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Bellmunt J.,Dana-Farber Cancer Institute | Bellmunt J.,Hospital Del Mar Medical Research Institute | De Wit R.,Netherlands Cancer Institute | Vaughn D.J.,University of Pennsylvania | And 17 more authors.
New England Journal of Medicine | Year: 2017

Background Patients with advanced urothelial carcinoma that progresses after platinum-based chemotherapy have a poor prognosis and limited treatment options. METHODS In this open-label, international, phase 3 trial, we randomly assigned 542 patients with advanced urothelial cancer that recurred or progressed after platinum-based chemotherapy to receive pembrolizumab (a highly selective, humanized monoclonal IgG4? isotype antibody against programmed death 1 [PD-1]) at a dose of 200 mg every 3 weeks or the investigator's choice of chemotherapy with paclitaxel, docetaxel, or vinflunine. The coprimary end points were overall survival and progression-free survival, which were assessed among all patients and among patients who had a tumor PD-1 ligand (PD-L1) combined positive score (the percentage of PD-L1expressing tumor and infiltrating immune cells relative to the total number of tumor cells) of 10% or more. RESULTS The median overall survival in the total population was 10.3 months (95% confidence interval [CI], 8.0 to 11.8) in the pembrolizumab group, as compared with 7.4 months (95% CI, 6.1 to 8.3) in the chemotherapy group (hazard ratio for death, 0.73; 95% CI, 0.59 to 0.91; P=0.002). The median overall survival among patients who had a tumor PD-L1 combined positive score of 10% or more was 8.0 months (95% CI, 5.0 to 12.3) in the pembrolizumab group, as compared with 5.2 months (95% CI, 4.0 to 7.4) in the chemotherapy group (hazard ratio, 0.57; 95% CI, 0.37 to 0.88; P=0.005). There was no significant between-group difference in the duration of progression-free survival in the total population (hazard ratio for death or disease progression, 0.98; 95% CI, 0.81 to 1.19; P=0.42) or among patients who had a tumor PD-L1 combined positive score of 10% or more (hazard ratio, 0.89; 95% CI, 0.61 to 1.28; P=0.24). Fewer treatment-related adverse events of any grade were reported in the pembrolizumab group than in the chemotherapy group (60.9% vs. 90.2%); there were also fewer events of grade 3, 4, or 5 severity reported in the pembrolizumab group than in the chemotherapy group (15.0% vs. 49.4%). CONCLUSIONS Pembrolizumab was associated with significantly longer overall survival (by approximately 3 months) and with a lower rate of treatment-related adverse events than chemotherapy as second-line therapy for platinum-refractory advanced urothelial carcinoma. © 2017 Massachusetts Medical Society.


Oza A.M.,Princess Margaret Cancer Center | Cook A.D.,University College London | Pfisterer J.,Gynecologic Oncology Center | Embleton A.,University College London | And 20 more authors.
The Lancet Oncology | Year: 2015

Background: The ICON7 trial previously reported improved progression-free survival in women with ovarian cancer with the addition of bevacizumab to standard chemotherapy, with the greatest effect in patients at high risk of disease progression. We report the final overall survival results of the trial. Methods: ICON7 was an international, phase 3, open-label, randomised trial undertaken at 263 centres in 11 countries across Europe, Canada, Australia and New Zealand. Eligible adult women with newly diagnosed ovarian cancer that was either high-risk early-stage disease (International Federation of Gynecology and Obstetrics [FIGO] stage I-IIa, grade 3 or clear cell histology) or more advanced disease (FIGO stage IIb-IV), with an Eastern Cooperative Oncology Group performance status of 0-2, were enrolled and randomly assigned in a 1:1 ratio to standard chemotherapy (six 3-weekly cycles of intravenous carboplatin [AUC 5 or 6] and paclitaxel 175 mg/m2 of body surface area) or the same chemotherapy regimen plus bevacizumab 7·5 mg per kg bodyweight intravenously every 3 weeks, given concurrently and continued with up to 12 further 3-weekly cycles of maintenance therapy. Randomisation was done by a minimisation algorithm stratified by FIGO stage, residual disease, interval between surgery and chemotherapy, and Gynecologic Cancer InterGroup group. The primary endpoint was progression-free survival; the study was also powered to detect a difference in overall survival. Analysis was by intention to treat. This trial is registered as an International Standard Randomised Controlled Trial, number ISRCTN91273375. Findings: Between Dec 18, 2006, and Feb 16, 2009, 1528 women were enrolled and randomly assigned to receive chemotherapy (n=764) or chemotherapy plus bevacizumab (n=764). Median follow-up at the end of the trial on March 31, 2013, was 48·9 months (IQR 26·6-56·2), at which point 714 patients had died (352 in the chemotherapy group and 362 in the bevacizumab group). Our results showed evidence of non-proportional hazards, so we used the difference in restricted mean survival time as the primary estimate of effect. No overall survival benefit of bevacizumab was recorded (restricted mean survival time 44·6 months [95% CI 43·2-45·9] in the standard chemotherapy group vs 45·5 months [44·2-46·7] in the bevacizumab group; log-rank p=0·85). In an exploratory analysis of a predefined subgroup of 502 patients with poor prognosis disease, 332 (66%) died (174 in the standard chemotherapy group and 158 in the bevacizumab group), and a significant difference in overall survival was noted between women who received bevacizumab plus chemotherapy and those who received chemotherapy alone (restricted mean survival time 34·5 months [95% CI 32·0-37·0] with standard chemotherapy vs 39·3 months [37·0-41·7] with bevacizumab; log-rank p=0·03). However, in non-high-risk patients, the restricted mean survival time did not differ significantly between the two treatment groups (49·7 months [95% CI 48·3-51·1]) in the standard chemotherapy group vs 48·4 months [47·0-49·9] in the bevacizumab group; p=0·20). An updated analysis of progression-free survival showed no difference between treatment groups. During extended follow-up, one further treatment-related grade 3 event (gastrointestinal fistula in a bevacizumab-treated patient), three grade 2 treatment-related events (cardiac failure, sarcoidosis, and foot fracture, all in bevacizumab-treated patients), and one grade 1 treatment-related event (vaginal haemorrhage, in a patient treated with standard chemotherapy) were reported. Interpretation: Bevacizumab, added to platinum-based chemotherapy, did not increase overall survival in the study population as a whole. However, an overall survival benefit was recorded in poor-prognosis patients, which is concordant with the progression-free survival results from ICON7 and GOG-218, and provides further evidence towards the optimum use of bevacizumab in the treatment of ovarian cancer. Funding: The National Institute for Health Research through the UK National Cancer Research Network, the Medical Research Council, and Roche. © 2015 Oza et al. Open Access article distributed under the terms of CC BY.


Monk B.J.,Arizona Cancer Center | Poveda A.,Fundacion Instituto Valenciano Of Oncologia | Vergote I.,University Hospital Leuven | Raspagliesi F.,Instituto Nazionale dei Tumori | And 20 more authors.
The Lancet Oncology | Year: 2014

Background: Angiogenesis is a valid target in the treatment of epithelial ovarian cancer. Trebananib inhibits the binding of angiopoietins 1 and 2 to the Tie2 receptor, and thereby inhibits angiogenesis. We aimed to assess whether the addition of trebananib to single-agent weekly paclitaxel in patients with recurrent epithelial ovarian cancer improved progression-free survival. Methods: For this randomised, double-blind phase 3 study undertaken between Nov 10, 2010, and Nov 19, 2012, we enrolled women with recurrent epithelial ovarian cancer from 32 countries. Patient eligibility criteria included having been treated with three or fewer previous regimens, and a platinum-free interval of less than 12 months. We enrolled patients with a computerised interactive voice response system, and patients were randomly assigned using a permuted block method (block size of four) in a 1:1 ratio to receive weekly intravenous paclitaxel (80 mg/m2) plus either weekly masked intravenous placebo or trebananib (15 mg/kg). Patients were stratified on the basis of platinum-free interval (≥0 and ≤6 months vs >6 and ≤12 months), presence or absence of measurable disease, and region (North America, western Europe and Australia, or rest of world). The sponsor, investigators, site staff, and patients were masked to the treatment assignment. The primary endpoint was progression-free survival assessed in the intention-to-treat population. The trial is registered with ClinicalTrials.gov, NCT01204749, and is no longer accruing patients. Findings: 919 patients were enrolled, of whom 461 were randomly assigned to the trebananib group and 458 to the placebo group. Median progression-free survival was significantly longer in the trebananib group than in the placebo group (7·2 months [5·8-7·4] vs 5·4 months [95% CI 4·3-5·5], respectively, hazard ratio 0·66, 95% CI 0·57-0·77, p<0·0001). Incidence of grade 3 or higher adverse events was similar between treatment groups (244 [54%] of 452 patients in the placebo group vs 258 [56%] of 461 patients in the trebananib group). Trebananib was associated with more adverse event-related treatment discontinuations than was placebo (77 [17%] patients vs 27 [6%], respectively) and higher incidences of oedema (294 [64%] patients had any-grade oedema in the trebananib group vs 127 [28%] patients in the placebo group). Grade 3 or higher adverse events included ascites (34 [8%] in the placebo group vs 52 [11%] in the trebananib group), neutropenia (40 [9%] vs 26 [6%]), and abdominal pain (21 [5%] vs 22 [5%]). We recorded serious adverse events in 125 (28%) patients in the placebo group and 159 (34%) patients in the trebananib group. There was a difference of 2% or less in class-specific adverse events associated with anti-VEGF therapy (hypertension, proteinuria, wound-healing complications, thrombotic events, gastrointestinal perforations), except bleeding, which was more common in the placebo group than in the trebananib group (75 [17%] vs 46 [10%]). Interpretation: Inhibition of angiopoietins 1 and 2 with trebananib provided a clinically meaningful prolongation in progression-free survival. This non-VEGF anti-angiogenesis option for women with recurrent epithelial ovarian cancer should be investigated in other settings and in combination with additional agents. Although oedema was increased, typical anti-VEGF associated adverse events were not prominent. Funding: Amgen. © 2014 Elsevier Ltd.


Cardoso F.,Champalimaud Cancer Center | Bischoff J.,Otto Von Guericke University of Magdeburg | Brain E.,Hopital Rene Huguenin Institute Curie | Brain E.,HopitalReneHuguenin Institute Curie | And 6 more authors.
Cancer Treatment Reviews | Year: 2013

Endocrine therapy is the corner stone treatment for postmenopausal women with hormone receptor-positive metastatic breast cancer (MBC). Besides tamoxifen and many older agents, recently developed endocrine agents for the treatment of MBC include the third generation aromatase inhibitors (AI) - anastrozole, exemestane, letrozole - and the pure oestrogen receptor antagonist fulvestrant. As treatment of breast cancer evolves, both tamoxifen and the AIs are being increasingly used in the adjuvant setting. As such, a significant proportion of patients with hormone receptor-positive MBC will have previously received tamoxifen, an AI or both, as adjuvant treatment. This has changed the metastatic landscape and has an impact on treatment choices for patients with hormone receptor-positive MBC. In this review, we evaluate the available evidence supporting the use of endocrine therapy for the treatment of hormone receptor-positive MBC. Additionally, we consider the effect of prior adjuvant therapy on treatment choice in the metastatic setting and the optimal treatment sequence. Finally, we discuss endocrine-responsive HER2 positive tumours and the ongoing research initiatives which aim to improve outcomes for patients with MBC. © 2012 Elsevier Ltd.


Molina-Ruiz A.M.,Fundacion Jimenez Diaz | Sanmartin O.,Fundacion Instituto Valenciano Of Oncologia | Santonja C.,Fundacion Jimenez Diaz | Kutzner H.,Dermatohistopathologisches Gemeinschaftslabor | Requena L.,Fundacion Jimenez Diaz
Journal of the American Academy of Dermatology | Year: 2013

Background: Polymorphous light eruption (PLE) is the most common form of idiopathic photodermatosis. Several morphologic variants of PLE have been described, including a localized form of PLE primarily affecting the helices of the ears. To our knowledge, the presence of lesions on the elbows as the unique manifestation of PLE has not yet been reported. We have studied 9 patients presenting with a recurrent eruption on the elbows, with clinical and histopathologic features indistinguishable from PLE, occurring during springtime. Recently, a peculiar eruption of the elbows, with similar clinical features to our patients, has been proposed as a manifestation of cutaneous lupus erythematosus. Objective: We sought to describe the clinical, histopathological, and immunohistochemical features of this peculiar eruption of the elbows. Methods: Nine patients presenting a recurrent spring eruption on the elbows, collected from April 1989 to June 2012, were retrospectively analyzed. We studied their clinical and histopathological features, and the immunophenotype of the infiltrate. Results: Five patients were men and 4 were women. The mean age was 44.7 years. The lesions consisted of pruriginous, erythematous-edematous papules and plaques, located on both elbows. The eruption appeared during the spring or early summer and recurred seasonally. No associated symptoms were present and the eruption regressed spontaneously or with topical corticosteroids after 7 to 15 days. Histopathologically, the lesions showed typical features of PLE, with variable degree of edema in the papillary dermis, and a papillary and reticular dermal perivascular infiltrate mostly composed of small lymphocytes. Immunohistochemical studies demonstrated strong immunoreactivity for CD2, CD4, and CD8, revealing the infiltrate was composed predominantly of T lymphocytes, with a predominance of T-helper over T-cytotoxic lymphocytes. Immunostaining for CD123 was negative, highlighting the absence of plasmacytoid dendritic cells. Other T- and B-cell markers, including CD30, PD-1, CXCL13, FoxP3, CD79a, and CD56 were also negative. Limitations: Retrospective case series design is a limitation. Phototests were not performed. Results of antinuclear antibodies were only available in 1 patient. Conclusions: We believe this recurrent eruption of the elbows represents a distinctive and localized variant of PLE rather than a peculiar manifestation of cutaneous lupus erythematosus and suggest the term "spring and summer eruption of the elbows" for this peculiar condition. The mechanism of this localization on the elbows, with sparing of other photoexposed areas, remains unknown. © 2011 by the American Academy of Dermatology, Inc.


Poveda A.,Fundacion Instituto Valenciano Of Oncologia | Ray-Coquard I.,Center Leon Berard | Romero I.,Fundacion Instituto Valenciano Of Oncologia | Lopez-Guerrero J.A.,Fundacion Instituto Valenciano Of Oncologia | Colombo N.,University of Milan Bicocca
Cancer Treatment Reviews | Year: 2014

Ovarian cancer (OC) is the leading cause of death from gynecological malignancies. In spite of high response rates to the standard front-line treatment for advanced disease with cytoreductive surgical debulking, followed by platinum/taxane-based chemotherapy, most patients eventually relapse developing drug-resistant disease. Owing to the molecular heterogeneity, genetic instability and mutagenicity of OC, increases in survival might be achieved by translating recent insights at the morpho-molecular levels to individual therapeutic strategies. Several emerging treatments have been shown to be active in platinum-sensitive (PS) recurrent OC (ROC), but an optimal strategy still has not been established. Based on the recent results, it is likely that the introduction of novel non-platinum based chemotherapies and molecular targeted therapies will have a major impact on the management of ROC. Some current strategies are focused on the extension of platinum-free interval (PFI) in patients with PS, particularly in those with partially PS disease. Apparently, the PFI extension by an effective non-platinum intervention, such as trabectedin plus pegylated liposomal doxorubicin (PLD), may reduce cumulative platinum-induced toxicities leading to longer survival after the reintroduction of subsequent platinum. The introduction of novel therapies, such as the antiangiogenic monoclonal antibody bevacizumab, opens a new field of targeted therapies in this indication. In this review, we aim to outline the therapeutic potential of new emerging approaches, particularly the role of non-platinum therapy with trabectedin in combination with PLD in patients with PS ROC. © 2013 The Authors.


Serra A.C.,Fundacion Instituto Valenciano Of Oncologia | Folkersma L.R.,Hospital Clinico San Carlos | Dominguez-Escrig J.L.,Fundacion Instituto Valenciano Of Oncologia | Gomez-Ferrer A.,Fundacion Instituto Valenciano Of Oncologia | And 2 more authors.
Urology | Year: 2013

Objective: To evaluate the efficacy of the AdVance transobturator male sling in the treatment of male stress urinary incontinence and to identify the preoperative predictors of a successful outcome. Materials and Methods: All patients were considered for sling placement 1 year after radical prostatectomy or transurethral resection of the prostate. The degree of incontinence was assessed using the 24-hour pad weight test. A preoperative urodynamic assessment and cystoscopy were performed in all cases. Patients without sphincter contractions during the "repositioning test" were excluded. Since September 2010, we have implanted the AdVance XP transobturator sling. Cure was defined as no pad use. Results: From February 2008 to June 2011, 61 patients underwent transobturator sling (34 AdVance and 27 AdVance XP) insertion. In 26 cases, the sling was anchored with bioabsorbable sutures, and in 35 cases, it was not fixed. Of the 61 patients, 7 had a history of anastomotic stricture and 3 of radiotherapy. Preoperatively, median 24-hour pad weight was 200 g (range 25-1848). Finally, 26 patients had detrusor overactivity or low bladder compliance. The median follow-up was 26 months (range 12-53). The overall cure rate was 80% (49 of 61). Deterioration of continence was observed during follow-up in 2 patients. The preoperative variables (age, body mass index, 24-hour pad weight, International Consultation on Incontinence Questionnaire-Short Form, adverse urodynamics, sling fixation, AdVance XP) and their association with the surgical outcome were analyzed. The preoperative 24-hour pad weight correlated inversely with the outcome (odds ratio 0.996), with a 0.4% decrease in cure rate for each 1-g increase in the preoperative 24-hour pad weight. The complications included perineal hematoma in 2, acute urinary retention in 9, perineal numbness in 5, and de novo storage symptoms (urgency) in 5 patients. Conclusion: The results of our study have shown that the AdVance and AdVance XP male slings are safe and efficient in patients with mild postprostatectomy stress incontinence. The severity of incontinence was the only predictor of a successful outcome. © 2013 Elsevier Inc. All Rights Reserved.


Rubio L.,Fundacion Instituto Valenciano Of Oncologia | Alemany R.,University of the Balearic Islands | Lopez-Guerrero J.A.,Fundacion Instituto Valenciano Of Oncologia
Clinical and Translational Oncology | Year: 2010

Gastrointestinal stromal tumours (GISTs) are the most common mesenchymal neoplasms of the gastrointestinal tract. GISTs are characterised by the expression of KIT, a type III tyrosine kinase receptor, and the presence of mutations in KIT or PDGFRA in about 80-85% of cases. The primary treatment for GIST is surgery, which cures most patients with low- or intermediate-risk tumours. The introduction of the kinase inhibitor imatinib mesylate, and sunitinib in second line, against KIT and PDGFRA has provided the first evidence of directed therapy in GIST. The aim of this review is to highlight the growing evidence that KIT and PDGFRA genotyping provides valuable information for the clinical management of GIST patients. We show that KIT and PDGFRA genotyping has emerged as one of the principal factors in the evaluation of GISTs, particularly in those tumours that are clearly malignant or have a high risk of recurrence. In addition to helping establish the diagnosis of GIST in unusual cases, genotyping can be very useful to physicians and patients in deciding on imatinib dose, in estimating the likelihood and duration of benefit, and potentially in selecting second-line therapies. © 2010 Feseo.


Casanova-Salas I.,Fundacion Instituto Valenciano Of Oncologia | Rubio-Briones J.,Fundacion Instituto Valenciano Of Oncologia | Fernandez-Serra A.,Fundacion Instituto Valenciano Of Oncologia | Lopez-Guerrero J.A.,Fundacion Instituto Valenciano Of Oncologia
Clinical and Translational Oncology | Year: 2012

Current prostate cancer (PCa) diagnosis is based in the serum prostate-specific antigen biomarker and digital rectal examination. However, these methods are limited by a low predictive value (24-37 %) and a high risk of mistaken results. During last years, new promising biomarkers such as Prostate Cancer Antigen 3 (PCA-3) and TMPRSS2-ETS fusion genes have been evaluated for their clinical use. However, the search of new biomarkers that could be used for PCa diagnosis and prognosis is still needed. Recent studies have demonstrated that the aberrant expression ofmicroRNAs (miRNAs), small non-coding RNAs that negatively regulate gene expression, is related with the development of several cancers, including PCa. Since miRNAs serve as phenotypic signatures of different cancers, they appear as potential diagnostic, prognostic and therapeutic tools. Here, we review the current knowledge of miRNA expression patterns in PCa and their role in PCa prognosis and therapeutics. © 2012 Federación de Sociedades Españolas de Oncología (FESEO).


Cervera Deval J.,Fundacion Instituto Valenciano Of Oncologia
Radiologia | Year: 2014

Biomedical imaging makes it possible not only to diagnose and stage cancer, but also to follow up patients and evaluate the response to treatment. RECIST (Response Evaluation Criteria In Solid Tumors) provides a method to monitor the response to treatment based on one dimensional measurements of tumors obtained with reproducible imaging techniques like CT, MRI, and PET. The metabolic changes induced by new treatments modify the biology and behavior of the tumor; occasionally, there is a discrepancy between the patient's clinical condition and the response measured by RECIST, which indicates that functional tests need to be included in the evaluation of the response to treatment. The objective is to review the RECIST criteria to include the contribution of functional imaging to enable the efficacy and effects of the treatment in patients with solid tumors. © 2011 SERAM. Publicado por Elsevier España, S.L. Todos los derechos reservados.

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