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Cancer; Caregivers; Patient education Cáncer; Cuidadores; Educación del paciente Càncer; Cuidadors; Educació del pacient Journal articles provide reliable and current information about cancer research. This can offer hope to people with cancer and help them make decisions about their care. Here, the authors suggest ways in which different groups may help people with cancer to find, view, and understand articles. For example, journals should make articles free to view if they describe research that could change patient care. Also, clear titles and easy-to-follow summaries or videos may help people to find relevant articles and understand the main findings. It is important to explore ways to best share research with all those whose lives it may affect.

The recommended starting dose of bosutinib is 500 mg/day for chronic-phase (CP) or accelerated-/blast-phase Philadelphia chromosome–positive (Ph+) chronic myeloid leukemia (CML) resistant/intolerant to prior therapy. However, some patients may require dose reductions to manage the occurrences of adverse events (AEs). Bosutinib efficacy and safety were evaluated following dose reductions in a phase I/II study of Ph+ patients with CP CML resistant/intolerant to imatinib or imatinib plus dasatinib and/or nilotinib, and those with accelerated-/blast-phase CML or acute lymphoblastic leukemia after at least imatinib treatment. In all, 570 patients with ≥4 years’ follow-up were included in this analysis. Among 144 patients who dose-reduced to bosutinib 400 mg/day (without reduction to 300 mg/day), 22 (15 %) had complete cytogenetic response (CCyR) before and after reduction, 40 (28 %) initially achieved CCyR after reduction, and 4 (3 %) only had CCyR before reduction. Among 95 patients who dose-reduced to bosutinib 300 mg/day, 23 (24 %) had CCyR before and after reduction, 13 (14 %) initially achieved CCyR after reduction, and 3 (3 %) only had CCyR before reduction. Results were similar to matched controls who remained on 500 mg/day, indicating dose reductions had not substantially affected efficacy. The incidence of treatment-emergent AEs was lower after dose reductions, particularly for gastrointestinal events. The incidence of hematologic toxicities generally was similar before and after dose reduction. The management of AEs with bosutinib through dose reduction can lead to improved/maintained efficacy and better tolerability; still, approximately half of patients on treatment at year 4 maintained a dose of ≥500 mg/day. ClinicalTrials.gov: NCT00261846.

Introduction Pancreatic neuroendocrine tumours (pNETs) are rare and the majority of patients present with advanced disease. Such patients have limited treatment options. We conducted a systematic review of published clinical trials of non-surgical interventions in pNET, to understand the efficacy, safety and health related quality of life (HRQoL) outcomes from the current evidence base. Methods Electronic databases and manual bibliographic searches were conducted to identify relevant studies. Data were extracted by two independent reviewers. Results Forty seven clinical studies met the predefined inclusion criteria. The following interventions were included: targeted therapies (two RCTs and six single-arm studies), chemotherapy (two RCTs, one prospective nonrandomised, comparative study and 14 single-arm studies);somatostatin analogues (SSA) and radiolabeled SSA therapies (nine single-arm studies), liver-directed therapies (six single-arm studies), mixed treatment regimens (one RCT, four single-arm studies) and other interventions such as interferon and recombinant human endostatin (one single-arm study for each). The paucity of RCT data and lack of consistency in reporting validated study outcomes and differing patient inclusion criteria between studies made it difficult to compare the relative efficacy of therapies. Discussion The majority of published studies assessing treatment regimens for the management of pNET are single arm, non-randomised studies, often enrolling a small number of patients and not reporting clinically meaningful outcomes. However data from recently conducted studies assessing targeted therapies indicate that it is possible to conduct adequately powered RCTs reporting standardised oncological endpoints in this rare cancer. Further, similarly robust studies should be conducted to define the optimal treatment algorithm.

Background Chronic myeloid leukemia (CML) is a myeloproliferative disorder of blood stem cells. The tyrosine kinase inhibitor (TKI) imatinib was the first targeted therapy licensed for patients with chronic-phase CML, and its introduction was associated with substantial improvements in response and survival compared with previous therapies. Clinical trial data are now available for the second-generation TKIs (nilotinib, dasatinib, and bosutinib) in the first-, second-, and third-line settings. A qualitative systematic review was conducted to qualitatively compare the clinical effectiveness, safety, and effect on quality of life of TKIs for the management of chronic-, accelerated-, or blast-phase CML patients. Methods Included studies were identified through a search of electronic databases in September 2011, relevant conference proceedings and the grey literature. Results In the first-line setting, the long-term efficacy (up to 8 years) of imatinib has been confirmed in a single randomized controlled trial (International Randomized Study of Interferon [IRIS]). All second-generation TKIs reported lower rates of transformation, and comparable or superior complete cytogenetic response (CCyR), major molecular response (MMR), and complete molecular response rates compared with imatinib by 2-year follow-up. Each of the second-generation TKIs was associated with a distinct adverse-event profile. Bosutinib was the only second-generation TKI to report quality-of-life data (no significant difference compared with imatinib treatment). Data in the second- and third-line setting confirmed the efficacy of the second-generation TKIs in either imatinib-resistant or -intolerant patients, as measured by CCyR and MMR rates. Conclusion Data from first-line randomized controlled trials reporting up to 2-year follow-up indicate superior response rates of the second-generation TKIs compared with imatinib. Current evidence from single-arm studies in the second-line setting confirm that nilotinib, dasatinib, and bosutinib are valuable treatment options for the significant subgroup of patients who are intolerant or resistant to imatinib treatment.

Introduction: Bosutinib, an oral dual Src/Abl tyrosine kinase inhibitor (TKI) is approved for patients with Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML), at a starting dose of 400 once daily (QD) in newly diagnosed patients in chronic phase (CP). Approval of first-line bosutinib was based on results from the phase 3 BFORE trial, which showed improved efficacy outcomes with bosutinib vs imatinib in this patient population. This analysis evaluated efficacy and safety of bosutinib and imatinib following dose reductions in adult patients with newly diagnosed CP CML. Methods: This retrospective analysis included data (≥24-month follow-up) from the ongoing, open-label, phase 3 BFORE trial (NCT02130557). In all, 536 patients were randomized 1:1 to bosutinib or imatinib at a starting dose of 400 mg QD. Doses could be reduced in 100 mg decrements for toxicity; dose reductions to Results: Of the 268 patients in the bosutinib arm, 80 dose-reduced to 300 mg only and 23 dose-reduced to 200 mg. The median (range) overall duration of bosutinib treatment for patients dose reduced to 300 mg was 24.3 months (1.4-33.5) and to 200 mg was 8.3 months (1.0-32.9) vs. 25.1 months (range: 0.26-33.2) for patients who remained on the 400 mg starting dose. Median (range) time to bosutinib dose reduction to 300 mg was 83 days (18-793) and to 200 mg was 121 days (29-882); respective median (range) duration on reduced dose was 138.5 days (1-957) and 28 days (3-463). Of the 268 (3 untreated) patients in the imatinib arm, 44 dose-reduced to 300 mg. The median duration of imatinib treatment for patients dose reduced to 300 mg was 22.4 months (range: 1.2-33.0) vs. 24.8 months (range: 0.7-33.4) for patients who remained on 400 mg. Median time to imatinib dose reduction to 300 mg was 85.0 days (range: 15-687); median duration on reduced dose was 99.0 days (range: 2-787). TEAEs leading to dose reduction in ≥10 patients were alanine aminotransferase increased and/or aspartate aminotransferase increased (n=21), thrombocytopenia (n=19), lipase increased (n=15) and diarrhea (n=11) with bosutinib, and neutropenia (n=11) with imatinib. The most common reason for treatment discontinuation in patients who dose-reduced was a TEAE related to bosutinib (300 mg: 22.5%; 200 mg: 52.2%) or imatinib (300 mg: 27.3%). Among patients who dose-reduced to 300 mg, 16 (20%) had a major molecular response (MMR) with bosutinib before and after reduction; an additional 36 (45%) achieved MMR for the first time after dose reduction. In the imatinib arm, 7 (15.9%) had an MMR before and after reduction; an additional 22 (50%) achieved MMR for the first time after dose reduction (Table 1). 1 (1.3%) patient lost a previously attained MMR following bosutinib dose reduction to 300 mg. Among patients who dose-reduced to 200 mg bosutinib, 4 (17.4%) had an MMR before and after reduction, and an additional 4 (17.4%) achieved MMR for the first time after dose reduction. Similar trends were seen for complete cytogenetic response (CCyR) before and after dose reduction (Table 1). Among patients who remained on 400 mg, 123/165 (74.5%) had a MMR with bosutinib; 131/152 (86.2%) achieved CCyR. In the imatinib arm, 130/219 (59.4%) had a MMR and 159/198 (80.3%) achieved CCyR. The majority of TEAEs decreased in incidence with dose reduction (Table 2). Following bosutinib dose reduction to 300 mg or to 200 mg decreases >10% were seen in the incidence of diarrhea and nausea; with a decrease for rash following dose reduction to bosutinib 200 mg. Decreases (>10%) were noted for nausea following dose reduction to 300 mg imatinib. Conclusions: Management of TEAEs through bosutinib dose reduction to 300 mg or 200 mg improved tolerability in patients with newly diagnosed CP CML. These reductions in TEAEs enabled patients to continue bosutinib treatment, with a substantial number of patients achieving MMR and CCyR for the first time after dose reduction. Findings were similar for patients who dose-reduced to 300 mg imatinib. Disclosures Brummendorf: Pfizer: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Takeda: Consultancy; Merck: Consultancy; Janssen: Consultancy. Gambacorti-Passerini:BMS: Consultancy; Pfizer: Consultancy, Honoraria, Research Funding. Hochhaus:Bristol-Myers Squibb: Research Funding; Pfizer: Research Funding; Novartis: Research Funding; Takeda: Research Funding; Incyte: Research Funding. Lipton:Novartis: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding. Kota:Pfizer: Honoraria; BMS: Honoraria; Incyte: Honoraria; Xcenda: Honoraria; Novartis: Honoraria. Deininger:Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Blueprint: Consultancy. Leip:Pfizer: Employment, Equity Ownership. Viqueira:Pfizer: Employment, Equity Ownership. Ferdinand:Pfizer: Employment, Equity Ownership. Cortes:Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Astellas Pharma: Consultancy, Research Funding; Arog: Research Funding.

Objectives.Bosutinib is a second-generation tyrosine kinase inhibitor (TKI) indicated for patients with previously treated Philadelphia chromosome positive chronic myeloid leukaemia (CML) when imatinib, nilotinib and dasatinib are not appropriate. Data describing the use of bosutinib in patients with CML in the real world clinical setting are limited. The objective of this study was to describe the efficacy and safety of bosutinib in patients with CML used under routine clinical practice. Methods.An international, multi-centre, retrospective, non-interventional study in hospitals in the UK (n=7) and the Netherlands (n=2). Fifty-three patients (32 [60%] male) with CML, aged ≥18 years at bosutinib initiation and with ≥3 months data available post-initiation were recruited. Surviving patients provided written informed consent for data collection; data from deceased patients were collected by a member of the direct care team to preserve confidentiality. Data were analysed using descriptive statistics with no imputation of missing values (denominators presented where data are missing). Results.Median age at bosutinib initiation was 63.6 (range: 25.5 to 90.1) years; median time from CML diagnosis to bosutinib initiation was 7.1 (range: 0.5 to 35.7) years; 74% (39/53) of patients had one or more co-morbidities at initiation. Bosutinib was 3rd-line TKI in 32% (17/53) of patients and 4th-line TKI in 53% (28/53) of patients. Fifty-seven percent (30/53) of patients switched to bosutinib due to intolerance and 26% (14/53) due to resistance to a previous TKI. The most common bosutinib starting dose was 300 mg/day (28% [15/53] of patients). Median bosutinib treatment duration was 15.6 (range: 0.4 to 66.0) months. The proportions of patients with cumulative complete cytogenetic response (CCyR), major molecular response (MMR), molecular response 4.0 (MR4.0) and molecular response 4.5 (MR4.5) with bosutinib were 62%, 54%, 34% and 26%, respectively (see figure). At data collection (median follow-up 25.1 [range: 3.0 to 66.0] months), 38% (20/53) of patients had discontinued bosutinib; 2% (1/53) discontinued due to progression, 8% (4/53) due to treatment failure, 15% (8/53) due to adverse events (AE), 6% (3/53) due to loss of response, and 4% (2/53) due to patient request. Ninety-two percent (49/53) of patients experienced ≥1 AE, most commonly diarrhoea (55% [29/53] of patients); 26% (14/53) of patients had grade 3/4 AEs (diarrhoea grade 3/4: 4% [2/53] of patients). Conclusions.Bosutinib used in normal clinical practice in pre-treated patients with CML demonstrates high rates of cytogenetic and major molecular response similar to those seen in clinical trials. Bosutinib is generally well tolerated, with the majority of patients not experiencing grade 3/4 AEs, despite most patients having pre-existing co-morbidities. Disclosures Apperley: Pfizer: Honoraria, Speakers Bureau; Ariad: Honoraria, Speakers Bureau; Bristol Myers Squibb: Honoraria, Speakers Bureau; Incyte: Speakers Bureau; Novartis: Honoraria, Speakers Bureau. Byrne:Bristol Myers Squipp: Consultancy, Speakers Bureau. Smith:Pfizer: Honoraria, Other: Advisory boards and talks at regional sponsored meetings. Viqueira:Pfizer: Employment. Ferdinand:Pfizer: Employment. Carter:pH Associates: Employment. Nock:pH Associates: Employment. Milojkovic:Ariad: Honoraria; Pfizer: Honoraria; Novartis: Honoraria; Bristol Myers Squibb: Honoraria.

Introduction: Vascular occlusive events (VOE) are an important late complication among chronic myeloid leukemia (CML) patients treated with tyrosine kinase inhibitors (TKI). This study examines the impact of VOE on risk of discontinuation and cost of care among patients treated with TKIs outside of research protocol settings. Methods: TKI treatment episodes for adult patients with CML diagnoses from 1/1/2009 to 1/31/2015 were identified in a large commercial insurance claims, Medicaid, and Medicare database in the US. Patients were required to have ≥6 months of enrollment prior to each TKI episode and ≥1 medical or pharmacy claims on or after the first CML diagnosis date for one of the TKIs: imatinib (IM), dasatinib (DAS), nilotinib (NIL), bosutinib (BOS), and ponatinib (PON). VOE include one or more of the following: myocardial infarction, congestive heart failure, thrombotic events, acute coronary syndrome, peripheral vascular, cerebrovascular, or coronary artery diseases. Cox proportional hazard model was used to evaluate time to discontinuation, as measured from the start date of each TKI episode to the earliest of the following: 1) switched TKI treatment, 2) stopped taking TKI defined as no refills for 90 days past end of drug supply, 3) had a bone marrow or stem cell transplant, or 4) death. Gamma log-link regression was used to model total all-cause healthcare costs for each treatment episode. Costs were measured in 2014 US dollars per patient per month (PPPM), and included patient out-of-pocket costs, insurance-paid costs for CML drugs, other outpatient prescriptions, inpatient services, emergency room visits, office visits, and other outpatient services. For both models, first occurrence of a treatment-emergent VOE within the TKI episode was included as a time-dependent variable. Other independent explanatory variables for the models included: age, gender, baseline Charlson Comorbidity Index from the National Cancer Institute (CCI NCI), type of TKI agent, and line of therapy. Results: A total of 4,541 TKI treatment episodes (IM 1,982; DAS 1,321; NIL 1,059; BOS 114; PON 65) for CML were identified (mean age: 53.1 years and males: 51.9%). IM was the most commonly used first line TKI (54%). DAS was used 1st line in 26% and 2nd line in 33%. NIL was used 1st line in 19% and 2nd line in 25%. BOS and PON were predominately used in 3rd line or later. 947 (20.9%) VOEs occurred in all treatment episodes with 371 (21.1%), 357 (22.3%), and 219 (18.6%) occurring in first, second, and third plus lines, respectively. Occurrence of a VOE was associated with a significantly increased risk of TKI discontinuation (adjusted hazard ratio: 1.4 [1.2-1.6]). Compared to BOS, adjusted risk of discontinuation was not significantly different for treatment episodes using IM, DAS, or NIL, but was significantly higher for PON (Table 1). Cost of care for patients experiencing a VOE was also significantly higher (mean $3,702 PPPM higher) than for patients not experiencing an event (p=0.0454). Treatment with PON was independently associated with significantly higher cost of care compared to BOS (p=0.0026; Table 1). Conclusions: Vascular Occlusive Events appear to be significantly associated with a higher risk of discontinuation and increased health care costs. Additionally, compared to BOS, PON appears to be independently associated with a significantly higher risk of discontinuation and higher costs. BOS appears comparable to IM, DAS, and NIL in duration of treatment and cost of care. It will be important to determine if factors other than VOE might underlie the higher discontinuations and costs observed with PON. Sensitivity analyses should also be conducted with deaths and transplants as censoring or true treatment discontinuation events. Sponsorship Statement: This study was sponsored by Pfizer, Inc. Disclosures Goldberg: Pfizer: Research Funding; Novartis: Research Funding, Speakers Bureau; BMS: Research Funding, Speakers Bureau; Ariad: Research Funding, Speakers Bureau; COTA: Employment, Equity Ownership, Other: Leadership, Stock. Su:Pfizer Inc: Employment, Other: Stock Ownership. Gunnarsson:Pfizer Inc: Consultancy. Irish:Pfizer Inc: Consultancy; Alexion: Consultancy; BMS: Consultancy; Novartis: Consultancy; Sanofi: Consultancy; Astellas: Consultancy. Ryan:Pfizer Inc: Consultancy. Woloj:Pfizer Inc: Employment, Other: Stock Ownership. Ferdinand:Pfizer Ltd: Employment. Shapiro:Pfizer Inc: Employment, Other: Stock Ownership.

e18026 Background: The growing number of TKIs available for CML increases complexity in choosing therapy in non-research settings. This study aims to determine patient (pt) characteristics & emerge...

This work presents the first application of high-resolution magic angle spinning (HR-MAS) 1H NMR spectroscopy to human liver biopsy samples, allowing a determination of their metabolic profiles before removal from donors, during cold perfusion, and after implantation into recipients. The assignment of peaks observed in the 1H HR-MAS NMR spectra was aided by the use of two-dimensional J-resolved, TOCSY and 1H-13C HMQC spectra. The spectra were dominated by resonances from triglycerides, phospholipids, and glycogen and from a variety of small molecules including glycerophosphocholine (GPC), glucose, lactate, creatine, acetate, amino acids, and nucleoside-related compounds such as uridine and adenosine. In agreement with histological data obtained on the same biopsies, two of the six livers were found to contain high amounts of triglycerides by NMR spectroscopy, which also indicated that these tissues contained a higher degree of unsaturated lipids and a lower proportion of phospholipids and low molecular weight compounds. Additionally, proton T2 relaxation times indicated two populations of lipids, a higher mobility triglyceride fraction and a lower mobility phospholipid fraction, the proportions of which changed according to the degree of fat content. GPC was found to decrease from the pretransplant to the posttransplant biopsy of all livers except for one with a histologically confirmed high lipid content, and this might represent a biomarker of liver function posttransplantation. NMR signals produced by the liver preservation solution were clearly detected in the cold perfusion stage biopsies of all livers but remained in the posttransplant spectra of only the two livers with a high lipid content and were prominent mainly in the graft that later developed primary graft dysfunction. This study has shown biochemical differences between livers used for transplants that can be related to the degree and type of lipid composition. This technology might therefore provide a novel screening approach for donor organ quality and a means to assess function in the recipient after transplantation.