Stefano Cereda

Carbohydrate Antigen 19-9 Change During Chemotherapy for Advanced Pancreatic Adenocarcinoma

Radiologic assessment of tumor response in pancreatic cancer is complicated by desmoplastic reactions within or around the tumor. The objective of this study was to evaluate the correlation between a decline in carbohydrate antigen 19‐9 (CA 19‐9) and survival in patients with advanced pancreatic cancer who received upfront chemotherapy.

Feasibility and safety of EUS-guided cryothermal ablation in patients with locally advanced pancreatic cancer

BACKGROUND New therapies are needed for pancreatic cancer. OBJECTIVE To determine the feasibility and safety of a new endoscopic treatment. Secondary endpoints were to determine effects on tumor growth measured with CT scan and to find the overall survival. DESIGN A cohort study of patients with local progression of advanced pancreatic adenocarcinoma after neoadjuvant therapy. The cryotherm probe (CTP), a flexible bipolar device that combines radiofrequency with cryogenic cooling, was used under EUS guidance. SETTING San Raffaele Hospital, Milan, Italy; University Medical Center, Hamburg-Eppendorf, Germany. PATIENTS A total of 22 patients (male/female 11/11; mean age 61.9 years) were enrolled from September 2009 to May 2011. INTERVENTION Radiofrequency heating: 18 W; pressure for cooling: 650 psi (Pounds per Square Inch); application time: depending on tumor size. MAIN OUTCOME MEASUREMENTS Feasibility was evaluated during the procedure. A clinical and radiologic follow-up was planned. RESULTS The CTP was successfully applied in 16 patients (72.8%); in 6 it was not possible because of stiffness of the GI wall and of the tumor. Amylase arose in 3 of 16 patients; none had clinical signs of pancreatitis. Late complications arose in 4 cases: 3 were mostly related to tumor progression. Median postablation survival time was 6 months. A CT scan was performed in all patients, but only in 6 of 16 was it possible to clearly define the tumor margins after ablation. In these patients, the tumor appeared smaller compared with the initial mass (P = .07). LIMITATIONS Small sample of patients, difficulty of objectifying the size of the ablated zone by CT scan. CONCLUSION EUS-guided CTP ablation is feasible and safe. Further investigations are needed to demonstrate progression-free survival and local control.

(Ir)relevance of Metformin Treatment in Patients with Metastatic Pancreatic Cancer: An Open-Label, Randomized Phase II Trial

Purpose: We aimed to assess the safety and efficacy of metformin for treating patients with metastatic pancreatic cancer and to identify endocrine and metabolic phenotypic features or tumor molecular markers associated with sensitivity to metformin antineoplastic action. Experimental Design: We designed an open-label, randomized, phase II trial to assess the efficacy of adding metformin to a standard systemic therapy with cisplatin, epirubicin, capecitabine, and gemcitabine (PEXG) in patients with metastatic pancreatic cancer. Patients ages 18 years or older with metastatic pancreatic cancer were randomly assigned (1:1) to receive PEXG every 4 weeks in combination or not with 2 g oral metformin daily. The primary endpoint was 6-months progression-free survival (PFS-6) in the intention-to-treat population. Results: Between August 2010 and January 2014, we randomly assigned 60 patients to receive PEXG with (n = 31) or without metformin (n = 29). At the preplanned interim analysis, the study was ended for futility. PFS-6 was 52% [95% confidence interval (CI), 33–69] in the control group and 42% (95% CI, 24–59) in the metformin group (P = 0.61). Furthermore, there was no difference in disease-free survival and overall survival between groups. Despite endocrine metabolic modifications induced by metformin, there was no correlation with the outcome. Single-nucleotide polymorphism rs11212617 predicted glycemic response, but not tumor response to metformin. Gene expression on tumor tissue did not predict tumor response to metformin. Conclusions: Addition of metformin at the dose commonly used in diabetes did not improve outcome in patients with metastatic pancreatic cancer treated with standard systemic therapy. Clin Cancer Res; 22(5); 1076–85. ©2015 AACR. See related commentary by Yang and Rustgi, p. 1031

Association between DNA-repair polymorphisms and survival in pancreatic cancer patients treated with combination chemotherapy

AIM This multicenter study evaluated the association of 11 candidate polymorphisms in eight genes with outcome of pancreatic cancer patients treated with the equivalent polychemotherapeutic regimens: cisplatin/epirubicin/capecitabine/gemcitabine, cisplatin/docetaxel/capecitabine/gemcitabine and gemcitabine/capecitabine plus epirubicin/cisplatin intra-arterial infusion. PATIENTS & METHODS Towards this end, polymorphisms were assessed in DNA from 122 pancreatic cancer stage-III/IV patients, and their associations with toxicity/response and progression-free survival (PFS) and overall survival were evaluated using Pearson-χ(2) and log-rank test. RESULTS Patients harboring XPD Gln751Gln, XPD Asp312Asn + Asn312Asn or XRCC1 Arg399Gln + Gln399Gln genotypes had a worse prognosis. XPD Gln751Gln (hazard ratio: 1.9; p = 0.003), as well as a combination of over two risk genotypes (hazard ratio: 2.7; p < 0.001), emerged as independent predictors for death risk at multivariate analysis. No correlations were observed with toxicity. Conversely, XPD Gln751Gln was associated with shorter PFS, while the lack of association with overall survival/PFS in gemcitabine monotherapy-treated patients suggested its role only for platinum-based regimens. CONCLUSION Polymorphisms of DNA-repair genes appear to be candidate biomarkers of primary resistance to gemcitabine/cisplatin-based polychemotherapeutic regimens. The relatively small sample size, coupled with the retrospective and exploratory design of the present study, imply that these results should be considered as hypothesis generators, and should be further evaluated in larger and adequately designed retrospective/prospective studies.

Panitumumab in combination with gemcitabine and oxaliplatin does not prolong survival in wild‐type KRAS advanced biliary tract cancer: A randomized phase 2 trial (Vecti‐BIL study)

Biliary tract cancer (BTC) is a rare and lethal disease with few therapeutic options. Preclinical data suggest that the epidermal growth factor receptor (EGFR) pathway could be involved in its progression.

Neoadjuvant therapy in resectable pancreatic cancer: a critical review.

BACKGROUND Pancreatic cancer is among the deadliest tumors. Due to intrinsic chemo- and radio-resistance, surgical resection remains the only chance for cure. However surgery alone is unable to considerably improve survival and complementary chemotherapy and radiotherapy in a multimodal approach have been tested. Adjuvant chemotherapy yielded a modest outcome improvement, whereas the use of adjuvant chemoradiation is highly controversial. In this scenario, the neoadjuvant approach has a strong theoretical rationale, but limited information on the efficacy of this strategy is available. MATERIALS AND METHODS This review critically overviews the current knowledge, the rationale, the available data and information on neoadjuvant treatment in resectable pancreatic cancer. RESULTS The very early systemic dissemination of pancreatic cancer endorses the rationale for an up-front use of systemic therapy. However, evidence collected so far depends on retrospective data, small case series that did not balance the different characteristics of patients suitable for surgery before or after neoadjuvant chemotherapy. CONCLUSION Currently there is no straightforward evidence to support the routine clinical use of this strategy. Only a properly designed randomized trial testing combination chemotherapy regimens selected on the basis of their efficacy and activity against metastatic disease can address this issue.

Multivariate prognostic factors analysis for second-line chemotherapy in advanced biliary tract cancer

Background:The role of second-line chemotherapy (CT) is not established in advanced biliary tract cancer (aBTC). We investigated the outcome of aBTC patients treated with second-line CT and devised a prognostic model.Methods:Baseline clinical and laboratory data of 300 consecutive aBTC patients were collected and association with overall survival (OS) was investigated by multivariable Cox models.Results:The following parameters resulted independently associated with longer OS: Eastern Cooperative Oncology Group performance status of 0 (P<0.001; hazard ratio (HR), 0.348; 95% confidence interval (CI) 0.215–0.562), CA19.9 lower than median (P=0.013; HR, 0.574; 95% CI 0.370–0.891), progression-free survival after first-line CT ⩾6 months (P=0.027; HR, 0.633; 95% CI 0.422–0.949) and previous surgery on primary tumour (P=0.027; HR, 0.609; 95% CI 0.392–0.945). We grouped the 249 patients with complete data available into three categories according to the number of fulfilled risk factors: median OS times for good-risk (zero to one factors), intermediate-risk (two factors) and poor-risk (three to four factors) groups were 13.1, 6.6 and 3.7 months, respectively (P<0.001).Conclusions:Easily available clinical and laboratory factors predict prognosis of aBTC patients undergoing second-line CT. This model allows individual patient-risk stratification and may help in treatment decision and trial design.

Maintenance sunitinib or observation in metastatic pancreatic adenocarcinoma: A phase II randomised trial

BACKGROUND New strategies to prolong disease control warrant investigation in patients with metastatic pancreatic adenocarcinoma. This open-label, randomised, multi-centre phase II trial explored the role of maintenance sunitinib after first-line chemotherapy in this setting. METHODS Patients with pathologic diagnosis of metastatic pancreatic adenocarcinoma, performance status >50%, no progression after 6 months of chemotherapy were centrally randomised by an independent contract research organisation, which was also responsible for data collection and monitoring, to observation (arm A) or sunitinib at 37.5mg daily until progression or a maximum of 6 months (arm B). The primary outcome measure was the probability of being progression-free at 6 months (PFS-6) from randomisation. Assuming P0 = 10%; P1 = 30%, α .10; β .10, the target accrual was 26 patients per arm. RESULTS 28 per arm were randomised. One arm B patient had kidney cancer and was excluded. Sunitinib was given for a median of 91 days (7-186). Main grade 3-4 toxicity was thrombocytopenia, neutropenia and hand-foot syndrome (12%), diarrhoea 8%. In arm A versus B, PFS-6 was 3.6% (95% confidence interval (CI): 0-10.6%) and 22.2% (95% CI: 6.2-38.2%; P<0.01); 2 y overall survival was 7.1% (95% CI: 0-16.8%) and 22.9% (95% CI: 5.8-40.0%; P = 0.11), stable disease 21.4% and 51.9% (P = 0.02). CONCLUSION This is the first randomised trial on maintenance therapy in metastatic pancreatic adenocarcinoma. The primary end-point was fulfilled and 2 y overall survival was remarkably high, suggesting that maintenance sunitinib is promising and should be further explored in this patient population.

Weekly Docetaxel as Salvage Therapy in Patients with Gemcitabine-Refractory Metastatic Pancreatic Cancer

Abstract Gemcitabine-based chemotherapy provides very limited disease control in the treatment of advanced pancreatic cancer. Approximately half of the patients failing upfront treatment present good performance status and are willing to undergo further treatment. Docetaxel activity against pancreatic cancer is reported both in the preclinical and clinical setting. Between November 2004 and November 2005, 10 patients (median age 59; median KPS 80) with metastatic pancreatic adenocarcinoma, progressive disease after gemcitabine-containing chemotherapy, KPS >50, adequate organ function, were treated with weekly docetaxel at 30 mg/m2 until progressive disease. Docetaxel dose intensity was 100% of the intended dose. No grade >2 toxicity was observed. No objective response to treatment was obtained. Median progression-free survival was 1.5 months (range 1-3.5 months); median survival was 4.0 months (range 2.0-7.5). Weekly administration of single-agent docetaxel does not seem to have any activity in the treatment of gemcitabine-resistant metastatic pancreatic cancer

Quality of Life Assessment in Advanced Pancreatic Adenocarcinoma: Results from a Phase III Randomized Trial

Background: A phase III trial suggested that a PEFG (cisplatin, epirubicin, 5-fluorouracil, gemcitabine) regimen might improve the outcome compared to gemcitabine in advanced pancreatic adenocarcinoma. The analysis of treatment impact on quality of life (QOL) is reported. Method: Patients completed the European Organization for Research and Treatment of Cancer QLQ-C30 and PAN-26 questionnaires at baseline and every second month of treatment until disease progression. Results: The largest differences between arms favored PEFG. Expressed as improvement ≧10 points from baseline (PEFG/gemcitabine), these were: emotional function (43/18%), fatigue (41/17%), QOL (55/29%), pain (64/41%), and flatulence (50/26%). Only change in sexual function favored gemcitabine (19/42%). Physical function, fatigue, appetite, and satisfaction with healthcare improved in 40–46% of partial responders compared with 0–12% of patients with stable disease. Conclusion: Clinically relevant improvement in QOL from baseline was observed more often after PEFG than after gemcitabine, suggesting that the PEFG regimen did not impair QOL, Partial response was associated with improved QOL suggesting that effective treatment of pancreatic adenocarcinoma may have an important role in these patients.