Silvia Bagué

Histotype-tailored neoadjuvant chemotherapy versus standard chemotherapy in patients with high-risk soft-tissue sarcomas (ISG-STS 1001): an international, open-label, randomised, controlled, phase 3, multicentre trial

BACKGROUND Previous trials from our group suggested an overall survival benefit with five cycles of adjuvant full-dose epirubicin plus ifosfamide in localised high-risk soft-tissue sarcoma of the extremities or trunk wall, and no difference in overall survival benefit between three cycles versus five cycles of the same neoadjuvant regimen. We aimed to show the superiority of the neoadjuvant administration of histotype-tailored regimen to standard chemotherapy. METHODS For this international, open-label, randomised, controlled, phase 3, multicentre trial, patients were enrolled from 32 hospitals in Italy, Spain, France, and Poland. Eligible patients were aged 18 years or older with localised, high-risk (high malignancy grade, 5 cm or longer in diameter, and deeply located according to the investing fascia), soft-tissue sarcoma of the extremities or trunk wall and belonging to one of five histological subtypes: high-grade myxoid liposarcoma, leiomyosarcoma, synovial sarcoma, malignant peripheral nerve sheath tumour, and undifferentiated pleomorphic sarcoma. Patients were randomly assigned (1:1) to receive three cycles of full-dose standard chemotherapy (epirubicin 60 mg/m2 per day [short infusion, days 1 and 2] plus ifosfamide 3 g/m2 per day [days 1, 2, and 3], repeated every 21 days) or histotype-tailored chemotherapy: for high-grade myxoid liposarcoma, trabectedin 1·3 mg/m2 via 24-h continuous infusion, repeated every 21 days; for leiomyosarcoma, gemcitabine 1800 mg/m2 on day 1 intravenously over 180 min plus dacarbazine 500 mg/m2 on day 1 intravenously over 20 min, repeated every 14 days; for synovial sarcoma, high-dose ifosfamide 14 g/m2, given over 14 days via an external infusion pump, every 28 days; for malignant peripheral nerve sheath tumour, intravenous etoposide 150 mg/m2 per day (days 1, 2, and 3) plus intravenous ifosfamide 3 g/m2 per day (days 1, 2, and 3), repeated every 21 days; and for undifferentiated pleomorphic sarcoma, gemcitabine 900 mg/m2 on days 1 and 8 intravenously over 90 min plus docetaxel 75 mg/m2 on day 8 intravenously over 1 h, repeated every 21 days. Randomisation was stratified by administration of preoperative radiotherapy and by country of enrolment. Computer-generated random lists were prepared by use of permuted balanced blocks of size 4 and 6 in random sequence. An internet-based randomisation system ensured concealment of the treatment assignment until the patient had been registered into the system. No masking of treatment assignments was done. The primary endpoint was disease-free survival. The primary and safety analyses were planned in the intention-to-treat population. We did yearly futility analyses on an intention-to-treat basis. The study was registered with ClinicalTrials.gov, number NCT01710176, and with the European Union Drug Regulating Authorities Clinical Trials, number EUDRACT 2010-023484-17, and is closed to patient entry. FINDINGS Between May 19, 2011, and May 13, 2016, 287 patients were randomly assigned to a group (145 to standard chemotherapy and 142 to histotype-tailored chemotherapy), all of whom, except one patient assigned to standard chemotherapy, were included in the efficacy analysis (97 [34%] with undifferentiated pleomorphic sarcoma; 64 [22%] with high-grade myxoid liposarcoma; 70 [24%] with synovial sarcoma; 27 [9%] with malignant peripheral nerve sheath tumour; and 28 [10%] with leiomyosarcoma). At the third futility analysis, with a median follow-up of 12·3 months (IQR 2·75-28·20), the projected disease-free survival at 46 months was 62% (95% CI 48-77) in the standard chemotherapy group and 38% (22-55) in the histotype-tailored chemotherapy group (stratified log-rank p=0·004; hazard ratio 2·00, 95% CI 1·22-3·26; p=0·006). The most common grade 3 or higher adverse events in the standard chemotherapy group (n=125) were neutropenia (107 [86%]), anaemia (24 [19%]), and thrombocytopenia (21 [17%]); the most common grade 3 or higher adverse event in the histotype-tailored chemotherapy group (n=114) was neutropenia (30 [26%]). No treatment-related deaths were reported in both groups. In agreement with the Independent Data Monitoring Committee, the study was closed to patient entry after the third futility analysis. INTERPRETATION In a population of patients with high-risk soft-tissue sarcoma, we did not show any benefit of a neoadjuvant histotype-tailored chemotherapy regimen over the standard chemotherapy regimen. The benefit seen with the standard chemotherapy regimen suggests that this benefit might be the added value of neoadjuvant chemotherapy itself in patients with high-risk soft-tissue sarcoma. FUNDING European Union grant (Eurosarc FP7 278472).

MRP1 Overexpression Determines Poor Prognosis in Prospectively Treated Patients with Localized High-Risk Soft Tissue Sarcoma of Limbs and Trunk Wall: An ISG/GEIS Study

Patients with localized high-risk soft tissue sarcomas (STS) of the limbs and trunk wall still have a considerable metastatic recurrence rate of more than 50%, in spite of adjuvant chemotherapy. This drug-ceiling effect of chemotherapy in sarcoma setting could be explained, at least partially, by multidrug resistance (MDR) mechanisms. The aim of this study was to ascertain whether mRNA and protein expression of ABCB1 (P-glycoprotein), ABCC1 (MRP1), and GSTA1 (glutathione S-transferase pi) was prognostic in localized high-risk STS. Immunohistochemistry and reverse transcriptase-PCR studies were performed from biopsies at the time of diagnosis. Patients of this series were prospectively enrolled into a phase III trial that compared three versus five cycles of epirubicin plus ifosfamide. The series of 102 patients found 41 events of recurrence and 37 of death with a median follow-up of 68 months. In univariate analysis, variables with a statistically significant relationship with relapse-free survival (RFS) were: MRP1 expression (5-year RFS rate of 23% in positive cases and 63% in negative cases, P = 0.029), histology (5-year RFS rate of 74% in undifferentiated pleomorphic sarcoma and 43% in synovial sarcoma, P = 0.028), and ABCC1 expression (5-year RFS rate of 33% in overexpression and 65% in downregulation, P = 0.012). Combined ABCC1/MRP1 was the only independent prognostic factor for both RFS (HR = 2.704, P = 0.005) and overall survival (HR = 2.208, P = 0.029). ABCC1/MRP1 expression shows robust prognostic relevance in patients with localized high-risk STS treated with anthracycline-based chemotherapy, which is the standard front line treatment in STS. This finding deserves attention as it points to a new targetable protein in STS. Mol Cancer Ther; 13(1); 249–59. ©2013 AACR.

Guía de práctica clínica en los sarcomas de partes blandas

Soft tissue sarcomas (STS) constitute a rare heterogeneous group of tumours that include a wide variety of histological subtypes, which require a multidisciplinary and, frequently specialized and complex management. Despite advances in our understanding of the pathophysiology of the disease, there are no consensus multidisciplinary recommendations about its diagnosis and treatment in our country. The objective of these guidelines is to provide practical therapeutic recommendations that may contribute to improve the therapeutic results of this disease in our environment. With this purpose, the Spanish Group for Research in Sarcomas (GEIS) held a meeting with a multidisciplinary group of experts for the study and management of sarcomas. The results of this meeting are compiled in this document, in which recommendations on diagnosis, treatment and monitoring of soft tissue sarcomas are included. In summary, these guidelines aim to facilitate the identification and management of STS for clinical practice in Spain.

Diferencias entre cirugía en bloque y enucleación en el tratamiento del sarcoma retroperitoneal

AIM Today, free margin surgery is the gold-standard management for soft-tissue sarcoma patients and one of the most important predictors of recurrence and survival. To obtain optimal results, a multidisciplinary approach is necessary. The aim of this study was to evaluate the evolution of patients with RPS treated by «en bloc«surgical resection versus those treated with enucleation in the first surgery. METHODS Fifty-six adult patients were divided into 2 groups. Patients in Group A underwent enucleation surgery, and patients in Group B underwent en bloc surgery. The endpoints of the study were survival time and time to recurrence, according to histological type and first surgical strategy. RESULTS Disease-free survival was longer for en bloc surgery (P<0,05), but there was no difference in overall survival. When comparing the histology of patients who underwent enucleation surgery and en bloc resection surgery, the disease-free survival and overall survival rates were longer for liposarcoma. In the multivariate analysis, only free margins and histology of liposarcoma were significantly associated with a better survival. CONCLUSIONS The surgical management of patients with retroperitoneal sarcoma must be very aggressive, often requiring multivisceral resection. Considering the disease-free survival and overall survival rates obtained, it is clear that it is critical to manage patients as early as possible by a radical en bloc surgery.

The role of HPV on the risk of second primary neoplasia in patients with oropharyngeal carcinoma

OBJECTIVES It has been reported that patients with HPV-positive oropharyngeal cancer (OPC) have a lower risk of appearance of second primary neoplasm (SPN) than HPV-negative OPC patients. The aim of our study was to analyze the risk of developing SPN in a large group of patients with OPC according to HPV status in the primary tumor. MATERIALS AND METHODS We included 412 OPC patients treated at our center from 1991 to 2014 for which the HPV DNA positivity was evaluated by PCR in available tumor specimens. HPV DNA positive samples were further tested for HPV E6∗I mRNA detection and/or p16INK4a immunohistochemistry. We estimated the incidence of SPN in all cancer sites and in cancer sites related to tobacco and alcohol consumption according to the HPV status in the primary tumor. RESULTS Fifty-one (12.4%) out of 412 OPCs included in the study were HPV-related. Five-year SPN-free survival for HPV-negative versus HPV-positive OPC patients was 57.0% and 89.0% (P<0.001), respectively. Corresponding estimates for 10-year SPN-free survival were 35.2% versus 78.5% (P<0.001). When restricting the analyses to tobacco/alcohol-related SPNs, the corresponding survival rates where 62.0% versus 97.6% (P<0.001) and 42.2% versus 97.6%, (P<0.001), for 5-year and 10-year survival rates, respectively. HPV status and previous toxic habits might allow classifying patients regarding the risk of tobacco/alcohol-related SPNs. CONCLUSION HPV-related OPC patients have a significant lower risk of SPN development, particularly in those locations related to tobacco use or alcohol consumption.

Validation of the pathological classification of lymph node metastasis for head and neck tumors according to the 8th edition of the TNM Classification of Malignant Tumors

OBJECTIVES One of the main changes in the 8th edition of the TNM Classification for head and neck tumors is the inclusion of extracapsular spread (ECS) as a criterion for evaluating the regional extension, both clinical (cN) and pathological (pN). The objective of our study is to evaluate the prognostic capacity derived from the inclusion of the ECS in the pathological classification of head and neck squamous cell carcinoma (HNSCC) patients treated with a neck dissection, as established by the 8th edition TNM Classification. MATERIALS AND METHODS Retrospective study of 1188 patients with HNSCC treated with a neck dissection between1990 and 2013. RESULTS There were lymph node metastasis in 50.1% of the neck dissections. The pathological record revealed ECS in 50.5% of the positive neck dissections. The implementation of the changes of the 8th edition TNM classification produced the upstaging of 20.9% of the patients classified as pN1 with the 7th edition TNM classification to pN2a¸ and the upstaging of 58.4% of the patients classified as pN2 with the 7th edition TNM classification to pN3b. We conducted an objective comparison of the quality of both classifications. The 8th TNM classification edition achieved better results regarding both the discrimination in cause-specific survival between pN categories and in the distribution in the number of cases between categories than the 7th edition TNM classification. CONCLUSION The inclusion of ECS in the pathological classification (pN) of the neck nodes improves the prognostic capacity of the 8th TNM Classification edition.

Protocolo para el estudio de muestras y estandarización del informe patológico de tumores óseos.

Primary bone neoplasms represent a rare and heterogeneous group of mesenchymal tumours. The prevalence of benign and malignant tumours varies; the latter (sarcomas) account for less than 0.2% of all malignant tumours. Primary bone neoplasms are usually diagnosed and classified according to the criteria established and published by the World Health Organization (WHO 2013). These criteria are a result of advances in molecular pathology, which complements the histopathological diagnosis. Bone tumours should be diagnosed and treated in referral centers by a multidisciplinary team including pathologists, radiologists, orthopedic surgeons and oncologists. We analyzed different national and international protocols in order to provide a guide of recommendations for the improvement of pathological evaluation and management of bone tumours. We include specific recommendations for the pre-analytical, analytical, and post-analytical phases, as well as protocols for gross and microscopic pathology.

227PPROGNOSIS OF PHOSPHORYLATED-INSULIN GROWTH FACTOR RECEPTOR (P-IGF-1R) AND METALLOPROTEINASE-3 (MMP3) EXPRESSION IN ADVANCED GASTROINTESTINAL STROMAL TUMORS (GIST) PATIENTS TREATED WITH IMATINIB. A GEIS STUDY

ABSTRACT Aim: Most GISTs have mutations in KIT or PDGFRA. Patients with advanced GIST with KIT exon 9, with PDGFRA mutation or WT for KIT and PDGFRA have a worse progression-free survival (PFS) compared to patients with KIT exon 11 mutated tumors. We evaluated expression of p-IGF-1R (Y1316) and MMP3 as predictors of PFS or overall survival (OS) Methods: Ninety-six advanced GIST patients included in GEIS-16 study with KIT and PDGFRA mutational information were examined for p-IGF-1R (Y1316) and MMP3 expression in a tissue micro-array. To study activation of the IGF-1R system, we have used an antibody (anti-pY1316) that specifically recognizes the phosphorylated (active) form of the IGF-1R. DNA was extracted from paraffin-embedded tissues and intronic PCR primers were used to amplify exons 9,11,13 and 17 of KIT, 12 and 18 of PDGFRA. Bidirecctional sequencing with specific primers was performed on a ABI3100 sequencer using the Big Dye Terminator v3.1 kit. Multivariate model was built using a stepwise automated variable selection approach with criterion to enter the variable in the model of p Results: MMP3 was overexpressed in 10% of cases and p-IGF-1R in only 2% of cases. 68% of patients had KIT mutations, 4% had PDGFRA mutations and 28% were WT for KIT and PDGFRA. At univariate analysis KIT exon 11/13 vs rest (WT/WT, KIT exon 9 mutations and PDGFRA mutations) had better PFS (p = 0.038; HR: 0.58; 95%CI (0.35-0.96). Less than 24 months disease free-interval (HR 24.2, 95% CI 10.5-55.8), poor performance status (PS) (HR 6.3, 95% CI 2.5-15.9), extension of disease; > 1 organ (HR 1.89; 95% CI 1.03-3.4) and positive expression of p-IGF-1R or MMP3 (HR 2.1; 95% CI 1.01-4,2) but not mutational analysis (HR 1.02; 95%CI 0.53-1.96) were the strongest prognostic factors for PFS in the multivariate analysis. For OS only PS, disease free-interval and number of metastatic sites remain significant. Conclusions: Our findings suggest that p-IGF-1R (Y1316) and MMP3 expression have major prognostic significance for PFS in advanced GIST treated with imatinib therapy. Disclosure: All authors have declared no conflicts of interest.

Conferencia de consensoGuía de práctica clínica en los sarcomas de partes blandasSoft tissue sarcomas: clinical practice guidelines

Soft tissue sarcomas (STS) constitute a rare heterogeneous group of tumours that include a wide variety of histological subtypes, which require a multidisciplinary and, frequently specialized and complex management. Despite advances in our understanding of the pathophysiology of the disease, there are no consensus multidisciplinary recommendations about its diagnosis and treatment in our country. The objective of these guidelines is to provide practical therapeutic recommendations that may contribute to improve the therapeutic results of this disease in our environment. With this purpose, the Spanish Group for Research in Sarcomas (GEIS) held a meeting with a multidisciplinary group of experts for the study and management of sarcomas. The results of this meeting are compiled in this document, in which recommendations on diagnosis, treatment and monitoring of soft tissue sarcomas are included. In summary, these guidelines aim to facilitate the identification and management of STS for clinical practice in Spain.