Pembrolizumab for advanced melanoma: experience from the Spanish Expanded Access Program

Background. The programmed death (PD-1) inhibitor pembrolizumab has been recently approved for the treatment of advanced melanoma. We evaluated the clinical activity of pembrolizumab in melanoma patients treated under the Spanish Expanded Access Program. Methods. Advanced melanoma patients who failed to previous treatment lines were treated with pembrolizumab 2 mg/kg every three weeks. Patients with brain metastases were not excluded if they were asymptomatic. Data were retrospectively collected from 21 centers in the Spanish Melanoma Group. Results. Sixty-seven advanced melanoma patients were analyzed. Most patients were stage M1c (73.1%), had high LDH levels (55.2%) and had ECOG PS 1 or higher (59.7%). For cutaneous melanoma patients, median overall survival was 14.0 months; the 18-month overall survival rate was 47.1%. Overall response rate was 27%, including three patients with complete responses (6.5%). Median response duration was not reached, with 83.3% of responses ongoing (3.5 m+ to 20.4 m+). From ten patients included with brain metastases, four (40%) had an objective response, two (20%) of them achieved a complete response. Significant prognostic factors for overall survival were LDH level, ECOG PS and objective response. There were no serious adverse events. Conclusion. Although this was a heavily pretreated cohort, pembrolizumab activity at the approved dose and schedule was confirmed in the clinical setting with long-term responders, also including patients with brain metastases (AU)

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Safety of vemurafenib in patients with BRAFV600 mutated metastatic melanoma: the Spanish experience

Objectives. Vemurafenib tolerability was assessed in a large, open-label, multicentre study in patients with BRAFV600 mutated advanced melanoma. We investigated safety, tolerability and efficacy of vemurafenib in Spanish patients participating in that study. Methods. Patients with previously treated or treatment-naive, unresectable stage IIIC or stage IV, BRAFV600 mutation-positive melanoma received vemurafenib 960 mg twice daily until disease progression, unacceptable toxicity, withdrawal of consent or death. The primary endpoint was safety; secondary endpoints included overall response rate (ORR), progression-free survival (PFS) and overall survival (OS). Results. 301 Spanish patients were included, 70 % with M1c disease, 22 % with brain metastases and 51 % with prior systemic therapy for metastatic disease. Most frequent adverse events included fatigue (48 %), arthralgia (45 %), rash (41 %), photosensitivity (34 %) and skin neoplasms (21 %). Grade 3/4 adverse events occurred in 156 patients (52 %), including cutaneous squamous cell carcinoma (including keratoacanthoma; 16 %), fatigue (6 %) and arthralgia (5 %). The ORR was 28 % (95 % CI 23-34 %). Responses occurred in patients with brain metastases (18 %), elevated baseline lactate dehydrogenase (19 %) and poor performance status (15 %), and elderly patients (22 %). Median PFS was 5.8 (95 % CI 5.0-6.4) months; median OS was 10.5 (95 % CI 9.5-13.5) months. Conclusion. Our results for Spanish patients in the vemurafenib safety study indicate similar efficacy and a comparable safety profile in Spanish patients with no new safety signals compared with the overall population. Clinical benefit was demonstrated in poor-prognosis patients and in those with favourable baseline characteristics, suggesting that poor-prognosis patients may also benefit from vemurafenib treatment (AU)

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Clinical use of ipilimumab for metastatic melanoma in Spain: towards a more consistent approach

Introduction: Ipilimumab has been approved in patients with advanced melanoma by different regulatory bodies worldwide, but its use in clinical practice is not fully consistent among oncologists. We have surveyed a representative sample of Spanish medical oncologists on issues related to the use of ipilimumab. Materials and methods: The survey was based on the Delphi method, where experts respond anonymously to two rounds of a questionnaire. Questionnaire consisted of 42 statements divided among the following eight categories: Pathology and Diagnosis; Patterns of Response; Parameters affecting Treatment Selection; Patient Profile; Sequencing of Treatment; Definition of Long-Term Survivors; Quality of Life; Concept of Immuno-oncology. The experts were asked to rate each statement on a scale of 1-9, where 1 meant 'completely disagree' and 9 meant 'completely agree'. Results: Thirty-three oncologists responded to both rounds of the survey (62.3 % of total surveyed). On issues related to pathology and diagnosis, patterns of response, and immuno-oncology, the specialists reached a high level of consensus. There was also a high level of agreement, albeit without consensus on assessment of BRAF mutations before deciding on treatment with ipilimumab. However, there was a lower level of agreement on sequencing treatment with BRAF inhibitors and ipilimumab, on predictive factors, on the use of corticosteroids, and on patient quality of life. Conclusions: The disparity in many of these topics suggests that oncologists need more information on certain aspects of ipilimumab treatment. We need to define generally accepted algorithms of treatment, especially with regard to issues that were shown to be controversial or unclear (AU)

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MYH polyposis syndrome: clinical findings, genetics issues and management

Colorectal cancer (CRC) is one of the most frequent cancer in first world. Two hereditary CCR syndrome have been described: familial adenomatous polyposis (FAP) and hereditary non-polyposis colorectal cancer. A recently described biallelic mutation of MYH, is responsible for adenomatous polyposis with an increased risk of CRC and is responsible for 30-40 % of adenomatous polyposis cases in which an APC mutation cannot be found. However, there is no clear consensus in the literature as whether a monoallelic mutation increases the risk for colorectal cancer. In addition, some authors have indicated that the spectrum of extracolonic lesions in MYH associated polyposis (MAP) might be far different from that observed in FAP and could be more similar to Lynch syndrome spectrum. In this review we are going to describe some general and specific aspects of MAP, including genetic topics, clinical features, different phenotypes and strategies to reduce CCR risk (AU)

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Guidelines for biomarker testing in metastatic melanoma: a National Consensus of the Spanish Society of Pathology and the Spanish Society of Medical Oncology

This consensus statement, conceived as a joint initiative of the Spanish Society of Pathology (SEAP) and the Spanish Society of Medical Oncology (SEOM), makes diagnostic and treatment recommendations for the management of patients with advanced or metastatic melanoma based on the current scientific evidence on biomarker use. This document thus provides an opportunity to improve healthcare efficiency and resource use, which will benefit these patients. Based on the data available so far, this expert group recommends routinely testing patients with metastatic melanoma for BRAF mutation status, as the result affects the subsequent therapeutic management of these patients. The analysis of genetic alterations in KIT may be reasonable in patients with primary tumours in acral or mucosal sites or on chronically sun-exposed skin, in an advanced condition, but not in patients with other types of melanomas. This panel believes that testing for other genetic alterations, such as NRAS mutation status in patients not carrying BRAF mutations, GNAQ/GNA11 mutational analysis or genetic alterations in PTEN, is not currently indicated as routine clinical practice, because the results do not influence treatment planning in these patients at the present time. Other important issues addressed in this document are the organisational requirements and quality controls needed for proper testing of these biomarkers, and the legal implications to be borne in mind (AU)

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Advances in cutaneous melanoma

After several decades of slow progress in the field of melanoma, significant advances have been reported in recent years. These include a better understanding of the molecular biology of the tumour, a new staging classification system, insights into the patterns of relapse in early stage, and new drugs for the treatment of advanced disease. Ipilimumab and vemurafenib have just been approved and provide a survival benefit in stage IV. Both compounds are under evaluation in the adjuvant setting, where interferon remains the only drug with proven efficacy. Further investigation is required to treat patients with primary or secondary resistance to new drugs (AU)

A new era in the treatment of melanoma: from biology to clinical practice

Melanoma is the deadliest cutaneous malignancy and its incidence continues to grow. Until 2011, the treatment options for metastatic melanoma were scarce and without any overall survival benefit. The emergence of new targeted therapies for BRAF mutant melanoma (vemurafenib) and immunotherapy (ipilimumab) has changed the standard of care for this disease. The objective of the present review is to summarise the biological background of the new therapeutic approaches in melanoma, focusing on apoptosis resistance, immune modulation and angiogenesis, and the direct translation into clinical practice (AU)

Management of platinum-resistant ovarian cancer with the combination of pemetrexed and gemcitabine

INTRODUCTION: Platinum resistant ovarian cancer is a current challenge in Oncology. Current approved therapies offer no more of a 20% of response. New therapeutic options are urgently needed. PATIENTS AND METHODS: Patients were treated with the combination of Pemetrexed 500 mg/m(2) d1 and Gemcitabine 1000 mg/m(2) d1,8 in a 21 days basis. RESULTS: 10 platinum-resistant ovarian cancer patients were treated under compassionate use. Mean previous chemotherapy lines were 3.3. Mean administered cycles were 4. Mean CA 125 decrease was on average of 47%, with one patient experiencing a 95% decrease in her CA 125 level. 1 patient had a complete clinical remission, and 2, had partial radiological responses. Mean Progression free survival was 16.5 weeks, and Overall Survival was 21.2 weeks. Treatment was well tolerated. CONCLUSIONS: Deemd to the observed activity, the combination of Pemetrexed and Gemcitabine deserves deeper investigation in platinum-resistant ovarian cancer patients (AU)

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Sarcoma de partes blandas: ¿existe posibilidad de rescate cuando la primera cirugía no fue resolutiva? / Soft tissue sarcoma: can a rescue procedure be performed when the first surgery was unsuccessful?

Objetivo. El objetivo de este trabajo es revisar la experiencia de nuestro centro en el tratamiento de pacientes diagnosticados de sarcoma de partes blandas (SPB) en una extremidad que consultan tras resecciones quirúrgicas inadecuadas o recidiva local. Material y método. Se trata de un estudio retrospectivo de 64 pacientes remitidos tras el tratamiento de un SPB en otro centro, divididos en 2 grupos: el grupo A, compuesto por 27 pacientes a quienes se realizó una escisión inadecuada inicial (whoops procedure) y el grupo B, con 37 pacientes afectos de una recidiva local de un SPB. Se calculó la tasa de supervivencia libre de enfermedad y la tasa de supervivencia acumulada (Kaplan-Meier). Resultados. Grupo A: la totalidad de los 27 pacientes fueron reintervenidos y en 12 casos se detectó enfermedad tumoral residual (un 44%). Veintitrés pacientes recibieron radioterapia asociada (intraoperatoria, braquiterapia y/o externa). El seguimiento medio ha sido de 67 meses (24-216) Tres pacientes presentaron recidiva local, uno de los cuales precisó amputación. El 11% de los pacientes habían fallecido en el momento de la revisión. La tasa de supervivencia libre de enfermedad a los 216 meses ha sido del 85%. Grupo B: 35 de los 37 pacientes fueron reintervenidos (94%). En 21 casos se asoció quimioterapia y en 4 perfusión aislada de la extremidad con factor de necrosis tumoral (TNF) y melfalan (10,8%). Veintisiete pacientes recibieron radioterapia (externa, intraoperatoria y/o braquiterapia) (72%), 19 de ellos habían recibido ya radioterapia después de la primera (70%). En 20 casos (10%) se asoció quimio-terapia y radioterapia. La media de seguimiento ha sido de 80 meses (12-264). Dieciséis pacientes presentaron metástasis después del tratamiento y diecinueve tuvieron complicaciones mayores. El 43% de los pacientes había fallecido en el momento de la revisión. La tasa de supervivencia libre de enfermedad a los 264 meses ha sido del 16%. Conclusiones. Después de una escisión inadecuada inicial se puede obtener una alta tasa de supervivencia libre de enfermedad en pacientes remitidos inmediatamente a centros especializados. Sin embargo, cuando aparece la recidiva local, las posibilidades de supervivencia libre de enfermedad disminuyen drásticamente

Purpose. The purpose of this paper is to review the experience of our hospital in treating patients diagnosed with a soft-tissue sarcoma (STS) in one of their limbs who sought consultation further to inappropriate surgical resections or a local relapse. Materials and methods. This is a retrospective study of 64 patients treated for STS in another hospital; the patients were divided into 2 groups: group A, comprised 27 patients where the initial excision proved to be inappropriate («whoops procedure»); group B was made up of 37 patients that had a local recurrence of a STS. The disease-free and accumulated (Kaplan-Meier) survivorship rates were calculated. Results. Group A: all 27 patients were reoperated and in 12 cases a residual tumoral disease was detected (44%). Twenty-three patients received associated radiotherapy (intraoperatively, brachytherapy and/or external beam radiotherapy). Mean follow up was 67 months (24-216) Three had a local recurrence, two of them requiring amputation. Eleven percent of patients had died at the time of examination. The disease-free survivorship rate at 216 months was 85%. Group B: 35 of the 37 patients were reoperated (94%). Chemotherapy was used in 21 cases and in four cases isolated limb perfusion was used with TNF and melphalan (10.8%). Twenty-seven patients received radiotherapy (external beam, intraoperative and/or brachytherapy) (72%), 19 of them had received radiotherapy after the first one (70%). In 20 cases (10%) both chemotherapy and radiotherapy were used. Mean follow-up was 80 months (range: 12-264). Sixteen patients had metastasis further to treatment and nineteen had major complications. Forty-three percent of patients had died at the time of this review. Disease-free survivorship at 264 months was 16%. Conclusions. After a «whoops procedure» it is possible to obtain a high disease-free survivorship rate in patients referred immediately to specialized units. Nevertheless, when local recurrence occurs, the disease-free survivorship rate decreases sharply

Carcinoma microcítico de pulmón / No disponible

El cáncer microcítico de pulmón es uno de los tumores sólidos más agresivos, por su rápido crecimiento y por su tendencia a metastatizar desde fases tempranas. Sin embargo, también es uno de los tumores más sensibles a los tratamientos de quimioterapia y radioterapia, con los cuales algunos pacientes con enfermedad limitada pueden sobrevivir a largo plazo. Estas características han hecho de este tumor un modelo clínico sobre el cual se han probado múltiples estrategias de tratamiento, incluyendo tratamientos concomitantes con quimioterapia y radioterapia, esquemas de quimioterapia alternante o de altas dosis con soporte hematológico o la utilización de radioterapia holocraneal profi láctica. Además en los últimos años el cáncer microcítico de pulmón también se ha empleado como plataforma de desarrollo de tratamientos dirigidos contra dianas específi cas o de inmunoterapia

Small cell lung cancer is one of the most aggressive solid tumors because of its rapid growth and early tendency to spread to distant organs. Nonetheless, it is also one of the most sensitive tumors to chemotherapy and radiotherapy, which can give patients with limited disease a chance to become long-term survivors. These characteristics have made this tumor a clinical model to explore various treatment strategies, including concomitant chemotherapy and radiotherapy, alternant chemotherapy, high-dose chemotherapy with hematologic support, or use of wholebrain prophylactic radiotherapy. In addition, in recent years, small cell lung cancer has been used as a platform to develop some new targeted therapy agents or immunotherapeutic approaches

Response of resistant melanoma to a combination of weekly paclitaxel and bevacizumab

We report here a taxol-bevacizumab-responsive metastatic melanoma case. Although the patient had been heavily pretreated for two years, she did not show any stabilisation or objective response of her disease. After treatment with taxol and bevacizumab combination an impressive response was obtained (AU)

Nuevos paradigmas en gestión clínica / New paradigms in clinical management

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