SWITCH : A randomised, sequential, open-label study to evaluate the efficacy and safety of Sorafenib-sunitinib versus Sunitinib-sorafenib in the treatment of metastatic renal cell cancer

Background Understanding how to sequence targeted therapies for metastatic renal cell carcinoma (mRCC) is important for maximisation of clinical benefit. Objectives To prospectively evaluate sequential use of the multikinase inhibitors sorafenib followed by sunitinib (So-Su) versus sunitinib followed by sorafenib (Su-So) in patients with mRCC. Design, setting, and participants The multicentre, randomised, open-label, phase 3 SWITCH study assessed So-Su versus Su-So in patients with mRCC without prior systemic therapy, and stratified by Memorial Sloan Kettering Cancer Center risk score (favourable or intermediate). Intervention Patients were randomised to sorafenib 400 mg twice daily followed, on progression or intolerable toxicity, by sunitinib 50 mg once daily (4 wk on, 2 wk off) (So-Su), or vice versa (Su-So). Outcome measurements and statistical analysis The primary endpoint was improvement in progression-free survival (PFS) with So-Su versus Su-So, assessed from randomisation to progression or death during second-line therapy. Secondary endpoints included overall survival (OS) and safety. Results and limitations In total, 365 patients were randomised (So-Su, n = 182; Su-So, n = 183). There was no significant difference in total PFS between So-Su and Su-So (median 12.5 vs 14.9 mo; hazard ratio [HR] 1.01; 90% confidence interval [CI] 0.81–1.27; p = 0.5 for superiority). OS was similar for So-Su and Su-So (median 31.5 and 30.2 mo; HR 1.00, 90% CI 0.77–1.30; p = 0.5 for superiority). More So-Su patients than Su-So patients reached protocol-defined second-line therapy (57% vs 42%). Overall, adverse event rates were generally similar between the treatment arms. The most frequent any-grade treatment-emergent first-line adverse events were diarrhoea (54%) and hand-foot skin reaction (39%) for sorafenib; and diarrhoea (40%) and fatigue (40%) for sunitinib. Conclusions Total PFS was not superior with So-Su versus Su-So. These results demonstrate that sorafenib followed by sunitinib and vice versa provide similar clinical benefit in mRCC

Multiple Myeloma Treatment in Real-world Clinical Practice : Results of a Prospective, Multinational, Noninterventional Study

Funding Information: The authors would like to thank all patients and their families and all the EMMOS investigators for their valuable contributions to the study. The authors would like to acknowledge Robert Olie for his significant contribution to the EMMOS study. Writing support during the development of our report was provided by Laura Mulcahy and Catherine Crookes of FireKite, an Ashfield company, a part of UDG Healthcare plc, which was funded by Millennium Pharmaceuticals, Inc, and Janssen Global Services, LLC. The EMMOS study was supported by research funding from Janssen Pharmaceutical NV and Millennium Pharmaceuticals, Inc. Funding Information: The authors would like to thank all patients and their families and all the EMMOS investigators for their valuable contributions to the study. The authors would like to acknowledge Robert Olie for his significant contribution to the EMMOS study. Writing support during the development of our report was provided by Laura Mulcahy and Catherine Crookes of FireKite, an Ashfield company, a part of UDG Healthcare plc, which was funded by Millennium Pharmaceuticals, Inc, and Janssen Global Services, LLC. The EMMOS study was supported by research funding from Janssen Pharmaceutical NV and Millennium Pharmaceuticals, Inc. Funding Information: M.M. has received personal fees from Janssen, Celgene, Amgen, Bristol-Myers Squibb, Sanofi, Novartis, and Takeda and grants from Janssen and Sanofi during the conduct of the study. E.T. has received grants from Janssen and personal fees from Janssen and Takeda during the conduct of the study, and grants from Amgen, Celgene/Genesis, personal fees from Amgen, Celgene/Genesis, Bristol-Myers Squibb, Novartis, and Glaxo-Smith Kline outside the submitted work. M.V.M. has received personal fees from Janssen, Celgene, Amgen, and Takeda outside the submitted work. M.C. reports honoraria from Janssen, outside the submitted work. M. B. reports grants from Janssen Cilag during the conduct of the study. M.D. has received honoraria for participation on advisory boards for Janssen, Celgene, Takeda, Amgen, and Novartis. H.S. has received honoraria from Janssen-Cilag, Celgene, Amgen, Bristol-Myers Squibb, Novartis, and Takeda outside the submitted work. V.P. reports personal fees from Janssen during the conduct of the study and grants, personal fees, and nonfinancial support from Amgen, grants and personal fees from Sanofi, and personal fees from Takeda outside the submitted work. W.W. has received personal fees and grants from Amgen, Celgene, Novartis, Roche, Takeda, Gilead, and Janssen and nonfinancial support from Roche outside the submitted work. J.S. reports grants and nonfinancial support from Janssen Pharmaceutical during the conduct of the study. V.L. reports funding from Janssen Global Services LLC during the conduct of the study and study support from Janssen-Cilag and Pharmion outside the submitted work. A.P. reports employment and shareholding of Janssen (Johnson & Johnson) during the conduct of the study. C.C. reports employment at Janssen-Cilag during the conduct of the study. C.F. reports employment at Janssen Research and Development during the conduct of the study. F.T.B. reports employment at Janssen-Cilag during the conduct of the study. The remaining authors have stated that they have no conflicts of interest. Publisher Copyright: © 2018 The AuthorsMultiple myeloma (MM) remains an incurable disease, with little information available on its management in real-world clinical practice. The results of the present prospective, noninterventional observational study revealed great diversity in the treatment regimens used to treat MM. Our results also provide data to inform health economic, pharmacoepidemiologic, and outcomes research, providing a framework for the design of protocols to improve the outcomes of patients with MM. Background: The present prospective, multinational, noninterventional study aimed to document and describe real-world treatment regimens and disease progression in multiple myeloma (MM) patients. Patients and Methods: Adult patients initiating any new MM therapy from October 2010 to October 2012 were eligible. A multistage patient/site recruitment model was applied to minimize the selection bias; enrollment was stratified by country, region, and practice type. The patient medical and disease features, treatment history, and remission status were recorded at baseline, and prospective data on treatment, efficacy, and safety were collected electronically every 3 months. Results: A total of 2358 patients were enrolled. Of these patients, 775 and 1583 did and did not undergo stem cell transplantation (SCT) at any time during treatment, respectively. Of the patients in the SCT and non-SCT groups, 49%, 21%, 14%, and 15% and 57%, 20%, 12% and 10% were enrolled at treatment line 1, 2, 3, and ≥ 4, respectively. In the SCT and non-SCT groups, 45% and 54% of the patients had received bortezomib-based therapy without thalidomide/lenalidomide, 12% and 18% had received thalidomide/lenalidomide-based therapy without bortezomib, and 30% and 4% had received bortezomib plus thalidomide/lenalidomide-based therapy as frontline treatment, respectively. The corresponding proportions of SCT and non-SCT patients in lines 2, 3, and ≥ 4 were 45% and 37%, 30% and 37%, and 12% and 3%, 33% and 27%, 35% and 32%, and 8% and 2%, and 27% and 27%, 27% and 23%, and 6% and 4%, respectively. In the SCT and non-SCT patients, the overall response rate was 86% to 97% and 64% to 85% in line 1, 74% to 78% and 59% to 68% in line 2, 55% to 83% and 48% to 60% in line 3, and 49% to 65% and 36% and 45% in line 4, respectively, for regimens that included bortezomib and/or thalidomide/lenalidomide. Conclusion: The results of our prospective study have revealed great diversity in the treatment regimens used to manage MM in real-life practice. This diversity was linked to factors such as novel agent accessibility and evolving treatment recommendations. Our results provide insight into associated clinical benefits.publishersversionPeer reviewe

Biocompatibility and surface structure of chemically modified immunoisolating alginate-PLL capsules

Grafting of encapsulated living cells has the potential to cure a wide variety of diseases. Large-scale application of the technique, however, is hampered by insufficient biocompatibility of the capsules. A major factor in the biocompatibility of capsules is inadequate covering of the inflammatory poly-L-lysine (PLL) on the capsules' surface. In the present study, we investigate whether tissue responses against alginate-PLL capsules can be reduced by crosslinking the surface of the capsules with heparin or polyacrylic acid. Our transplant study in rats shows a tissue response composed of fibroblasts and macrophages on alginate-PLL-alginate and alginate-PLL-heparin capsules that was completely absent on alginate-PLL-polyacrylic acid capsules. Atomic force microscopy analyses of the capsules demonstrates that the improved biocompatibility of alginate-PLL-capsules by polyacrylic acid coating should not only be explained by a more adequate binding of PLL but also by the induction of a smoother surface. This study shows for the first time that biologic responses against capsules can be successfully deleted by chemically crosslinking biocompatible molecules on the surface of alginate-PLL capsules. (C) 2003 Wiley Periodicals, Inc

Phosphorylated FADD is not prognostic for local control in T1-T2 supraglottic laryngeal carcinoma treated with radiotherapy

OBJECTIVE: The Fas-Associated Death Domain (FADD) gene is located in the chromosome 11q13-region and frequently is amplified in head and neck squamous cell carcinoma. Expression of FADD and its phosphorylated isoform (pFADD) have been associated with aggressive tumor growth, lymph node metastasis, and overall survival. Previously, we demonstrated that pFADD expression was related to a significantly improved local control in early stage (tumor [T]1 to T2) glottic laryngeal squamous cell carcinoma (LSCC). The aim of this study was to examine the prognostic value of pFADD and FADD in T1 to T2 supraglottic LSCC treated with primarily radiotherapy. METHODS: Tumor tissue sections of 60 patients with T1 to T2 supraglottic LSCC treated with primarily radiotherapy were assessed immunohistochemically for expression of pFADD and FADD. Expression percentages and clinical parameters and their associations with clinical outcome were studied using Cox regression and Kaplan-Meier survival analyses. Expression percentages in supraglottic and glottic LSCC were compared using the Mann-Whitney U test. RESULTS: Expression of pFADD and FADD in supraglottic and glottic LSCC did not significantly differ. In supraglottic LSCC, both pFADD and FADD did not show prognostic value for local control (hazard ratio [HR] 1.00, 95% confidence interval [CI] 0.98-1.03; HR 1.03, 95% CI 0.60-1.78, respectively) and overall survival (HR 0.99, 95% CI 0.98-1.01; HR 1.19, 95% CI 0.83-1.71 respectively). In this cohort, lymph node status was the best predictor for local control (HR 3.73, 95% CI 1.30-10.67). CONCLUSION: In this homogeneous cohort of T1 to T2 supraglottic LSCC primarily treated with radiotherapy, lymph node status was associated with local recurrence, whereas the expression of pFADD was not. LEVEL OF EVIDENCE: NA. Laryngoscope, 2017

Patient assessment and feasibility of treatment in older patients with cancer: results from the IN-GHO® Registry

Purpose!#!Predicting feasibility of treatment in older patients with cancer is a major clinical task. The Initiative Geriatrische Hämatologie und Onkologie (IN-GHO!##!Patients and methods!#!The registry included 3169 patients from 93 centres and evaluated clinical course and treatment outcomes 2-3 and 6 months after initial assessment. Fitness for treatment was classified as fit, compromised and frail according to results of a CGA, and in addition by an experienced physician's and by patient's itself. Feasibility of treatment (termed IN-GHO!##!Results!#!CGA classified 30.0% as fit, 35.8% as compromised, and 34.2% as frail. Physician's and patient's-self assessment classified 61.8%/52.3% as fit, 34.2%/42.4% as compromised, and 3.9%/5.3%, as frail, respectively. Survival status at day 180 was available in 2072 patients, of which 625 (30.2%) had died. After 2-3 months, feasibility of treatment could be assessed in 1984 patients. 62.8% fulfilled IN-GHO®-FIT criteria. Multivariable analysis identified physician's assessment as the single most important item regarding feasibility of treatment.!##!Conclusion!#!Geriatricians were involved in 2% of patients only. Classification of fitness for treatment by CGA, and physician's or patient's-self assessment showed marked discrepancies. For the prediction of feasibility of treatment no single item was superior to physician's assessment. However CGA was not performed by trained geriatricians