIMS: We investigated whether antioxidant therapy reduces pain and improves quality of life in patients with chronic pancreatitis. METHODS: We performed a double-blind, randomized, controlled trial that compared the effects of antioxidant therapy with placebo in 70 patients with chronic pancreatitis. Patients provided 1 month of baseline data and were followed for 6 months while receiving either antioxidant therapy (Antox version 1.2, Pharma Nord, Morpeth, UK) or matched placebo (2 tablets, 3 times/day). The primary analysis was baseline-adjusted change in pain score at 6 months, assessed by an 11-point numeric rating scale. Secondary analyses included alternative assessments of clinical and diary pain scores, scores on quality-of-life tests (the European Organization for Research and Treatment of Cancer [EORTC-QLQ-C30], Quality of Life Questionnaire-Pancreatic modification [QLQ-PAN28], European Quality of Life questionnaire [EuroQOL EQ-5D], and European Quality of Life questionnaire - Visual Analog Score [EQ-VAS]), levels of antioxidants, use of opiates, and adverse events. Analyses, reported by intention to treat, were prospectively defined by protocol. RESULTS: After 6 months, pain scores reported to the clinic were reduced by 1.97 from baseline in the placebo group and by 2.33 in the antioxidant group but were similar between groups (-0.36; 95% confidence interval [CI], -1.44 to 0.72; P = .509). Average daily pain scores from diaries were also similar (3.05 for the placebo group and 2.93 for the antioxidant group, a difference of 0.11; 95% CI, 1.05-0.82; P = .808). Measures of quality of life were similar between groups, as was opiate use and number of hospital admissions and outpatient visits. Blood levels of vitamin C and E, ß-carotene, and selenium were increased significantly in the antioxidant group. CONCLUSIONS: Administration of antioxidants to patients with painful chronic pancreatitis of predominantly alcoholic origin does not reduce pain or improve quality of life, despite causing a sustained increase in blood levels of antioxidants.

Green tea polyphenols ameliorate pancreatic injury in cerulein-induced murine acute pancreatitis.

OBJECTIVE: Green tea polyphenols (GTPs) are naturally occurring antioxidants acting through pathways that include reactive oxygen species and nuclear factor kappa B (NF-kappaB). This study investigates the effect of GTPs in a cerulein-induced murine model of acute pancreatitis (AP). METHODS: Male CD mice (median weight, 37.7 g) were divided into 4 groups: mice administered with cerulein alone, cerulein and GTP, saline alone (sham), and GTP alone. Acute pancreatitis was induced by serial intraperitoneal administration of cerulein (50 microg/kg, x6). Green tea polyphenol was administered intraperitoneally at 25 mg/kg on the first, third, and sixth hours after pancreatitis induction.We analyzed histologic and biochemical features of AP, NF-kappaB pathway activity, leukocyte-mediated damage, cytokine levels, oxidative stress injury, lipid peroxidation, expression of poly-(adenosine diphosphate-ribose) synthetase, and presence of apoptosis. RESULTS: Treatment with GTP reduced the histologic and biochemical features of AP. Western blot revealed significant NF-kappaB inactivation. Immunostaining for P selectin and intercellular adhesion molecule 1, tumor necrosis factor alpha, transforming growth factor beta, vascular endothelial growth factor, nitrotirosine, poly-(adenosine diphosphate ribose) synthetase, and malondialdheide levels were significantly reduced. There was a significant down-regulation of apoptotic markers. CONCLUSIONS: Our results demonstrated that GTP significantly ameliorated the effects of cerulein-induced AP in mice. These effects of GTP are mediated by actions at the NF-kappaB/IkB (inhibitor kB) proteins and oxidative stress pathways.

Randomised, double blind, placebo controlled trial of intravenous antioxidant (n-acetylcysteine, selenium, vitamin C) therapy in severe acute pancreatitis.

BACKGROUND: Based on equivocal clinical data, intravenous antioxidant therapy has been used for the treatment of severe acute pancreatitis. To date there is no randomised comparison of this therapy in severe acute pancreatitis. METHODS: We conducted a randomised, double blind, placebo controlled trial of intravenous antioxidant (n-acetylcysteine, selenium, vitamin C) therapy in patients with predicted severe acute pancreatitis. Forty-three patients were enrolled from three hospitals in the Manchester (UK) area over the period June 2001 to November 2004. Randomisation stratified for APACHE-II score and hospital site, and delivered groups that were similar at baseline. RESULTS: Relative serum levels of antioxidants rose while markers of oxidative stress fell in the active treatment group during the course of the trial. However, at 7 days, there was no statistically significant difference in the primary end point, organ dysfunction (antioxidant vs placebo: 32% vs 17%, p = 0.33) or any secondary end point of organ dysfunction or patient outcome. CONCLUSIONS: This study provides no evidence to justify continued use of n-acetylcysteine, selenium, vitamin C based antioxidant therapy in severe acute pancreatitis. In the context of any future trial design, careful consideration must be given to the risks raised by the greater trend towards adverse outcome in patients in the treatment arm of this study.

Intravenous selenium modulates L-arginine-induced experimental acute pancreatitis.

CONTEXT: Oxidative stress is understood to have a critical role in the development of acinar injury in experimental acute pancreatitis. We have previously demonstrated that compound multiple antioxidant therapy ameliorates end-organ damage in the intra-peritoneal L-arginine rat model. As the principal co-factor for glutathione, selenium is a key constituent of multiple antioxidant preparations. OBJECTIVE: The intention of this study was to investigate the effect of selenium on pancreatic and remote organ injury in a well-validated experimental model of acute pancreatitis. METHODS: Male Sprague-Dawley rats were randomly allocated to one of 3 groups (n=5/group) and sacrificed at 72 hours. Acute pancreatitis was induced by 250 mg per 100 g body weight of 20% L-arginine hydrochloride in 0.15 mol/L sodium chloride. Group allocations were: Group 1, control; Group 2, acute pancreatitis; Group 3, selenium. MAIN OUTCOME MEASURES: Serum amylase, anti-oxidant levels, bronchoalveolar lavage protein, lung myeloperoxidase activity, and histological assessment of pancreatic injury. RESULTS: L-arginine induced acute pancreatitis characterised by oedema, neutrophil infiltration, acinar cell degranulation and elevated serum amylase. Selenium treatment was associated with reduced pancreatic oedema and inflammatory cell infiltration. Acinar degranulation and dilatation were completely absent. A reduction in bronchoalveolar lavage protein content was also demonstrated. CONCLUSION: Intravenous selenium given 24 hours after induction of experimental acute pancreatitis was associated with a reduction in the histological stigmata of pancreatic injury and a dramatic reduction in broncho-alveolar lavage protein content. Serum selenium fell during the course of experimental acute pancreatitis and this effect was not reversed by exogenous selenium supplementation.