A Growth Modulation Index-Based GEISTRA Score as a New Prognostic Tool for Trabectedin Efficacy in Patients with Advanced Soft Tissue Sarcomas: A Spanish Group for Sarcoma Research (GEIS) Retrospective Study

L-sarcoma; Índex de modulació del creixement; SarcomaL-sarcoma; Indice de modulación del crecimiento; SarcomaL-sarcoma; Growth modulation index; SarcomaThe aim of this study was to identify an easily reliable prognostic score that selects the subset of advanced soft tissue sarcoma (ASTS) patients with a higher benefit with trabectedin in terms of time to progression and overall survival. A retrospective series of 357 patients with ASTS treated with trabectedin as second- or further-line in 19 centers across Spain was analyzed. First, it was confirmed that patients with high growth modulation index (GMI > 1.33) were associated with the better clinical outcome. Univariate and multivariate analyses were performed to identify factors associated with a GMI > 1.33. Thus, GEISTRA score was based on metastasis free-interval (MFI ≤ 9.7 months), Karnofsky 1.33. The lowest GEISTRA score showed a median of time-to-progression (TTP) and overall survival (OS) of 5.7 and 19.5 months, respectively, whereas it was 1.8 and 3.1 months for TTP and OS, respectively, for the GEISTRA 4 score. This prognostic tool can contribute to better selecting candidates for trabectedin treatment in ASTS.This research was funded by the Spanish Group for Research on Sarcoma (grant number: NA) and partially by PharmaMar. PharmaMar S.A. did not have any role in study design, or in collection, analysis and interpretation of data

Factores pronósticos de supervivencia en cáncer de laringe e hipofaringe localmente avanzado tratado con quimioterapa de inducción seguido de quimiorradioterapia con más de 15 años de experiencia en población no seleccionada de la vida real. Propuesta de un Score pronóstico

En esta tesis doctoral se basa en la siguiente hipótesis:• Una evaluación pronóstica global en cáncer de laringe e hipofaringe localmente avanzado tratado con QTi + QT-RT concomitante, teniendo en cuenta el mayor número posible de factores relacionados con el paciente, el tumor y el tratamiento recibido, puede ser clave para establecer no sólo un pronóstico sino también un SCORE que nos permita una mejor selección de los pacientes.• Existen factores pronósticos relacionados con el paciente (comorbilidad, valores de Hb, valores de albúmina, parámetros relacionados con la respuesta inmune) y el tratamiento recibido (calidad de QT recibida) que pueden aportar mayor información que los factores pronósticos clásicos.• Los pacientes tratados con una QTi o concomitante subóptima pueden tener menor supervivencia que los pacientes tratados con una QT óptima. • La evolución a lo largo del tratamiento de diferentes valores analíticos puede tener mayor relevancia pronóstica que las determinaciones aisladas.Tiene los siguientes objetivos:Objetivo principal:• Calcular un SCORE pronóstico de carácter global en una población real con pacientes no seleccionados con carcinoma escamoso localmente avanzado tratados con QTi +QT-RT concomitante de inicio. De esta manera, evitaremos el sesgo de selección que se produce en los ensayos clínicos que han testado este tipo de tratamientos y nos puede ayudar a detectar los pacientes que no se vayan a beneficiar de la modalidad no quirúrgica.Objetivos secundarios:• Analizar las características clínicas de los pacientes, del tumor y del tratamiento recibido de manera multidisciplinar de la población a estudio entre 1997 y 2016 en el Hospital Universitario Miguel Servet con cáncer de laringe e hipofaringe localmente avanzado.• Realizar un análisis de la supervivencia con respecto a las diferentes variables recogidas en el estudio para descubrir cuáles son factores pronósticos de supervivencia de forma independiente.• Comparar los factores pronósticos clásicos analizados en este estudio (grado de diferenciación, comorbilidad, estadío etc.) con otros factores dinámicos (biomarcadores séricos) o relacionados con el tratamiento como la calidad de la QT de inducción para valorar los que tienen mayor peso a nivel pronóstico.• Verificar si nuestros resultados en población real sobre Supervivencia Global, Supervivencia Libre de Recidiva y control locorregional son equiparables con los de la literatura científica hasta la actualidad.Y se llegaron a las siguientes conclusiones:1. La población estudiada en este trabajo presenta unas características epidemiológicas similares a la de otros estudios, a pesar de ser pacientes en condiciones reales.2. La implantación progresiva de la multidisciplinariedad a través de la formación de un Comité de Tumores de Cabeza y Cuello en la mayoría de los hospitales ha permitido sacar el mayor partido a los tratamientos disponibles en cada momento. También se ha podido individualizar el tratamiento para cada paciente con mejoras desde el punto de vista de preservación de órgano, calidad de vida y supervivencia comparado con los tratamientos clásicos de Cirugía y Radioterapia.3. Los factores establecidos como grado de diferenciación, la comorbilidad y el estadío tienen menor peso pronóstico independiente cuando se confrontan con otros factores mas dinámicos durante el tratamiento como son los biomarcadores séricos (Hemoglóbina o albúmina). En nuestro estudio, no podemos afirmar que sean factores pronósticos independientes.4. La localización anatómica es el único de los factores pronósticos clásicos analizados en nuestra serie que ha resultado ser factor pronóstico independiente en Supervivencia Global.5. Los factores dinámicos (biomarcadores séricos) analizados en nuestro estudio tienen mayor valor pronóstico sobre la supervivencia que los estáticos (grado de diferenciación, comorbilidad etc.). De hecho, valores de la Hb post-QTi 6. La respuesta a la quimioterapia de inducción es un factor pronóstico independiente en la Supervivencia Global, Supervivencia Global Específica y la Supervivencia Libre de Recidiva. Además, nos permite dirigir al paciente hacia el mejor tratamiento (Cirugía o QT+ RT concomitante).7. La calidad de QT de inducción es un factor pronóstico independiente con más peso que otros factores pronósticos clásicos. Los pacientes que reciban QT de inducción óptima tienen una mejor supervivencia que los pacientes a los que se les pautó un esquema subóptimo. El término subóptimo es nuevo y no ha sido descrito hasta ahora.8. El uso de Cisplatino durante la QT concomitante no tiene un peso pronostico independiente frente al uso de otras terapias concomitantes. En nuestra serie la calidad de la QT de inducción tiene mas importancia que la calidad de la QT concomitante, cuando se realiza un tratamiento secuencial.9. Nuestros datos, a pesar de estar basados en población real, tienen resultados de supervivencia global, supervivencia libre de recidiva y control locoregional equiparables a otros estudios prospectivos de planteamiento similar en la literatura.10. El SCORE pronóstico diseñado permite predecir el riesgo de muerte a 5 años en los pacientes con cáncer de laringe e hipofaringe localmente avanzados tratados con terapia secuencial QTi+QT-RTconcomitante en población real. Puede ser una herramienta clínica fácilmente accesible para ayudar a la selección de tratamientos.<br /

Peripheral Inflammatory Indexes Neutrophil/Lymphocyte Ratio (NLR) and Red Cell Distribution Width (RDW) as Prognostic Biomarkers in Advanced Solitary Fibrous Tumour (SFT) Treated with Pazopanib

Simple Summary Pazopanib treatment in advanced solitary fibrous tumour patients, assessed in the prospective GEIS-32 phase II clinical trial, has shown longer progression-free survival and overall survival versus chemotherapy treatment in control patients. In recent years, the interest in the prognostic and predictive value of different peripheral inflammatory indexes, such as neutrophil/lymphocyte ratio, platelet/lymphocyte ratio, and red cell distribution width, has been increased in sarcomas, showing significant results in different soft tissue sarcomas. However, they have not been previously analysed in solitary fibrous tumour (SFT) patients. These indexes were retrospectively analysed in the typical- and malignant-SFT cohorts treated with pazopanib of the GEIS-32 trial to evaluate their predictive or prognostic value. Pazopanib was assessed prospectively in the GEIS-32 phase II study (NCT02066285) on advanced solitary fibrous tumour (SFT), resulting in a longer progression-free survival (PFS) and overall survival (OS) compared with historical controls treated with chemotherapy. A retrospective analysis of peripheral inflammatory indexes in patients enrolled into GEIS-32 was performed to evaluate their prognostic and predictive value. Patients received pazopanib 800 mg/day as the first antiangiogenic line. The impacts of baseline neutrophil/lymphocyte ratio (NLR), platelet/lymphocyte ratio (PLR), and red cell distribution width (RDW) on PFS, OS, and Choi response were evaluated by univariate and multivariate analysis. Metastasis-free interval (MFI), mitotic count, and ECOG were also included as potential prognostic factors. Sixty-seven SFT patients, enrolled in this study, showed a median age of 63 years and a female/male distribution of 57/43. The median follow-up from treatment initiation was 16.8 months. High baseline NLR, PLR, and standardised RDW were significantly associated with worse PFS and OS. NLR, RDW, MFI, and mitotic count were independent variables for PFS, while RDW and ECOG were independent for OS. Further, NLR and mitotic count were independent factors for Choi response. High baseline NLR and RDW values were independent prognostic biomarkers for worse outcome in advanced SFT patients treated with pazopanib

A DNA damage repair gene-associated signature predicts responses of patients with advanced soft-tissue sarcoma to treatment with trabectedin

Predictive biomarkers of trabectedin represent an unmet need in advanced soft-tissue sarcomas (STS). DNA damage repair (DDR) genes, involved in homologous recombination or nucleotide excision repair, had been previously described as biomarkers of trabectedin resistance or sensitivity, respectively. The majority of these studies only focused on specific factors (ERCC1, ERCC5, and BRCA1) and did not evaluate several other DDR-related genes that could have a relevant role for trabectedin efficacy. In this retrospective translational study, 118 genes involved in DDR were evaluated to determine, by transcriptomics, a predictive gene signature of trabectedin efficacy. A six-gene predictive signature of trabectedin efficacy was built in a series of 139 tumor samples from patients with advanced STS. Patients in the high-risk gene signature group showed a significantly worse progression-free survival compared with patients in the low-risk group (2.1 vs 6.0 months, respectively). Differential gene expression analysis defined new potential predictive biomarkers of trabectedin sensitivity (PARP3 and CCNH) or resistance (DNAJB11 and PARP1). Our study identified a new gene signature that significantly predicts patients with higher probability to respond to treatment with trabectedin. Targeting some genes of this signature emerges as a potential strategy to enhance trabectedin efficacy.This study was funded by the Spanish Group for Research on Sarcoma (GEIS) and partially by PharmaMar. The authors would like to thank the GEIS data center for data management. The authors also thank the donors and the Hospital Universitario Virgen del Rocío—Instituto de Biomedicina de Sevilla Biobank (Andalusian Public Health System Biobank and ISCIII-Red de Biobancos PT17/0015/0041) for part of the human specimens used in this study. David S. Moura is recipient of a Sara Borrell postdoctoral fellowship funded by the National Institute of Health Carlos III (ISCIII) (CD20/00155)

TTCC-2019-02: real-world evidence of first-line cetuximab plus paclitaxel in recurrent or metastatic squamous cell carcinoma of the head and neck

ObjectivesThe aim of this study was to confirm the efficacy of the ERBITAX scheme (paclitaxel 80 mg/m2 weekly and cetuximab 400 mg/m2 loading dose, and then 250 mg/m2 weekly) as first-line treatment for patients with recurrent/metastatic squamous cell carcinoma of the head and neck (SCCHN) who are medically unfit for cisplatin-based (PT) chemotherapy.Materials and methodsThis retrospective, non-interventional study involved 16 centers in Spain. Inclusion criteria were to have started receiving ERBITAX regimen from January 2012 to December 2018; histologically confirmed SCCHN including oral cavity, oropharynx, hypopharynx, and larynx; age ≥18 years; and platinum (PT) chemotherapy ineligibility due to performance status, comorbidities, high accumulated dose of PT, or PT refractoriness.ResultsA total of 531 patients from 16 hospitals in Spain were enrolled. The median age was 66 years, 82.7% were male, and 83.5% were current/former smokers. Patients were ineligible to receive PT due to ECOG 2 (50.3%), comorbidities (32%), PT cumulative dose ≥ 225 mg/m2 (10.5%), or PT refractoriness (7.2%). Response rate was 37.7%. Median duration of response was 5.6 months (95% CI: 4.4–6.6). With a median follow-up of 8.7 months (95% CI: 7.7–10.2), median PFS and OS were 4.5 months (95% CI: 3.9–5.0) and 8.9 months (95% CI: 7.8–10.3), respectively. Patients treated with immunotherapy after ERBITAX had better OS with a median of 29.8 months compared to 13.8 months for those who received other treatments. The most common grade ≥ 3 toxicities were acne-like rash in 36 patients (6.8%) and oral mucositis in 8 patients (1.5%). Five (0.9%) patients experienced grade ≥ 3 febrile neutropenia.ConclusionThis study confirms the real-world efficacy and tolerability of ERBITAX as first-line treatment in recurrent/metastatic SCCHN when PT is not feasible. Immunotherapy after treatment with ERBITAX showed remarkable promising survival, despite potential selection bias

Estudio de los factores pronósticos epidemiológicos, clínicos, anatomopatológicos y moleculares en el cáncer epidermoide faringo-laríngeo localmente avanzado dentro de un protocolo de tratamiento multidisciplinar con quimioterapia, radioterapia y cirugía.

Estudio restrospectivo sobre una muestra homogénea en sí misma y homogéneamente tratada, afecta de cáncer epidermoide faringo-laríngeo localmente avanzado estadíos III y IV que recibe el siguiente esquema de tratamiento: tres ciclos de quimioterapia de inducción seguida de quimio-radioterapia concomitante en caso de respuesta mayor al 80%, o de rescate quirúrgico en caso contrario. Realizamos un análisis descriptivo de la muestra y un estudio de factores pronósticos comprobándose lo siguiente: * Los factores pronósticos clásicos siguen teniendo validez en el cáncer faringo-laríngeo tratado de forma combinada. * La comorbilidad es un factor pronóstico independiente de supervivencia global, global específica y libre de enfermedad, constituyendo una aportación novedosa la aplicación de este índice en cáncer de cabeza y cuello en nuestro país, siendo determinación obligada en un futuro como complemento al sistema TNM. * El descenso porcentual de hemoglobina mayor al 75% del valor basal, es un factor pronostico independiente de supervivencia libre de enfermedad. Este hallazgo también es una aportación novedosa de nuestro estudio, apuntando a la corrección de este factor como posibilidad para lograr mejores resultados en control loco-regional y preservación de órgano. * La respuesta a la quimioterapia de inducción es un factor pronóstico independiente de supervivencia global, global específica y libre de enfermedad, confirmando de esta manera la capacidad de la quimioterapia de inducción de seleccionar a los pacientes para tratamientos ulteriores, así como optimizar los resultados de la quimio-radioterapia concomitante posterior. * La determinación sistemática de los factores p53 y Ki-67 no está justificada, al no aportar información pronostica alguna en nuestra serie. El descenso porcentual de hemoglobina mayor al 75% del valor basal, es un factor pronostico independiente de supervivencia libre de enfermedad. Este hallazgo también es una aportación novedosa de nuestro estudio, apuntando a la corrección de este factor como posibilidad para lograr mejores resutlados en control loco-regional y preservación de órgano. * La respuesta a la quimioterapia de inducción es un factor pronóstico independiente de supervivencia global, global específica y libre de enfermedad, confirmando de esta manera la capacidad de la quimioterapia de inducción de seleccionar a los pacientes para tratamientos ulteriores, así como optimizar los resultados de la quimio-radioterapia concomitante posterior. * La determinación sistemática de los factores p53 y Ki-67 no está justificada, al no aportar información pronostica alguna en nuestra serie. Retrospective study on a homogeneous sample itself and homogeneously treated, affected of locally advanced stage III and IV pharyngo-laryngeal squamous cell cancer that received the following treatment schedule: three cycles of induction chemotherapy followed by concomitant chemoradiotherapy in case of a greater than 80% response, or surgical rescue otherwise. We conducted a descriptive analysis of the sample and a prognostic factors study and verified that: * Classic prognostic factors remain valid in pharyngo-laryngeal cancer treated under a combination protocol. * Comorbidity is an independent predictor of overall survival, specific global survival and free of disease survival, constituting a novel contribution to the implementation of this index in head and neck cancer in our country, with determination required in the future as a supplement to the TNM system. * The percentage decrease in hemoglobin greater than 75% of baseline, is an independent prognostic factor for disease-free survival. This finding is also a novel contribution of our study, pointing out the correction of this factor as a possibility for better loco-regional control and organ preservation. * The response to induction chemotherapy is an independent predictor of overall survival, specific overall and disease-free, thus confirming the ability of induction chemotherapy to select patients for further treatment and optimize outcomes Concomitant chemo-radiotherapy later. * The systematic identification of factors p53 and Ki-67 is not justified, by failing to provide any prognostic information in our series. The percentage decrease in hemoglobin greater than 75% of baseline, is an independent prognostic factor for disease-free survival. This finding is also a novel contribution of our study, pointing to the correction of this factor as a possibility for better Somedays it works in locoregional control and organ preservation. * The response to induction chemotherapy is an independent predictor of overall survival, specific overall and disease-free survival, thus confirming the ability of induction chemotherapy to select patients for further treatment and optimize outcomes of concomitant chemo-radiotherapy. * The systematic identification of factors p53 and Ki-67 is not justified, by failing to provide any prognostic information in our series

Nivolumab and sunitinib combination in advanced soft tissue sarcomas: a multicenter, single-arm, phase Ib/II trial

Immunoteràpia; Sarcoma; Investigació mèdica translacionalInmunoterapia; Sarcoma; Investigación médica traslacionalImmunotherapy; Sarcoma; Translational medical researchBackground Sarcomas exhibit low expression of factors related to immune response, which could explain the modest activity of PD-1 inhibitors. A potential strategy to convert a cold into an inflamed microenvironment lies on a combination therapy. As tumor angiogenesis promotes immunosuppression, we designed a phase Ib/II trial to test the double inhibition of angiogenesis (sunitinib) and PD-1/PD-L1 axis (nivolumab). Methods This single-arm, phase Ib/II trial enrolled adult patients with selected subtypes of sarcoma. Phase Ib established two dose levels: level 0 with sunitinib 37.5 mg daily from day 1, plus nivolumab 3 mg/kg intravenously on day 15, and then every 2 weeks; and level −1 with sunitinib 37.5 mg on the first 14 days (induction) and then 25 mg per day plus nivolumab on the same schedule. The primary endpoint was to determine the recommended dose for phase II (phase I) and the 6-month progression-free survival rate, according to Response Evaluation Criteria in Solid Tumors 1.1 (phase II). Results From May 2017 to April 2019, 68 patients were enrolled: 16 in phase Ib and 52 in phase II. The recommended dose of sunitinib for phase II was 37.5 mg as induction and then 25 mg in combination with nivolumab. After a median follow-up of 17 months (4–26), the 6-month progression-free survival rate was 48% (95% CI 41% to 55%). The most common grade 3–4 adverse events included transaminitis (17.3%) and neutropenia (11.5%). Conclusions Sunitinib plus nivolumab is an active scheme with manageable toxicity in the treatment of selected patients with advanced soft tissue sarcoma, with almost half of patients free of progression at 6 months.This work was supported by GEIS and ISG. BMS and Pfizer provided drug supply and partial funding for shipping. Translational studies were partially funded by Beca Buesa from the GEIS group

Nivolumab and sunitinib combination in advanced soft tissue sarcomas: a multicenter, single-arm, phase Ib/II trial

Background: Sarcomas exhibit low expression of factors related to immune response, which could explain the modest activity of PD-1 inhibitors. A potential strategy to convert a cold into an inflamed microenvironment lies on a combination therapy. As tumor angiogenesis promotes immunosuppression, we designed a phase Ib/II trial to test the double inhibition of angiogenesis (sunitinib) and PD-1/PD-L1 axis (nivolumab). Methods: This single-arm, phase Ib/II trial enrolled adult patients with selected subtypes of sarcoma. Phase Ib established two dose levels: level 0 with sunitinib 37.5mg daily from day 1, plus nivolumab 3mg/kg intravenously on day 15, and then every 2weeks; and level −1 with sunitinib 37.5mg on the first 14 days (induction) and then 25mg per day plus nivolumab on the same schedule. The primary endpoint was to determine the recommended dose for phase II (phase I) and the 6-month progression free survival rate, according to Response Evaluation Criteria in Solid Tumors 1.1 (phase II). Results: From May 2017 to April 2019, 68 patients were enrolled: 16 in phase Ib and 52 in phase II. The recommended dose of sunitinib for phase II was 37.5mg as induction and then 25mg in combination with nivolumab. After a median follow-up of 17months (4–26), the 6-month progression-free survival rate was 48% (95% CI 41% to 55%). The most common grade 3–4 adverse events included transaminitis (17.3%) and neutropenia (11.5%). Conclusions: Sunitinib plus nivolumab is an active scheme with manageable toxicity in the treatment of selected patients with advanced soft tissue sarcoma, with almost half of patients free of progression at 6months.GEISISGBMSPfize

SEOM Clinical Guideline of management of soft-tissue sarcoma (2016)

Soft-tissue sarcomas are uncommon and heterogeneous tumors of mesenchymal origin. A soft-tissue mass that is increasing in size, greater than 5 cm, or located under deep fascia are criteria for suspicion of sarcoma. Diagnosis, treatment, and management should preferably be performed by a multidisciplinary team in reference centers. MRI and lung CT scan are mandatory for local and distant assessment. A biopsy indicating histological type and grade is needed previous to the treatment. Wide surgical resection with tumor-free tissue margin is the primary treatment for localized disease. Radiotherapy is indicated in large, deep, high-grade tumors, or after marginal resection not likely of being improved with reexcision. Neoadjuvant and adjuvant chemotherapy improve survival in selected cases, usually in high-grade sarcomas of the extremities. In the case of metastatic disease, patients with exclusive lung metastasis could be considered for surgery. First-line treatment with anthracyclines (or in combination with ifosfamide) is the treatment of choice. New drugs have shown activity in second-line therapy and in specific histological subtypes

Recent Therapeutic Advances and Change in Treatment Paradigm of Patients with Merkel Cell Carcinoma

Merkel cell carcinoma (MCC) is a rare, aggressive, primary cutaneous neuroendocrine tumor that typically presents as an indurated nodule on sun‐exposed areas of the head and neck in the white population. Major risk factors include immunosuppression, UV light exposure, and advanced age. Up to 80% of MCC are associated with Merkel cell polyomavirus. About 50% of patients present with localized disease, and surgical resection with or without adjuvant radiotherapy is generally indicated in this context. However, recurrence rates are high and overall prognosis rather poor, with mortality rates of 33%–46%. MCC is a chemosensitive disease, but responses in the advanced setting are seldom durable and not clearly associated with improved survival. Several recent trials with checkpoint inhibitors (pembrolizumab, avelumab, nivolumab) have shown very promising results with a favorable safety profile, in both chemonaïve and pretreated patients. In 2017, avelumab was approved by several regulatory agencies for the treatment of metastatic MCC, the first drug to be approved for this orphan disease. More recently, pembrolizumab has also been approved by the U.S. Food and Drug Administration in this setting. Immunotherapy has therefore become the new standard of care in advanced MCC. This article reviews current evidence and recommendations for the diagnosis and treatment of MCC and discusses recent therapeutic advances and their implications for care in patients with advanced disease. This consensus statement is the result of a collaboration between the Spanish Cooperative Group for Neuroendocrine Tumors, the Spanish Group of Treatment on Head and Neck Tumors, and the Spanish Melanoma Group.Merck KGaA and Pfizer financially supported medical writer assistance and should also be acknowledged