Failure Of First-line Treatment Research Articles

Experience with Pegylated Interferon α-2a in 30 Patients Diagnosed with Hematologic Neoplasms

Introduction:Interferon (IFN-α) is frequently used in various hematologic neoplastic disorders either at failure of first-line treatment or as first-line therapy in selected patients. IFN-α has shown significant activity in treatment, but the therapy is handicapped by high dropout rates due to side effects and cumbersome dosing schedules. Pegylated (peg) IFN- α is formulated by the covalent binding of one 40 kDa branched PEG-polymer to a lysine side chain of IFN- α. This modification prolongs serum half-life and patient exposure to medicine, decreases renal excretion, thus allowing for weekly administration, acceptable toxicity, tolerability and activity profiles.The results of peg-IFN in polycythemia vera (PV) and essential thrombocythemia (ET) in phase 2 studies are encouraging, with molecular responses in some patients. There is at least one phase 3 study of hydroxyurea versus peg-IFN as first-line cytoreductive therapy for PV. In spite of ongoing international efforts to evaluate peg-IFN in PV, there is limited experience on peg-IFN use in other hematologic neoplasms.Method: <>All patients who were put on peg-IFN in our center were found in our institutional electronic database. The patients had been recorded prospectively. All patients who had been treated with peg-IFN had been approved by national health authority and all patients had given informed written consent. Responses were evaluated by ELN (chronic myeloid leukemia), IWG-MRT (PV and ET), EUMNET (myelofibrosis), Nordic proposal criteria (hypereosinophilic syndrome), modified consensus criteria (systemic mastocytosis) (Am. J. Hematol 2009;84:790), Cheson criteria (lymphomatoid granulomatosis) and PET response criteria (Erdheim Chester disease) standardized criteria. Adverse effects were classified according to Common Terminology Criteria for Adverse Events (CTCAE4.0). Categorical and continuous data were expressed as ratio (%) and median (range). Statistical analyses were done by SPSS v17 (Chicago, IL).Results:There were 30 patients with 8 different hematologic neoplasms: 12 PV, 6 ET, 2 chronic myeloid leukemia (CML), 3 systemic mastocytosis (SM), 4 Erdheim-Chester disease (ECD), 1 primary myelofibrosis (PM), 1 hypereosinophilic syndrome (HES), and 1 lymphomatoid granulomatosis (LG). Detailed descriptive data, toxicity and treatment results are presented in table 1. Responses were observed in all disease categories. Toxicities were frequent in PV/Et, including significant autoimmune disorders (nephritic syndrome, autoimmune hepatitis)Conclusion:Peg-IFN is effective in many hematologic neoplastic disorders. Unfortunately, toxicity is a major concern in this treatment. [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

P14.08 Neurological complications of emerging targeted therapies

AbstractIntroduction:The development of new biological and immunotherapeutic agents to treat cancer associates unknown neurological toxicities. Crizotinib (Cri), an anaplastic lymphoma kinase and c-ros oncogene 1 hepatocyte growth factor receptor tyrosine-kinase inhibitor, has been approved for the treatment of advanced ALK-positive non-small cell lung cancer. Ipilimumab (Ipi), an anticytotoxic T-lymphocyte antigen-4 antibody, was the first agent to demonstrate improved survival in patients with metastatic melanoma. This report describes a patient treated with Ipi showing a not previously reported neurological adverse event; and a patient treated with Cri showing atypical brain metastases.Patients and methods:Patient 1(P1): 66-year-old male with a history of irresectable nasal melanoma, started on Ipi plus concomitant radiotherapy on September/2015, obtaining a radiological partial response. Two months later he developed progressive cognitive impairment, urinary incontinence and gait difficulties. A neuroaxis MRI revealed multiple acute and subacute subcentimeter ischemic lesions with contrast enhancement and restricted diffusion with diffuse FLAIR signal changes. CSF reported protein elevation, normal glucose and mild lymphocytic pleocytosis without neoplastic cells. Microbiological cultures and PCRs were negative. Echocardiography was normal. Patient 2(P2): 54-year-old non-smoker female with lung adenocarcinoma (EGFR wild-type and ALK translocation) and spinal metastatic disease at diagnosis, started on Cri after failure of first-line treatment with cisplatin plus pemetrexed. After 16 cycles, an increase in carcinoembryonic antigen was noted without progression of ganglio-pulmonary disease. Although asymptomatic, CNS progression was suspected and follow-up brain MRI reported multiple bilateral supra and infratentorial large cystic lesions with perilesional edema and no contrast enhancement.Results:P1: primary angiitis of the CNS was suspected, although arteriography was unremarkable. He received high-dose metilprednisolone followed by cyclophosphamide bolus. The inflammatory component of CSF and neurological symptoms presented partial improvement but brain MRI showed a dissociate response. P2: PET scan revealed irregular distribution of the radiotracer and hypometabolic lesions. Follow-up brain MRI revealed stabilization with a perfusion-weighted sequence reporting an increase in the relative cerebral blood volume of the bigger cystic lesion. These features led us to the diagnostic of indolent brain metastases.Conclusions:Early recognition of new neurological patterns of toxicity may lead to drug discontinuation or dose adjustment preventing further neurological deterioration. A better knowledge of these toxicities will help differentiate treatment-related complications from metastatic progression.

Economic evaluation of desvenlafaxine in the treatment of major depressive disorder in Spain

IntroductionThe objective of this analysis was to evaluate the clinical and economic value of the use of 50mg-desvenlafaxine compared to the usual care (mix of duloxetine and venlafaxine) in the outpatient treatment of major depressive disorder after first line treatment failure (relapse) in Spain. Materials and methodsA Markov model was used to follow up a cohort of major depressive disorder patients for 1 year after failure of first-line treatment with a serotonin-specific reuptake inhibitor and estimate outcome measures (percentage remission and depression-free days) and accrued and direct costs incurred during outpatient treatment of major depressive disorder. In order to obtain the efficacy data related to the treatment alternatives, a literature review of clinical trials was performed. A panel of clinical experts validated the use of clinical resources employed in the estimation of economic outcomes together with model assumptions. The analysis was performed in 2014 from the perspective of the National Health System. ResultsDue to fewer discontinuations, initiating second line treatment with desvenlafaxine was associated with more depression-free days and a higher percentage of patients in remission versus usual care: 1.7 days and 0.5%, respectively. This was translated into lower drug and events management costs, and an overall cost reduction of €108 for the National Health System. ConclusionsIn patients who have not responded to a first-line serotonin-specific reuptake inhibitor therapy, desvenlafaxine-50mg was clinically similar in effectiveness, but a less costly option, compared with a weighted average of duloxetine and venlafaxine for the second-line treatment of major depressive disorder patients from a payer (National Health System) perspective in Spain.

Abstract OT3-02-09: Seraphina – Safety efficacy and patient reported outcomes of advanced breast cancer patients: Therapy management with NAB-paclitaxel in daily routine

Abstract BACKGROUND Treatment of patients with advanced breast cancer (ABC) has evolved significantly. Nevertheless, further improvement in ABC treatment is a high medical need. Besides the prolongation of progression free survival (PFS) and overall survival (OS) the major objective of new therapeutic approaches is the enhancement of quality of life (QoL). A recent advance for the treatment of ABC was the development of the cremophor-free albumin-bound paclitaxel, nab-Paclitaxel. SPECIFIC AIMS/TRIAL DESIGN The aim of this non-interventional study is the analysis of efficacy and safety data of ABC patients within routine treatment with nab-Paclitaxel. A key focus will be the assessment of patient reported outcomes (PRO), health economic aspects and the influence of breast cancer patient characteristics on prognosis, adverse event frequencies, PRO and therapy decision making. Patients with ABC, who experienced failure of first-line treatment for metastatic disease and for whom standard anthracycline-containing therapy is not indicated, will be followed up under real-life conditions. Sixty sites, equally distributed with regard to their organizational structure (hospital and office based) and medical disciplines (gyneco-oncologists and medical oncologists) will document 1,200 patients. The primary objective is the assessment of PFS under real-life conditions. Secondary objectives include the assessment of overall and breast cancer specific survival, the influence of age on prognosis and QoL, as well as the incidence of (serious) adverse events (AE). PRO including FACT-B, FACT-Taxane, and nab-Paclitaxel treatment specific questions will be collected in a web based application and compared to paper based reporting. Furthermore, biomaterials will be collected to allow translational research projects. ELIGIBILITY CRITERIA: Adult women (&amp;gt;18 years) with ABC and treated with nab-Paclitaxel. STATISTICAL METHODS/TARGET ACCRUAL: In Germany nab-Paclitaxel is indicated for patients with metastatic breast cancer after failure of a previous therapy in ABC. In this therapeutic setting several studies have shown high efficacy and acceptable toxicity. However, populations within clinical trials are selected and may be different from the general patient population in clinical practice. Therefore this study aims at the capture of PFS, PRO and AE in the general population for which nab-Paclitaxel is used in clinical practice. Nab-Paclitaxel treatment will be documented over a period of up to 6 months, followed by a 30 months progression/ survival follow-up. Target accrual is 1,200 patients. We assume that at most 10% are lost to follow-up before the median survival time is reached. Kaplan-Meier curves will be calculated, especially the median survival time with 95% confidence interval. Citation Format: Fasching PA, Wallwiener M, Lux MP, Mueller V, Schneeweiss A, Tesch H, Brucker SY, Haeberle L, Spall T, Belleville E, Lück H-J. Seraphina – Safety efficacy and patient reported outcomes of advanced breast cancer patients: Therapy management with NAB-paclitaxel in daily routine. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr OT3-02-09.

Second-line treatment of recurrent HNSCC: tumor debulking in combination with high-dose-rate brachytherapy and a simultaneous cetuximab-paclitaxel protocol.

Background and purposeAfter the failure of first-line treatment, the clinical prognosis in head and neck cancer (HNSCC) deteriorates. Effective therapeutic strategies are limited due to the toxicity of previous treatments and the diminished tolerance of surrounding normal tissue. This study demonstrates a promising second-line regimen, with function preserving surgical tumor debulking, followed by a combination of postoperative interstitial brachytherapy and a simultaneous protocol of cetuximab and taxol.Patients and methodsFrom January 2006 to May 2013, 197 patients with HNSCC were treated with brachytherapy at the University Hospital Schleswig-Holstein Campus Lübeck, including 94 patients due to recurrent cancer. Within these, 18 patients were referred to our clinic because of early progressive disease following first- or second-line treatment failure. They received the new palliative regimen. A matched-pair analysis including recurrent tumor stage, status of resection margins, tissue invasion and previous therapy was performed to evaluate this treatment retrospectively. Overall survival (OS), disease-free survival (DFS), functional outcome and treatment toxicity was analyzed on the basis of medical records and follow-up data.ResultsDFS and OS of the study group were 8.7 and 14.8 months. Whereas, DFS and OS of the control group, treated only by function preserving tumor debulking and brachytherapy, was 3.9 and 6.1 months respectively. This demonstrates a positive trend through the additional use of the cetuximab-taxane protocol. Furthermore, no increase of therapy induced toxicities was displayed.ConclusionPre-treated patients with a further relapse benefit from the ‘cetuximab-taxane recurrency scheme’. It seems to be a valuable complement to interdisciplinary and multimodal tumor therapy, which improves OS and results in acceptable toxicity.Electronic supplementary materialThe online version of this article (doi:10.1186/s13014-016-0583-0) contains supplementary material, which is available to authorized users.

Prognostic value of hemoglobin level increase during axitinib treatment for metastatic renal cell carcinoma.

580 Background: Axitinib is used after failure of first line treatment for metastatic renal cell carcinoma (mRCC). A common side effect of axitinib is the increase of hemoglobin level (HbL) during treatment with a suspected correlation with better outcome. We examined whether HbL increase during the first 3 months of axitinib treatment is associated with better prognosis. Methods: Retrospective multicenter analysis including patients with mRCC treated with axitinib for at least 3 months from 2012 to 2014 as part of the French temporary use authorization cohort. Progression-free survival (PFS) was analyzed according to the following factors: gender, International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) prognostic score at axitinib initiation, polycythemia (HbL above 16.5/18.5 g/dL or hematocrit above 56/60% for women/men), and maximum increase in HbL within the first 3 months of treatment. Results: 97 patients were analyzed (71% men; median age at diagnosis: 54.7 years [22; 80]; IMDC: 23%, 49%, and 27% in the favorable, intermediate, and poor-risk group, respectively). Patients received axitinib for a median of 8 months [3; 30]. Grade 2-3 toxicities were observed in 81% of patients. Objective response rate was 32%. The median PFS and OS were 8.9 [7.4; 9.3] and 22 [19.4; not reached] months, respectively. During the first 3 months, 81 patients (84%) experienced HbL increase with a median increase of +2.3g/dL [-1.1; 7.2] and 40 of them (51%) had an increase above this median. Eight patients (8%) presented polycythemia. In univariate analysis, significantly longer PFS was observed for men (p = 0.02), for patients who had a better IMDC prognostic score (p = 0.004), and for patients who experienced an increase of HbL ≥ 2.3 g/dL (with a median PFS of 11.7 vs. 7.4 months; p = 0.025), but not for patients with polycythemia. In a multivariate analysis, after adjustment for IMDC score (p &lt; 0.0001) and gender (p = 0.029), an increase in HbL ≥ 2.3 g/dL was significantly associated with a longer PFS (HR = 0.57, 95%CI [0.34; 0.95]). Conclusions: HbL increase ≥ 2.3g/dL in the first 3 months of axitinib treatment was associated with longer PFS. These results require validation in a prospective trial setting.

Second-Line Low-Dose Cytarabine after First-Line Treatment with 5-Azacitidine in Elderly Patients with AML or High-Risk MDS Ineligible for Intensive Chemotherapy. A Retrospective Single Center Analysis

Introduction: Although there have been progress in treatment and outcomes of acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) in younger patients, treatment of elderly patients, who are not eligible for intensive treatment is still challenging. The demethylating agents azacitidine (AZA) or decitabine recently became a standard of care for first line treatment of elderly or unfit patients with high-risk MDS or AML. Despite the improvement in overall survival with epigenetic therapies, almost all patients eventually develop disease progression, for which no standard therapeutic option is available. The aim of this retrospective analysis was to evaluate the outcome of low-dose cytarabine (LDARAC) treatment compared to best supportive care (BSC) as second-line palliative treatment options after failure of AZA.Patients and Methods: From 2009 to 2014 we treated 75 consecutive patients with newly diagnosed high-risk MDS or de novo AML, with AZA (75mg/m2 sc. d1-7, qd29). Patients who responded to AZA after at least four courses and had a subsequent relapse, as defined by worsening of peripheral blood counts, increase of blasts or increase in transfusion frequency, received a second-line treatment with subcutaneous LDARAC (2x 10 mg/m2/d sc., d1-10, qd29) until progression or were followed by best supportive care, including symptomatic treatment, transfusions or treatment of clinical infections- but without chemotherapy.Results: After first-line AZA 48/75 (64%) achieved a partial hematologic response (n=23), stable disease (n=14) or clinical benefit (n=7). The median overall survival (OS) of all 48 patients with response or clinical benefit to AZA was 27 months. Median duration of response was 13 (4-56) months. Cytogenetic risk at diagnosis was a significant prognostic factor for OS (P<0.001), but not age or ECOG-PS (P =0.17 and P =0.68, respectively). After a median follow-up of 24 months, 31 patients had a loss of hematologic response. Fifteen of 31 relapsed patients were treated with a second-line therapy with LDARAC until progression. Two of those 15 patients received an initial re-induction therapy with intermediate dose cytarabine plus daunorubicine ("5+2"). 16 patients were followed by BSC. Four of 15 patients who were treated with LDARAC achieved a partial hematologic response and 6/15 had stable disease with a median response duration of 4 months. In the BSC group no objective responses were observed. The median overall survival from the time of progression on AZA (OS-2) was 7.2 months in patients treated with LDARAC versus 2.9 months in patients who received BSC care only (P<0.01). In a multivariate analysis response to LDARAC was the only significant prognostic factor for OS-2 (P =0.02, HR: 3.16), while age, ECOG-PS or cytogenetic risk did not reach statistical significance.Conclusions: Our analysis shows that second-line treatment with LDARAC may add a survival benefit of approximately 3 months compared to BSC alone. The second overall survival (OS-2) of 7.2 months is within the range achieved with LDARAC as primary treatment for this patient population. Our data indicate that LDARAC can be considered as a reasonable therapeutic option after failure of first-line treatment with demethylating agents like AZA. This clinical observation is supported by recent pre-clinical data, showing that epigenetic modifications in AML cells can have a sensitizing effect for the subsequent administration of cytarabine. DisclosuresNo relevant conflicts of interest to declare.

OP70 – 2417: Plasma exchange (PLEX) in pediatric neurologic diseases: Assessment of safety and efficacy

Objective We aim to assess the indication, safety and outcome of PLEX in pediatric patients with neurologic diseases. Methods Retrospective cohort study of consecutive patients seen in the dialysis and apheresis clinic of a tertiary care center between April 2007 and March 2013. Included were all pediatric patients treated with PLEX for an underlying neurologic disease. Adverse events (AE) were recorded according to the Common Terminology Criteria for Adverse Events classification. The key neurological deficit was graded as none, mild (fully ambulatory, no impact on activities of daily living (ADL)), moderate (limiting ambulation and/or ADL), and severe (wheelchair/bed ridden and/or ventilated), assessed at beginning/end of PLEX, at discharge from the acute care facility and at last clinical encounter. Primary outcome was the neurological deficit at last clinical encounter. Results A total of 109 (48 female, 44%) patients received PLEX. Eighteen (12%; 13 female (72%)) had an underlying neurologic disease consisting of: demyelinating (10), antibody-associated (2), other inflammatory neurologic diseases (6). Indication for PLEX was failure of first line treatment in all but one patient. Median (range) age at PLEX was 10.8 years (0.8–17.9 years). The key neurological deficit at PLEX start was severe in 15 (83%) and moderate in three (17%) patients. A total of 39 AE were recorded, consisting of hypotension (8), allergic reaction (3), anemia (15), thrombosis (2) and hypocalcemia (11). Twelve (31%) AE were graded as severe. At discharge from the acute care facility, six patients (33%) were ambulatory with support. At last clinical encounter after a median (range) follow up time of 2.0 years (0.3–6.6 years), the neurological deficit was none/mild in ten patients (59%). Conclusion For pediatric patients with severe inflammatory neurologic diseases PLEX is a safe treatment option. One third showed early improvement and almost 60% regained independent ambulation over the follow up period.

L’interferon alfa a-t-il encore des indications dans la prise en charge du syndrome de Kasabach-Merrit ?

Kasabach-Merritt syndrome (KMS), characterized by thrombocytopenia, may complicate vascular tumors such as kaposiform hemangioendothelioma and tufted angioma. We report on two infants, respectively 2 months and 15 days old at the onset of symptoms, the first of whom presented with a left cervico-occipito-scapular hemangioma with parotid extension, and the second with a vascular tumor located on the left shoulder with fast extension on the left inferior hemithorax and the left arm. Thrombocytopenia (< 20 G/L) was associated in both cases. Treatment comprised first high-dose corticosteroids (2mg/kg) in association with vincristine (1mg/m(2)/week). Interferon was introduced as third-line treatment at 3 MIU/m(2)/day. In the first patient, interferon was effective both on thrombocytopenia and tumor in 2 months. In the second patient, the first interferon treatment was not effective despite 6 months of therapy. However, a second treatment 8 years later was successful. After 10 and 3 years follow-up, respectively, there were no side effects and most particularly no neurologic complications. These two observations open the discussion of the role of interferon (3 MIU/m(2)/day) as well as new therapies in the control of angiogenesis in case of failure of first-line treatment of complicated KMS vascular tumors.

The combination of DPP-4 inhibitors versus sulfonylureas with metformin after failure of first-line treatment in the risk for major cardiovascular events and death.

To determine whether the combination of dipeptidyl-peptidase 4 (DPP-4) inhibitors vs. sulfonylureas with metformin after failure of first-line treatment is associated with a decreased risk for major adverse cardiovascular events (myocardial infarction and stroke) and for all-cause mortality. Using the UK Clinical Practice Research Datalink, a cohort of patients newly treated with metformin or sulfonylurea monotherapy between January 1, 1988, and December 31, 2011, was identified and was followed until December 31, 2012. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazards models to compare the DPP-4 inhibitor-metformin combination to the sulfonylurea-metformin combination so as to study the risk for a composite endpoint consisting of myocardial infarction, stroke and all-cause mortality. The models were adjusted for high-dimensional propensity score deciles. The cohort consisted of 11,807 patients that included 2286 on a DPP-4 inhibitor-metformin combination and 9521 on a sulfonylurea-metformin combination. The crude incidence rates (95% CIs) of the composite endpoint were 1.2% (0.8% to 1.7%) and 2.2% (1.9% to 2.5%) per year for the DPP-4 inhibitor-metformin and sulfonylurea-metformin combinations, respectively. In the high-dimensional propensity score-adjusted model, the use of the DPP-4 inhibitor-metformin combination was associated with a 38% decreased risk for the composite endpoint (adjusted HR: 0.62; 95% CI 0.40 to 0.98), compared with the sulfonylurea-metformin combination. The use of a DPP-4 inhibitor combination with metformin, compared with a sulfonylurea-metformin combination, was associated with decreased risks for major cardiovascular events and all-cause mortality.

Therapy in pancreatic cancer - and still it moves along!

According to predictions pancreatic ductal adenocarcinoma will be the third most common cancer-related cause of death in 2030 due to its growing incidence and advances in prevention and treatment of other tumor entities. Pancreatic cancer is usually a (too) late diagnosed disease. Already at time of primary diagnosis nearly 80 % of patients have palliative disease due to local irresectability or distant metastases. Even after R0 resection of the primary tumor followed by adjuvant chemotherapy the 5-year overall survival rate does not exceed 20 %. Recently the treatment landscape has significanty changed in metastatic pancreatic cancer. For the first time, we have the opportunity to personalize our therapies in the field of pancreatic cancer. In addition, the range of therapeutic options after failure of first-line treatment expands more and more. After years of stagnation and negative results in clinical trials these advances inspire and dynamize the landscape of new clinical trials in this entity.

Cost-consequences Analysis of Desvenlafaxine Versus Usual Care in the Treatment of Major Depressive Disorder After Failure of First-line Treatment with a Selective-serotonin-reuptake-inhibitor (SSRI) in Spain

Aim To carry out a cost-consequences analysis for 50mg-desvenlafaxine in the second-line outpatient treatment of major depressive disorder (MDD) from the payer (National Health System) perspective in Spain. Methods The model (Markov simulation) follows a cohort of MDD patients through 1 year after failure of first-line treatment with a SSRI and estimates outcome measures (% remission and depression-free days) accrued and costs incurred during outpatient treatment of MDD. Selected comparator is usual care (UC), which is assumed to be made of a mix of duloxetine and venlafaxine that make up the majority of the serotonin-norepinephrine reuptake inhibitor (SNRI) market in Spain. The model also considers drug treatment beyond the second-line of therapy (3 rd and 4 th -lines) in cases of patient discontinuation or lack of remission according with outcomes from STAR-D trial and other clinical trial published. The model generates outcomes and cost from the NHS in year 2014. Results Due to fewer discontinuations, desvenlafaxine was associated with numerically more depression-free days and a higher percentage of patients in remission versus UC: 1.7 days and 0.5% more in remission. Also, healthcare costs were lower with desvenlafaxine than with UC: €1,114 vs. €1,224 (-110€). Conclusion In patients who have not responded to a first-line SSRI therapy, desvenlafaxine-50mg was clinically similar in effectiveness but a less costly option, approximately 9% lower, compared with a weighted average of duloxetine and venlafaxine for the second-line treatment of MDD patients from a payer (NHS) perspective in Spain.

Modelling the Economic Impact of Desvenlafaxine Versus Venlafaxine as a Second Line Therapy of Major Depressive Disorder Patients in Spain

Aim To model the cost and consequences of desvenlafaxine and venlafaxine in the second-line outpatient treatment of major depressive disorder (MDD) from the payer (National Health System) perspective in Spain. Methods The model (a Markov simulation) follows a cohort of MDD patients through 1 year after failure of first-line treatment with a Selective-Serotonin-Reuptake-Inhibitor (SSRI) and estimates outcome measures (% in remission and depression-free days) accrued and costs incurred during outpatient treatment of MDD. Selected comparator is venlafaxine because its actual generic price. The model also considers drug treatment switching beyond the second-line of therapy (3rd line) or changing to another drugs in 4th-line in cases of patient discontinuation or lack of remission according with outcomes from STAR-D trial. Efficacy of drugs was extracted from clinical trial published. The model generates outcomes and cost from the NHS in year 2014. Results Due to fewer discontinuations, desvenlafaxine was associated with numerically more depression-free days and a higher percentage of patients in remission versus venlafaxine: 1.7 days and 0.5% more in remission. Also, healthcare costs were a little bit lower with desvenlafaxine than with venlafaxine: €1,114 vs. €1,166 (-52€). Conclusion In patients who have not responded to a first-line SSRI therapy, desvenlafaxine-50mg was clinically similar in effectiveness but a less costly option (about 5% lower) compared with venlafaxine for the second-line treatment of MDD patients from a payer (NHS) perspective in Spain.

Phase II Randomized, Multicenter Study of Lenalidomide Vs Best Investigator’s Choice in Relapsed/Refractory Mantle Cell Lymphoma: Results of the MCL-002 (SPRINT) Study

Introduction: Mantle cell lymphoma (MCL) is an aggressive non-Hodgkin’s lymphoma with poor outcome, especially after failure of first-line treatment. Lenalidomide, an immunomodulatory drug with antineoplastic and antiproliferative effects, has shown activity in single-arm phase II studies of patients with relapsed/refractory (R/R) MCL. The present controlled randomized study compared the efficacy and safety of lenalidomide vs investigator’s choice (IC) in patients with R/R MCL.Methods: MCL-002 (SPRINT), a European multicenter, open-label, phase II study enrolled patients with up to 3 relapses or who failed prior therapy and were ineligible for intensified treatment or stem cell transplantation (NCT00875667). Oral lenalidomide was given at 25 mg/day on days 1-21 of each 28-day cycle until progressive disease (PD) or intolerability. The IC treatment consisted of single-agent therapy with cytarabine, rituximab, gemcitabine, fludarabine, or chlorambucil. Patients who progressed on IC per investigator judgment were allowed to crossover to lenalidomide. The primary endpoint was progression-free survival (PFS); secondary endpoints included overall response rate (ORR), time to first response, duration of response (DOR), overall survival (OS), and safety. Response assessments were centrally reviewed using the modified IWG criteria.Results: 254 patients with R/R MCL were randomized 2:1 to lenalidomide (n=170) or IC (n=84). Patients had median age 68.5 years, were predominantly male (73%), and had received a median of 2 prior therapies. 91% had stage III/IV disease at diagnosis, with 34% high-risk MIPI, 43% high tumor burden, and 20% bulky disease at baseline. Overall, patients on the lenalidomide arm had a worse prognostic profile than the IC arm due to higher tumor burden and disease risk (>5 percentage points for a number of parameters). After a median time of 2.9 months, 39 patients (46%) from the IC arm crossed over to lenalidomide due to PD. Overall, 84 patients remain on lenalidomide (15 having crossed over from IC) and 11 patients on IC without PD.At a median follow-up time on study of 15.9 months, the risk reduction for PFS was 39% (HR=0.61 [95% CI, 0.44-0.84]; P=0.004; Table) in favor of lenalidomide (median PFS: 8.7 months lenalidomide vs 5.2 months IC). ORR was significantly improved for lenalidomide vs IC (40% vs 11%; CR/CRu 5% vs 0%). Median time to first response was 4.3 months for lenalidomide (not reached for IC). Median DOR (16.1 vs 10.4 months) and OS on mature data (27.9 vs 21.2 months) were longer for lenalidomide vs IC. Efficacy results were consistent among subgroups. Safety data in 250 patients receiving ≥1 dose showed more dose reductions in lenalidomide-treated patients (41%) vs IC (17%), due in part to a longer median duration of lenalidomide treatment vs IC, and to strict dose modification rules for lenalidomide. The most common grade 3/4 adverse events (AEs) were neutropenia (lenalidomide 44% vs IC 34% [without increased risk of infection]), thrombocytopenia (18% vs 28%), and leukopenia (8% vs 11%). Tumor flare reaction occurred in lenalidomide patients only (10%; 2% grade ≥3); 1 patient in each arm experienced tumor lysis syndrome. Invasive second primary malignancies were identified in 4% and 5% of lenalidomide and IC treated patients, respectively.Conclusions: The MCL-002 study demonstrated a statistically significant and clinically meaningful improvement in PFS for lenalidomide over best IC monotherapy in patients with advanced R/R MCL despite a worse prognostic profile in the lenalidomide arm at baseline. In addition, ORR and CR rates, TTR, DOR, and OS were improved for lenalidomide over IC. The DOR has been remarkably consistent in various studies with lenalidomide in MCL patients. The safety profile for lenalidomide was as expected and no new safety signals were identified. The results of this first randomized, controlled study of lenalidomide showed superior efficacy compared to IC in patients with R/R MCL with a manageable toxicity profile.TableEfficacy of lenalidomide vs IC in R/R MCLEfficacyLenalidomide (n=170)IC (n=84)PPFS (Lenalidomide vs IC)Median PFS, mo (95% CI)8.7 (5.54-12.14)5.2 (3.67-6.95)Sequential HR (95% CI)0.61 (0.44-0.84)Sequential log-rank test p-value0.004ORR, n (%)68 (40)9 (11)<0.001CR/CRu, n (%)8 (5)0 (0)0.043Median DOR, mo16.110.40.421Median OS, mo27.921.20.52 DisclosuresTrneny:Celgene, Roche: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Novartis: Research Funding. Walewski:Celgene: Consultancy, Other, Research Funding; Janssen-Cilag: Consultancy; Mundipharma : Consultancy, Research Funding; Roche: Consultancy, Honoraria, Other, Research Funding. Jurczak:Celgene, Eisai, Gilead, Janssen, Pharmacyclics, Pfizer, Roche, Novartis, Spectrum, Takeda, Teva: Research Funding. Belada:Celgene: Research Funding. Mayer:Janssen Research & Development: Research Funding; Roche: Research Funding; GlaxoSmithKline: Research Funding; Celgene: Research Funding. Biyukov:Celgene: Employment. Patturajan:Celgene: Employment. Casadebaig Bravo:Celgene: Employment. Arcaini:Celgene, Roche, Pfizer: Consultancy, Membership on an entity’s Board of Directors or advisory committees.

Second-line docetaxel-based chemotherapy after failure of fluorouracil-based first-line treatment for advanced esophageal squamous cell carcinoma.

PurposeThis retrospective analysis evaluates the clinical efficacy and toxicity of second-line docetaxel-based chemotherapy after failure of fluorouracil-based first-line treatment for advanced esophageal squamous cell carcinoma (ESCC).MethodsWe retrospectively reviewed patients who had received second-line docetaxel-based chemotherapy for advanced ESCC in Zhejiang Cancer Hospital between January 2008 and December 2011. Survival curves were plotted using the Kaplan–Meier method. The Cox proportional hazard model was used for multivariate analysis.ResultsEighty-five patients received docetaxel-based second-line chemotherapy after the failure of first-line fluorouracil-based treatment. Forty-four patients received docetaxel-platinum chemotherapy, and 41 received docetaxel single-agent treatment. The progression-free survival (PFS) and overall survival (OS) were 3.5 and 5.5 months in all of the patients, respectively. There were no statistically significant differences in PFS and OS between docetaxel-platinum and docetaxel single-agent chemotherapy groups (P-value 0.38 and 0.64, respectively). Response to first-line chemotherapy was a favorable prognostic factor for PFS in uni- and multivariate analyses (P-value 0.005 and 0.028, respectively).ConclusionPatients with docetaxel-based second-line treatment obtained a moderate PFS advantage in advanced ESCC. Response to first-line chemotherapy was a favorable prognostic factor for PFS of second-line chemotherapy in advanced ESCC.

Improving outcomes in metastatic clear cell renal cell carcinoma by sequencing therapy.

Targeted agents have substantially improved outcomes in metastatic clear cell renal cell carcinoma. However, due to multiple mechanisms of evasive resistance, almost all patients progress at some point and may require subsequent therapies. Various agents have been explored after failure of first-line treatment in randomized clinical trials. However, so far few questions about the optimal sequence have been answered. Both everolimus and axitinib have been considered standard of care after failure of first-line VEGF-TKI; sorafenib has been proposed as an additional option. In clinical practice, several factors may influence the choice of subsequent treatment: these include considerations on appropriate drug exposure in first-line, gained insights on prognostic and predictive factors as well as mechanisms of resistance. Once the decision in second-line has been made and treatment has been initiated, treating physicians may already be challenged by the question of what to offer in third- and later lines. Treatment beyond second-line treatment isn't supported by strong evidence, and at this stage of disease, retrospective reports on rechallenge may help to guide decisions. In addition, local treatment approaches including metastasectomy and stereotactic radiosurgery may help to optimize outcomes in all treatment lines.

Proximal Humeral Fracture Treatment in Adults

Most proximal humeral fractures affect elderly patients and can be treated nonoperatively with good functional outcomes.The treatment of displaced three and four-part fractures remains controversial and depends on a variety of underlying factors related to the patient (e.g., comorbidity, functional demand), the fracture (e.g., osteoporosis), and the surgeon (e.g., experience).Throughout the literature, open reduction and locking plate osteosynthesis is associated with considerable complication rates, particularly in the presence of osteoporosis.Low local bone mineral density, humeral head ischemia, residual varus displacement, insufficient restoration of the medial column, and nonanatomic reduction promote failure of fixation and impair functional outcome.The outcome of hemiarthroplasty is closely related to tuberosity healing in an anatomic position to enable the restoration of rotator cuff function. Reverse shoulder arthroplasty may provide satisfactory shoulder function in geriatric patients with preexisting rotator cuff dysfunction or after the failure of first-line treatment.

The Prognostic Value Of Dynamic Monitoring C-Reactive Protein (CRP) Serum Levels In NK/T-Cell Lymphoma

The prognostic value of dynamic monitoring C-reactive protein (CRP) serum levels in NK/T-cell lymphoma Background and ObjectiveC-reactive protein (CRP) is a kind of acute phase protein against inflammatory reaction. CRP has been proved to be associated with prognosis in various malignancies. Yet, the prognostic value of CRP in natural killer/T-cell lymphoma (NK/TCL) remains to be discussed. In this study, we aimed to observe the dynamic change of CRP serum levels during anti-lymphoma treatment, and to evaluate the prognostic value of CRP as a simple and economical biomarker during the early stage of treatment in patients with NK/T-cell lymphoma. Patients and MethodsBetween January 2003 and December 2011, 161 patients with newly diagnosed NK/TCL at the Sun Yat-sen University Cancer Center (SYSUCC) were reviewed retrospectively. Clinical and laboratory information was collected and analyzed. The following CRP serum levels were evaluated: pretreatment CRP (CRP0), early-treatment CRP (CRP1, after one cycle of chemotherapy, or two or three weeks since beginning of radiation), and post-treatment CRP (CRP2, after first-line treatment, or failure of first-line treatment). ResultsOverall, 161 patients were reviewed and analyzed. The median age was 44 years (range, 11¨C74). The majority had localized disease (stage I/ II; 75.5%). The CRP serum levels (mean ± standard deviation) were as follows: CRP0, 17.2±23.1 mg/L; CRP1, 14.0±30.0 mg/L; CRP2, 14.1±27.0 mg/L. The pretreatment CRP serum levels correlated with others unfavorable factors, including serum lactate dehydrogenase (LDH) (P = 0.005), presence of bulky disease (P = 0.002), presence of B symptoms (P = 0.017), the International Prognostic Index (IPI) score (P = 0.001) and the Korean Prognostic Index (KPI) score (P = 0.001). By the time of the final follow up assessment (May 2013), the median follow-up time was 23.0 months (range, 1.0-106.0 months). The median overall survival (OS) and progression-free survival (PFS) were 45.0 months (range, 1.0-106.0 months) and 32.0 months (range, 1.0-74.0 months), respectively. The independent unfavorable prognostic factors for OS (P < 0.05) in multivariate analysis included: elevated CRP1 (P < 0.001), presence of bulky disease (P = 0.007), and elevated β2-microglobulin (β2-mg) serum levels (P = 0.004). The receiver operating characteristic analysis revealed a similar cut-off value of CRP (8.16 mg/L) to the default value of the biochemical analyzer (8.2 mg/L). In addition, the result suggested a satisfying capacity of CRP1 in predicting response to initial treatment (sensitivity 94%, specificity 74%) and 5-year OS (sensitivity 75%, specificity 90%), among different serum biomarkers, including EBV-DNA, LDH, β2-mg, CRP0, CRP1, and CRP2. In all groups of patients classified according to dynamic CRP values, the patients with CRP0 (+) /CRP1(-) presented the most favorable prognosis (5-year estimated OS: 72.5%). ConclusionsOur study suggests that elevated early-treatment CRP is an independent unfavorable prognostic factor for patients with NK/TCL. Compared with the baseline CRP, the dynamic change of CRP levels may provide more important information for prognosis during treatment. [Display omitted] [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Gemcitabine and docetaxel, an effective second-line chemotherapy for lung metastasis of urothelial carcinoma

The objective of this study was to evaluate the efficacy of a gemcitabine and docetaxel (GD) combination as a second-line treatment for patients with metastatic urothelial carcinoma (UC) after failure of first-line treatment with platinum-based chemotherapy. From June 2006 to January 2012, 38 patients with metastatic UC previously treated with platinum-based chemotherapy received GD therapy. This consisted of gemcitabine 800 mg/m(2) and docetaxel 40 mg/m(2) on days 1 and 8 of each 21-day cycle as second-line chemotherapy. All the patients were evaluated for toxicity and assessed every cycle by imaging. We analyzed the efficacy of GD as second-line chemotherapy in the follow-up study. The median number of GD treatment cycles was 4 (range 2-9); the objective response rate was 47.4 %; and the median progression-free survival and median overall survival were 4.1 and 10.8 months, respectively. Univariate and multivariate analyses on the GD treated group showed that the existence of lung metastases was the only prognostic factor for tumor response. Grade 3 treatment-related toxicity included neutropenia (31.6 %) and thrombocytopenia (15.8 %), and only one patient with grade 4 toxicity had thrombocytopenia (2.6 %). The GD regimen as second-line chemotherapy was especially effective for lung metastatic UC and yielded favorable results in patients whose first-line platinum-based chemotherapy had failed. Given the safety and benefit profile seen in this study, a large prospective study is warranted to consider the potential utility of GD chemotherapy as a second-line for UC.

Pazopanib as Second-Line Treatment After Sunitinib or Bevacizumab in Patients With Advanced Renal Cell Carcinoma: A Sarah Cannon Oncology Research Consortium Phase II Trial

BackgroundThis phase II trial examined the activity and toxicity of second-line treatment with pazopanib after failure of first-line single-agent treatment with sunitinib or bevacizumab in patients with advanced clear cell renal carcinoma. Patients and MethodsFifty-five patients with metastatic clear cell renal carcinoma who had previously received first-line treatment with sunitinib (39 patients) or bevacizumab (16 patients) were enrolled. Patients received pazopanib 800 mg orally daily and were evaluated for response after 8 weeks of treatment. Responses were measured using Response Evaluation Criteria in Solid Tumors (RECIST), version 1.0, and confirmed with repeated scans after 8 weeks. Patients with objective response or stable disease continued treatment until disease progression or unacceptable toxicity occurred. ResultsFifteen of 55 patients (27%) had objective response to pazopanib. An additional 27 patients (49%) had stable disease, for a disease control rate of 76%. After a median follow-up of 16.7 months, the median progression-free survival for the entire group was 7.5 months (95% confidence interval, 5.4-9.4 months). Similar progression-free survival was observed regardless of whether previous treatment was with sunitinib or bevacizumab. The estimated overall survival rate for the entire group at 24 months was 43%. ConclusionPazopanib is an active agent for the treatment of advanced clear cell renal carcinoma, even after failure of sunitinib or bevacizumab. Treatment with pazopanib should be considered early in the sequence of therapy for patients with advanced renal cell carcinoma.