Final Overall Survival Analysis of the SOGUG Phase 2 MAJA Study: Maintenance Vinflunine Versus Best Supportive Care After First-Line Chemotherapy in Advanced Urothelial Carcinoma.

INTRODUCTION: The MAJA study compared vinflunine (VFL) plus best supportive care (BSC) maintenance therapy versus BSC alone in advanced urothelial carcinoma responsive to first-line chemotherapy. The primary end point of progression-free survival was achieved. We present the final overall survival (OS) and long-term follow-up safety analyses. PATIENTS AND METHODS: Patients were enrolled, and a subsequent post hoc analysis was performed on the basis of radiologic response or stabilization to first-line cisplatin/gemcitabine (CG) chemotherapy (4-6 cycles), according to Response Evaluation Criteria in Solid Tumors (RECIST). VFL + BSC versus BSC alone were randomly assigned until disease progression. RESULTS: At final analysis, 58 patients (66.7%) had died while 29 (33.3%) had survived; the BSC arm had higher mortality (VFL + BSC, n = 26, 59.1% vs. BSC, n = 32, 74.4%). Median follow-up of surviving patients was 38.8 months (interquartile range, 23.8-61.6). Median OS was 16.7 months (95% confidence interval, 0-34.5) in VFL and 13.2 months (95% confidence interval, 6-20.4) in the BSC groups (hazard ratio, 0.736; 95% confidence interval, 0.44-1.24, P = .182). Post hoc group division did not affect median OS in either study arm. CONCLUSION: Final analysis supported a benefit of VFL in maintenance therapy in patients with disease control after first-line treatment with CG, with no unexpected long-term adverse effects. The study was insufficiently powered to show a significant OS advantage.

Opioid-Induced Constipation in Oncological Patients: New Strategies of Management.

OPINION STATEMENT: Cancer-associated pain has traditionally been treated with opioid analgesics, often in escalating doses. Opioid-induced constipation (OIC) is a common problem associated with chronic use of opioid analgesics. Typical treatment strategies to alleviate constipation are based on dietary changes, exercise, and laxatives. However, laxatives have a nonspecific action and do not target underlying mechanisms of OIC. This article will review prevalent, clinical presentation and recommendations for the treatment of OIC. An independent literature search was carried out by the authors. We reviewed the literature for randomized controlled trials that studied the efficacy of laxatives, naloxone, and naloxegol in treating OIC. Newer strategies addressing the causal pathophysiology of OIC are needed for a more effective assessment and management of OIC. Finally, traditional recommended therapies are appraised and compared with the latest pharmacological developments. Future research should address whether naloxegol is more efficacious by its comparison directly with first-line treatments, including laxatives.

Abordaje de la fibrilación auricular en pacientes con cáncer activo. Documento de consenso de expertos y recomendaciones / Atrial fibrillation in active cancer patients: expert position paper and recommendations

La mejora en la supervivencia de los pacientes con cáncer ha puesto de manifiesto el impacto clínico que la cardiotoxicidad tiene en el pronóstico tanto cardiovascular como onco-hematológico, sobre todo cuando motiva la interrupción de terapias antitumorales altamente eficaces. La fibrilación auricular es una complicación frecuente en pacientes con cáncer activo y su tratamiento supone un gran reto. Estos pacientes tienen mayores riesgos tromboembólico y hemorrágico y, sin embargo, no se dispone de escalas específicas para guiar la atención clínica. El objetivo de este documento promovido por los grupos de Cardio-Onco-Hematología y Trombosis de la Sociedad Española de Cardiología y elaborado de manera conjunta con las diferentes áreas de conocimiento de la Sociedad Española de Cardiología y con expertos de la Sociedad Española de Oncología Médica, la Sociedad Española de Oncología Radioterápica y la Sociedad Española de Hematología y Hemoterapia, es proporcionar un enfoque multidisciplinario y práctico para la prevención y el tratamiento de la fibrilación auricular de pacientes con cáncer activo y basado en el consenso de expertos

Improvements in survival among cancer patients have revealed the clinical impact of cardiotoxicity on both cardiovascular and hematological and oncological outcomes, especially when it leads to the interruption of highly effective antitumor therapies. Atrial fibrillation is a common complication in patients with active cancer and its treatment poses a major challenge. These patients have an increased thromboembolic and hemorrhagic risk but standard stroke prediction scores have not been validated in this population. The aim of this expert consensus-based document is to provide a multidisciplinary and practical approach to the prevention and treatment of atrial fibrillation in patients with active cancer. This is a position paper of the Spanish Cardio-Oncology working group and the Spanish Thrombosis working group, drafted in collaboration with experts from the Spanish Society of Cardiology, the Spanish Society of Medical Oncology, the Spanish Society of Radiation Oncology, and the Spanish Society of Hematology

Atrial Fibrillation in Active Cancer Patients: Expert Position Paper and Recommendations.

Improvements in survival among cancer patients have revealed the clinical impact of cardiotoxicity on both cardiovascular and hematological and oncological outcomes, especially when it leads to the interruption of highly effective antitumor therapies. Atrial fibrillation is a common complication in patients with active cancer and its treatment poses a major challenge. These patients have an increased thromboembolic and hemorrhagic risk but standard stroke prediction scores have not been validated in this population. The aim of this expert consensus-based document is to provide a multidisciplinary and practical approach to the prevention and treatment of atrial fibrillation in patients with active cancer. This is a position paper of the Spanish Cardio-Oncology working group and the Spanish Thrombosis working group, drafted in collaboration with experts from the Spanish Society of Cardiology, the Spanish Society of Medical Oncology, the Spanish Society of Radiation Oncology, and the Spanish Society of Hematology.

Cardio-Onco-Hematología en la práctica clínica. Documento de consenso y recomendaciones / Cardio-Onco-Hematology in clinical practice. Position paper and recommendations

Los avances en la detección precoz y el tratamiento del cáncer han reducido de manera significativa la mortalidad de los pacientes. Sin embargo, mejorar el pronóstico no es solo curar el tumor, sino prevenir, diagnosticar y tratar eficazmente las complicaciones derivadas de las terapias onco-hematológicas. La toxicidad cardiovascular es un problema ampliamente reconocido con múltiples esquemas terapéuticos; sin embargo, la evidencia científica en el manejo de las complicaciones cardiovasculares de pacientes onco-hematológicos es escasa, pues sistemáticamente se ha excluido de los ensayos clínicos a estos enfermos y las recomendaciones actuales están basadas en consensos de expertos. Es imprescindible crear equipos multidisciplinarios locales para optimizar los resultados en salud de los supervivientes al cáncer. Una preocupación excesiva por la aparición de toxicidad cardiovascular puede impedir terapias potencialmente curativas, mientras que la subestimación de este riesgo compromete el pronóstico vital a largo plazo. El objetivo de este documento, elaborado en colaboración con la Sociedad Española de Cardiología, la Sociedad Española de Oncología Médica, la Sociedad Española de Oncología Radioterápica y la Sociedad Española de Hematología, es actualizar los conocimientos aplicables a la práctica clínica diaria de la cardio-onco-hematología y promover el desarrollo de equipos multidisciplinarios locales que mejoren la salud cardiovascular de los pacientes con cáncer (AU)

Improvements in early detection and treatment have markedly reduced cancer-related mortality. However survival not only depends on effectively cure cancer, but prevention, diagnosis and treatment of cancer-related complications is also needed. Cardiovascular toxicity is a widespread problem across many classes of therapeutic schemes, however scientific evidence in the management of cardiovascular complications of onco-hematological patients is scarce, as these patients have been systematically excluded from clinical trials and current recommendations are based on expert consensus. Multidisciplinary teams are mandatory to decrease morbidity and mortality from both cardiotoxicity and cancer itself. An excessive concern for the occurrence of cardiovascular toxicity, can avoid potentially curative therapies, while underestimating this risk, increases long-term mortality of cancer survivors. The objective of this consensus document, developed in collaboration of the Spanish Society of Cardiology, the Spanish Society of Medical Oncology, the Spanish Society of Radiation Oncology and the Spanish Society of Hematology, is to update the necessary concepts and expertise on cardio-onco-hematology that enable its application in daily clinical practice and to promote the development of local multidisciplinary teams, to improve the cardiovascular health of patients with cancer (AU)

Dolor irruptivo y calidad de vida: estudio comparativo de la percepción por parte de los médicos y los pacientes oncológicos / Breakthrough pain and quality of life: A comparative study of the perception by physicians and cancer patients

OBJETIVO: El propósito de este estudio fue investigar el grado de concordancia entre pacientes que sufren dolor irruptivo oncológico y los médicos que los tratan en la percepción del dolor y la calidad de vida (CdV). MÉTODO: Se llevó a cabo un estudio multicéntrico, transversal y observacional. La información sobre el dolor y la CdV se recogió mediante las herramientas Brief Pain Inventory (BPI) y EuroQoL five-dimensional questionnaire (EQ-5D), ambas completadas por los médicos y los pacientes. También se recogieron los datos sociodemográficos y clínicos, incluyendo la puntuación de la capacidad funcional ECOG. Para el análisis de la concordancia en las percepciones de la CdV y el dolor entre médicos y pacientes se calcularon los coeficientes de correlación intraclase y el estadístico κ ponderado. Resultado: Un total de 129 médicos y 472 pacientes participaron en el estudio. Casi todos los doctores (98,4%) tenían experiencia previa en el manejo de pacientes con dolor irruptivo oncológico. Con relación a la intensidad de dolor y al impacto de este en la vida cotidiana, los coeficientes de correlación intraclase (todos por encima de 0,84) indicaron que había un alto grado de acuerdo entre las valoraciones de los médicos y la de los pacientes. Para la CdV, se observó una buena concordancia entre médicos y pacientes, con estadísticos κ desde 0,61 (ítem de ansiedad/depresión) a 0,75 (ítem de actividades de la vida diaria). La declaración del dolor experimentado por los pacientes fue de 8 para la intensidad máxima y de 5 para la intensidad media. CONCLUSIONES: En este estudio de práctica clínica habitual, los médicos participantes eran razonablemente conocedores del nivel de funcionalidad y bienestar de sus pacientes, siendo la percepción del componente psicológico (ansiedad/depresión) de la CdV la menos concordante. Estos hallazgos ayudan a conocer mejor la prevalencia e intensidad del dolor, su interferencia con las actividades de la vida diaria y la CdV en pacientes oncológicos con dolor irruptivo oncológico, un paso esencial para mejorar el manejo del dolor asociado a cáncer

OBJECTIVE: To analyse the agreement on perceptions of pain and quality of life (QoL) between patients with cancer-related breakthrough pain and their treating physicians. METHOD: A multicentre, cross-sectional, observational study was performed. Pain and QoL information was collected using the Brief Pain Inventory and the EuroQoL five-dimensional questionnaire completed by physicians and PATIENTS: Agreement between patient- and physician-perceived QoL and pain scores was evaluated using intraclass correlation coefficients and weighted κ statistics. RESULTS: A total of 129 physicians and 472 patients participated in the study. Almost all doctors (98.4%) had previous experience in managing patients with cancer breakthrough pain. For pain intensity and impact of pain on daily life, intraclass correlation coefficients (all exceeding 0.84) indicated that there was strong agreement between physician and patient assessments. For QoL, good concordance was found between patients and physicians, with weighted κ statistic ranging from 0.61 (anxiety/depression item) to 0.75 (daily activities item). Patient pain reports were 8.0 for the worst pain, and 5.0 for mean pain. CONCLUSIONS: In this setting, physicians were reasonably aware of their patients' level of functioning and well-being, with gaps only in the psychological dimension (anxiety/depression) of QoL. These findings contribute to a better understanding of pain prevalence and intensity, interference of pain with daily activities, and QoL in cancer patients with breakthrough pain, and are an essential step towards improving cancer pain management

Cardio-Onco-Hematology in Clinical Practice. Position Paper and Recommendations.

Improvements in early detection and treatment have markedly reduced cancer-related mortality. However survival not only depends on effectively cure cancer, but prevention, diagnosis and treatment of cancer-related complications is also needed. Cardiovascular toxicity is a widespread problem across many classes of therapeutic schemes, however scientific evidence in the management of cardiovascular complications of onco-hematological patients is scarce, as these patients have been systematically excluded from clinical trials and current recommendations are based on expert consensus. Multidisciplinary teams are mandatory to decrease morbidity and mortality from both cardiotoxicity and cancer itself. An excessive concern for the occurrence of cardiovascular toxicity, can avoid potentially curative therapies, while underestimating this risk, increases long-term mortality of cancer survivors. The objective of this consensus document, developed in collaboration of the Spanish Society of Cardiology, the Spanish Society of Medical Oncology, the Spanish Society of Radiation Oncology and the Spanish Society of Hematology, is to update the necessary concepts and expertise on cardio-onco-hematology that enable its application in daily clinical practice and to promote the development of local multidisciplinary teams, to improve the cardiovascular health of patients with cancer.

Gastrointestinal stromal tumors: morphological, immunohistochemical and molecular changes associated with kinase inhibitor therapy.

Recurrent or metastatic GISTs are currently treated with kinase inhibitors since they achieves disease control in 70-85% of patients but this response depend on KIT and PDGFRA gene mutation status. We review the morfological and molecular findings associated to kinase inhibitors administration in GISTs based on the literature on Medline and authors' own experience. The initial response to kinase inhibitors (imatinib mesylate, Gleevec, Novartis) usually is partial and depend on the mutational KIT or PDGFRA state. Amongst patients wih KIT mutations, the best results are achived in those harboring exon 11 (85%) and exon 9 (45%) mutations. GISTs harboring PDGFRA gene mutations generally respond favorably except those involving the Asp842Val mutation. In the absence of KIT/PDGFRA gene mutations, partial response or disease stabilization is reported in 23% and 50% of patients, respectively, and disease progression in 19%. Histological examination of tumors displaying an initial response to imatinib reveals a highly-variable reduction in the number of tumor cells, a decline in the proliferative index, myxohyaline or sclerohyaline stroma, and a varying degree of bleeding and edema, necrosis and cystification. 72% of patients with initial good response to imatinib, display metastases or new nodule growth within an existing clinically-quiescent tumor after 12-36 months of treatment. This secondary resistance is characterized by a number of well-defined morphological and molecular changes. Histologically, the new growths display increased mitotic activity, pleomorphism, an epithelioid or mixed phenotype and persistent KIT expression although more rarely, dedifferentiation and loss of KIT expression (Fig. 4), as well as trans-differentiation into a rhabdomyosarcoma or epithelial phenotype has been reported. Molecularly, 46-67% of patients present additional KIT mutations, generally in the kinase domain (exons 13, 14 and 17) but also in the ATP-binding domain (exons 15,16) of the same allele. Secondary PDGFRA mutations are very rare. Secondary mutations have not been observed in GISTs not harboring KIT/PDGFRA mutations, or in tumors displaying an unusual morphology or loss of CD117 expression. A number of studies highlight the presence of different resistance mutations within different new tumor nodules, as well as the simultaneous development of distinct resistant tumor subclones within a single lesion (acquired polyclonal resistance). Secondary mutation in genes other than KIT/PDGFRA has only been reported in BRAF (Val600Glu).

Expression of P-glycoprotein and metallothionein in gastrointestinal stromal tumor and leiomyosarcomas. Clinical implications.

We investigated the expression of P-glycoprotein (P-GP) and metallothionein (MT) in a series of 92 GIST and 14 gastrointestinal leiomyosarcomas (GILMS) with the purpose to expand our knowledge on the biological bases of GIST chemo-resistance and to ascertain their significance in patients' prognosis. P-GP expression was more frequent in GIST than in GI-LMS (83.7% vs. 21.4%, p<0.001), with no difference between low- and high-risk GIST (p=1.000) or low- and high-grade GI-LMS (p=0.538). P-GP expression was unrelated to anatomic location (gastric vs. intestinal) in GIST (39/45 vs. 35/43, p=0.770) and in GI-LMS (0/2 vs. 2/6, p=1.000). MT expression was non-significantly higher in GI-LMS than in GIST (35.7% vs. 14.1%, p=0.060), with no difference between low- and high-risk GIST (p=1.000) or low- and high-grade GI-LMS (p=1.000). MT expression was unrelated to the anatomic location (gastric vs. intestinal) in GIST (7/45 vs. 6/43) and GI-LMS (0/2 vs. 1/6) (p=1.000 and p=0.1000, respectively). Overall tumor-specific survival (p< 0.001) and disease-free survival (p<0.001) were different in GIST as compared with GI-LMS, and the number of events was higher in GI-LMS. When the survival analysis took into consideration P-GP or MT expression, the overall survival in GIST was influenced by the expression of MT (p=0.021) but not by that of P-GP (p=0.638). However, in GI-LMS, P-GP expression influenced disease-free survival (p=0.050); in addition, it is important to recognize the limited value of these results because of the low number of cases involved in the study. Differential expression of P-GP and MT might explain the known variability in response to systemic chemotherapy in these tumors. Detection of P-GP and MT seems to add certain prognostic value in GIST (MT) or GI-LMS (P-GP).