COMMUNI.CARE (COMMUNIcation and Patient Engagement at Diagnosis of PAncreatic CAncer) : Study Protocol

Background: In many cases of pancreatic adenocarcinoma (PDAC), the diagnosis comes as a surprise to the patient, who often faces a disease that is already at an advanced stage, with poor prognosis. The clinical visit during which the diagnosis is communicated together with the first information regarding the planned treatments is of paramount importance. We hypothesize that the clarity of such information can influence patients' engagement and thus their level of compliance. Aims: This study aims to collect (a) quantitative data on the level of PDAC patient engagement, (b) data on the rate of understanding of the information received from the doctor, and (c) data on level of compliance; the possible associations between these variables will be analyzed. Methods: This is a single-center, observational, cross-sectional cohort study on patients diagnosed with PDAC, approved by the Ethics Committee of the San Raffaele Hospital. As no preliminary data are available on the association between PDAC patients' understanding rate and their level of engagement and of compliance, no power calculation is possible. This is a pilot study, aimed at enrolling at least 45 PDAC patients during a period of 3 months. Conclusion: COMMUNIcation and Patient Engagement at Diagnosis of PAncreatic CAncer (COMMUNI. CARE) will be the first study specifically investigating whether there is a relation between PDAC patients' engagement, rate of understanding at the time of diagnosis, and compliance.Peer reviewe

Maintenance Olaparib for Germline BRCA-Mutated Metastatic Pancreatic Cancer

Actividad antitumoral; Calidad de vida con cáncer; PARPActivitat antitumoral; Qualitat de vida amb càncer; PARPAntitumor activity; Quality of life with cancer; PARPBACKGROUND Patients with a germline BRCA1 or BRCA2 mutation make up a small subgroup of those with metastatic pancreatic cancer. The poly(adenosine diphosphate–ribose) polymerase (PARP) inhibitor olaparib has had antitumor activity in this population. METHODS We conducted a randomized, double-blind, placebo-controlled, phase 3 trial to evaluate the efficacy of olaparib as maintenance therapy in patients who had a germline BRCA1 or BRCA2 mutation and metastatic pancreatic cancer and disease that had not progressed during first-line platinum-based chemotherapy. Patients were randomly assigned, in a 3:2 ratio, to receive maintenance olaparib tablets (300 mg twice daily) or placebo. The primary end point was progression-free survival, which was assessed by blinded independent central review. RESULTS Of the 3315 patients who underwent screening, 154 underwent randomization and were assigned to a trial intervention (92 to receive olaparib and 62 to receive placebo). The median progression-free survival was significantly longer in the olaparib group than in the placebo group (7.4 months vs. 3.8 months; hazard ratio for disease progression or death, 0.53; 95% confidence interval [CI], 0.35 to 0.82; P=0.004). An interim analysis of overall survival, at a data maturity of 46%, showed no difference between the olaparib and placebo groups (median, 18.9 months vs. 18.1 months; hazard ratio for death, 0.91; 95% CI, 0.56 to 1.46; P=0.68). There was no significant between-group difference in health-related quality of life, as indicated by the overall change from baseline in the global quality-of-life score (on a 100-point scale, with higher scores indicating better quality of life) based on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (between-group difference, −2.47 points; 95% CI, −7.27 to 2.33). The incidence of grade 3 or higher adverse events was 40% in the olaparib group and 23% in the placebo group (between-group difference, 16 percentage points; 95% CI, −0.02 to 31); 5% and 2% of the patients, respectively, discontinued the trial intervention because of an adverse event. CONCLUSIONS Among patients with a germline BRCA mutation and metastatic pancreatic cancer, progression-free survival was longer with maintenance olaparib than with placebo.Supported by AstraZeneca (as part of an alliance between AstraZeneca and Merck Sharp & Dohme, a subsidiary of Merck) and by a grant (P30-17 CA008748) from the National Institutes of Health National Cancer Institute Cancer Center

Treatment sequences and prognostic/predictive factors in metastatic pancreatic ductal adenocarcinoma: univariate and multivariate analyses of a real-world study in Europe

Metastatic; Pancreatic cancer; Prognostic factorsMetastàtica; Càncer de pàncrees; Factors pronòsticsMetastásico; Cáncer de páncreas; Factores pronósticosBackground Real-world data on treatment patterns/outcomes for metastatic pancreatic cancer (mPAC) are limited. This study aims to assess real-world treatment patterns, survival outcomes, and prognostic/predictive factors in patients with mPAC. Methods Retrospective, observational, chart-review involving medical oncologists and gastroenterologists from five European countries. Physicians reported information on disease and patient characteristics, diagnosis, and treatment for patients diagnosed with mPAC from January-October 2016. Outcomes included median progression-free survival (mPFS), median overall survival (mOS), and the impact of baseline performance status on survival. Univariate/multivariate regression analyses were undertaken to identify prognostic/predictive factors. Results Three hundred four physicians and 3432 patients were included. First-line therapies included modified (m)FOLFIRINOX (28.4%), gemcitabine + nab-paclitaxel (28.0%), and gemcitabine monotherapy (23.0%). Frequent second-line therapies were gemcitabine monotherapy (25.0%), fluorouracil (5-FU) + oxaliplatin (21.8%), and gemcitabine + nab-paclitaxel (16.7%). Most frequent first- to second-line treatment sequences were gemcitabine + nab-paclitaxel followed by fluoropyrimidine combinations. Longest unadjusted estimated mOS was observed with (m)FOLFIRINOX followed by gemcitabine-based combinations (19.1 months). Multivariate analysis identified significant prognostic/predictive factors for OS and PFS including performance status and carbohydrate antigen 19–9 (CA 19–9) levels. Conclusions Treatment and treatment sequences were generally in accordance with guidelines at the time of the study. Identification of prognostic/predictive factors for survival may help inform the individualised management of mPAC patients in the future.The chart review was funded by Institut de Recherches Internationales, Servier, France

Prognostic factors in gemcitabine-cisplatin polychemotherapy regimens in pancreatic cancer: XPD-Lys751Gln polymorphism strikes back

: The use of platinated agents in combination chemotherapy regimens for advanced pancreatic cancer is controversial owing to the lack of an outstanding impact on the outcome and a substantial increase in hematologic and extra-hematologic toxicities. Pharmacogenetic studies to identify patients who could benefit most from such therapies are urgently needed. The Xeroderma-Pigmentosum group-D polymorphism at codon-751 (XPD-Lys751Gln) emerged as the most significant independent predictor for death- and progression-risk in our previous study on functional polymorphisms in 122 advanced pancreatic cancer patients treated with cisplatin-docetaxel-capecitabine-gemcitabine and cisplatin-epirubicin-capecitabine-gemcitabine (or EC-GemCap). To confirm the prognostic role of this variable, we further evaluated the correlation of XPD-Lys751Gln with outcome in another 125 patients treated with the same regimens, and 90 treated with gemcitabine monotherapy. Genotyping was successfully carried out in the vast majority of DNA samples. Genotype frequencies followed Hardy-Weinberg equilibrium, and XPD-Lys751Gln was associated with differential progression-free and overall-survival. Multivariate analysis confirmed its prognostic significance in platinum-based regimens. In particular, XPD-Gln751Gln was significantly associated with risk of death (hazard ratio, HR = 1.7, 95% confidence interval [CI], 1.1-2.6, p = 0.011) and risk of progression (HR = 1.7, 95% CI, 1.1-2.5, p = 0.013). No correlation was observed in gemcitabine monotherapy-treated patients. The analysis of DNA damage using extra-long-PCR in lymphocytes supported the association of XPD-Gln751Gln with greater resistance to cisplatin-induced damage. The increasing evidence of XPD-Lys751Gln impact on the outcome of gemcitabine-cisplatin-based polychemotherapy leads to plan prospective studies to validate the role of this polymorphism as a new tool for optimization of the currently available treatments in pancreatic cancer

Ibrutinib in combination with nab-paclitaxel and gemcitabine for first-line treatment of patients with metastatic pancreatic adenocarcinoma: phase III RESOLVE study

Ibrutinib; Metastatic pancreatic adenocarcinoma; Phase IIIIbrutinib; Adenocarcinoma de páncreas metastásico; Fase IIIIbrutinib; Adenocarcinoma de pàncrees metastàtic; Fase IIIFirst-line treatment of metastatic pancreatic ductal adenocarcinoma (PDAC) includes nab-paclitaxel/gemcitabine. Ibrutinib, a Bruton's tyrosine kinase inhibitor, exhibits antitumor activity through tumor microenvironment modulation. The safety and efficacy of first-line ibrutinib plus nab-paclitaxel/gemcitabine treatment in patients with PDAC were evaluated. Patients and methods RESOLVE (NCT02436668) was a phase III, randomized, double-blind, placebo-controlled study. Patients (histologically-confirmed PDAC; stage IV diagnosis ≥6 weeks of randomization; Karnofsky performance score ≥70) were randomized to once-daily oral ibrutinib (560 mg) or placebo plus nab-paclitaxel (125 mg/m2) and gemcitabine (1000 mg/m2). Primary endpoints were overall survival (OS) and investigator-assessed progression-free survival (PFS); overall response rate and safety were assessed. Results In total, 424 patients were randomized (ibrutinib arm, n = 211; placebo arm, n = 213). Baseline characteristics were balanced across arms. After a median follow-up of 25 months, there was no significant difference in OS between ibrutinib plus nab-paclitaxel/gemcitabine versus placebo plus nab-paclitaxel/gemcitabine (median of 9.7 versus 10.8 months; P = 0.3225). PFS was shorter for ibrutinib plus nab-paclitaxel/gemcitabine compared with placebo plus nab-paclitaxel/gemcitabine (median 5.3 versus 6.0 months; P < 0.0001). Overall response rates were 29% and 42%, respectively (P = 0.0058). Patients in the ibrutinib arm had less time on treatment and received lower cumulative doses for all agents compared with the placebo arm. The most common grade ≥3 adverse events for ibrutinib versus placebo arms included neutropenia (24% versus 35%), peripheral sensory neuropathy (17% versus 8%), and anemia (16% versus 17%). Primary reasons for any treatment discontinuation were disease progression and adverse events. Conclusions Ibrutinib plus nab-paclitaxel/gemcitabine did not improve OS or PFS for patients with PDAC. Safety was consistent with known profiles for these agents.This work was supported by Pharmacyclics LLC, an AbbVie Company (no grant number)

Global ph 3, randomized, double-blind, placebo-controlled study of PEGylated recombinant human hyaluronidase PH20 (PEGPH20) + nab-paclitaxel & gemcitabine in pts with previously untreated, hyaluronan-high, stage iv pancreatic ductal adenocarcinoma

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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 &gt;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&lt;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

A polymorphism in the promoter is associated with EZH2 expression but not with outcome in advanced pancreatic cancer patients

Aim: EZH2 expression is a prognostic marker in radically resected pancreatic ductal adenocarcinoma (PDAC) patients. Here we investigated its role in locally advanced/metastatic patients, as well as candidate polymorphisms. Materials &amp; methods: EZH2 expression and polymorphisms were evaluated by quantitative reverse transcription PCR in 32 laser microdissected tumors, while polymorphisms were also studied in blood samples from two additional cohorts treated with gemcitabine monotherapy (n = 93) or polychemotherapeutic regimens (n = 247). Results: EZH2 expression correlated with survival and with the rs6958683 polymorphism in the first cohort of patients, but this polymorphism was not associated with survival in our larger cohorts. Conclusion: EZH2 is a prognostic factor for locally advanced/metastatic PDACs, while candidate polymorphisms cannot predict clinical outcome. Other factors involved in EZH2 regulation, such as miR-101, should be investigated in accessible samples in order to improve the clinical management of advanced PDAC

Treatment sequences and prognostic/predictive factors in metastatic pancreatic ductal adenocarcinoma: univariate and multivariate analyses of a real-world study in Europe

BACKGROUND: Real-world data on treatment patterns/outcomes for metastatic pancreatic cancer (mPAC) are limited. This study aims to assess real-world treatment patterns, survival outcomes, and prognostic/predictive factors in patients with mPAC. METHODS: Retrospective, observational, chart-review involving medical oncologists and gastroenterologists from five European countries. Physicians reported information on disease and patient characteristics, diagnosis, and treatment for patients diagnosed with mPAC from January-October 2016. Outcomes included median progression-free survival (mPFS), median overall survival (mOS), and the impact of baseline performance status on survival. Univariate/multivariate regression analyses were undertaken to identify prognostic/predictive factors. RESULTS: Three hundred four physicians and 3432 patients were included. First-line therapies included modified (m)FOLFIRINOX (28.4%), gemcitabine + nab-paclitaxel (28.0%), and gemcitabine monotherapy (23.0%). Frequent second-line therapies were gemcitabine monotherapy (25.0%), fluorouracil (5-FU) + oxaliplatin (21.8%), and gemcitabine + nab-paclitaxel (16.7%). Most frequent first- to second-line treatment sequences were gemcitabine + nab-paclitaxel followed by fluoropyrimidine combinations. Longest unadjusted estimated mOS was observed with (m)FOLFIRINOX followed by gemcitabine-based combinations (19.1 months). Multivariate analysis identified significant prognostic/predictive factors for OS and PFS including performance status and carbohydrate antigen 19-9 (CA 19-9) levels. CONCLUSIONS: Treatment and treatment sequences were generally in accordance with guidelines at the time of the study. Identification of prognostic/predictive factors for survival may help inform the individualised management of mPAC patients in the future

CanStem111P trial: A Phase 3 Study of napabucasin (NAPA) plus nab-paclitaxel (nPTX) with gemcitabine (Gem) in adult patients with metastatic pancreatic adenocarcinoma (mPDAC) - Trial in progress

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