S. Bonvalot

Phase II Study of ET-743 in Advanced Soft Tissue Sarcomas: A European Organisation for the Research and Treatment of Cancer (EORTC) Soft Tissue and Bone Sarcoma Group Trial

PURPOSE This nonrandomized multicenter phase II study was performed to evaluate the activity and safety of Ecteinascidin (ET-743) administered at a dose of 1.5 mg/m(2) as a 24-hour continuous infusion every 3 weeks in patients with pretreated advanced soft tissue sarcoma. PATIENTS AND METHODS Patients with documented progressive advanced soft tissue sarcoma received ET-743 as second- or third-line chemotherapy. Antitumor activity was evaluated every 6 weeks until progression, excessive toxicity, or patient refusal. RESULTS One hundred four patients from eight European institutions were included in the study (March 1999 to November 2000). A total of 410 cycles were administered in 99 assessable patients. Toxicity mainly involved reversible grade 3 to 4 asymptomatic elevation of transaminases in 40% of patients, and grade 3 to 4 neutropenia was observed in 52% of patients. There were eight partial responses (PR; objective regression rate, 8%), 45 no change (NC; > 6 months in 26% of patients), and 39 progressive disease. A progression arrest rate (PR + NC) of 56% was observed in leiomyosarcoma and 61% in synovialosarcoma. The median duration of the time to progression was 105 days, and the 6-month progression-free survival was 29%. The median duration of survival was 9.2 months. CONCLUSION ET-743 seems to be a promising active agent in advanced soft tissue sarcoma, with no cumulative toxicities. The 6-months progression-free survival observed in advanced soft tissue sarcoma compares favorably with those obtained with other active drugs tested in second-line chemotherapy in previous European Organisation for the Research and Treatment of Cancer trials. The median overall survival was unusually long in these heavily pretreated patients mainly due to the high number of patients who benefit from the drug in terms of tumor control.

Soft tissue and visceral sarcomas: ESMO–EURACAN Clinical Practice Guidelines for diagnosis, treatment and follow-up

Fondazione IRCCS Istituto Nazionale dei Tumori and University of Milan, Milan, Italy; Instituto Portugues de Oncologia de Lisboa Francisco Gentil, EPE, Lisbon, Portugal; University Hospital Essen, Essen, Germany; Department of Oncological Orthopedics, Musculoskeletal Tissue Bank, IFO, Regina Elena National Cancer Institute, Rome, Italy; Klinikum Stuttgart-Olgahospital, Stuttgart, Germany; Institut Curie, Paris, France; NORDIX, Athens, Greece; Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands; Vienna General Hospital (AKH), Medizinische Universität Wien, Vienna, Austria; Hospital Universitario Virgen del Rocio-CIBERONC, Seville, Spain; Centro di Riferimento Oncologico di Aviano, Aviano; Ospedale Regionale di Treviso “S.Maria di Cà Foncello”, Treviso, Italy; Integrated Unit ICO Hospitalet, HUB, Barcelona, Spain; Sarcoma Unit, University College London Hospitals, London, UK; Skane University Hospital-Lund, Lund, Sweden; N. N. Blokhin Russian Cancer Research Center, Moscow, Russian Federation; Institute of Scientific Hospital Care (IRCCS), Regina Elena National Cancer Institute, Rome; Pediatric Oncology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan; Istituto Ortopedico Rizzoli, Bologna; Azienda Ospedaliera Universitaria Careggi Firenze, Florence, Italy; Department of Medical Oncology, Leiden University Medical Centre, Leiden, The Netherlands; Institut Jules Bordet, Brussels, Belgium; Candiolo Cancer Institute, FPO IRCCS, Candiolo, Italy; Department of Radiotherapy, The Netherlands Cancer Institute, Amsterdam and Department of Radiotherapy, Leiden University Medical Centre, Leiden, The Netherlands; Turku University Hospital (Turun Yliopistollinen Keskussairaala), Turlu, Finland; Oxford University Hospitals NHS Foundation Trust, Oxford, UK; Mannheim University Medical Center, Mannheim; Department of Medicine III, University Hospital, Ludwig-Maximilians-University Munich, Munich, Germany; Helsinki University Central Hospital (HUCH), Helsinki, Finland; Royal Marsden Hospital, London; The Institute of Cancer Research, London, UK; University Medical Center Groningen, Groningen; Radboud University Medical Center, Nijmegen, The Netherlands; University Hospital Motol, Prague; Masaryk Memorial Cancer Institute, Brno, Czech Republic; Gustave Roussy Cancer Campus, Villejuif, France; Maria Skłodowska Curie Institute, Oncology Centre, Warsaw, Poland; Tel Aviv Sourasky Medical Center (Ichilov), Tel Aviv, Israel; Medical Oncology, University Hospital of Lausanne, Lausanne, Switzerland; Azienda Ospedaliera, Universitaria, Policlinico S Orsola-Malpighi Università di Bologna, Bologna; Azienda Ospedaliero, Universitaria Cita della Salute e della Scienza di Torino, Turin, Italy; Fundacio de Gestio Sanitaria de L’hospital de la SANTA CREU I Sant Pau, Barcelona, Spain; Helios Klinikum Berlin Buch, Berlin, Germany; YCRC Department of Clinical Oncology, Weston Park Hospital NHS Trust, Sheffield, UK; Aarhus University Hospital, Aarhus, Finland; Leuven Cancer Institute, Leuven, Belgium; Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands; Fondazione Istituto di Ricovero e Cura a Carattere Scientifico, Istituto Nazionale dei Tumori, Milan, Italy; Department of Oncology, Oslo University Hospital, The Norwegian Radium Hospital, Oslo, Norway; Institute of Oncology of Ljubljana, Ljubljana, Slovenia; Netherlands Cancer Institute Antoni van Leeuwenhoek, Amsterdam, The Netherlands; University College Hospital, London, UK; Gerhard-Domagk-Institut für Pathologie, Universitätsklinikum Münster, Münster, Germany; Oslo University Hospital, Norwegian Radium Hospital, Oslo, Norway; Centre Leon Bernard and UCBL1, Lyon, France

Phase II clinical trial of neoadjuvant trabectedin in patients with advanced localized myxoid liposarcoma

BACKGROUND To evaluate neoadjuvant trabectedin (1.5 mg/m2 24-h i.v. infusion every 3 weeks; three to six cycles) in patients with locally advanced myoxid liposarcoma (ML) previously untreated with chemotherapy or radiation. PATIENTS AND METHODS Primary efficacy end point was pathological complete response (pCR) or tumoral regression rate. Objective response according to RECIST (v.1.0) was a secondary end point. RESULTS Three of 23 assessable patients had pCR [13%; 95% confidence interval (CI), 3% to 34%]. Furthermore, very good and moderate histological responses were observed in another 2 and 10 patients, respectively. Histological decrement in the cellular and vascular tumor component and maturation of tumor cells to lipoblasts were observed in both myoxid and myoxid/round cell variants. Seven patients had partial response according to RECIST (objective response rate of 24%; 95% CI, 10% to 44%). No disease progression was reported. Neoadjuvant trabectedin was usually well tolerated, with a safety profile similar to that described in patients with soft tissue sarcoma or other tumor types. CONCLUSION Trabectedin 1.5 mg/m2 given as a 24-h i.v. infusion every 3 weeks is a therapeutic option in the neoadjuvant setting of ML.BACKGROUND To evaluate neoadjuvant trabectedin (1.5 mg/m(2) 24-h i.v. infusion every 3 weeks; three to six cycles) in patients with locally advanced myoxid liposarcoma (ML) previously untreated with chemotherapy or radiation. PATIENTS AND METHODS Primary efficacy end point was pathological complete response (pCR) or tumoral regression rate. Objective response according to RECIST (v.1.0) was a secondary end point. RESULTS Three of 23 assessable patients had pCR [13%; 95% confidence interval (CI), 3% to 34%]. Furthermore, very good and moderate histological responses were observed in another 2 and 10 patients, respectively. Histological decrement in the cellular and vascular tumor component and maturation of tumor cells to lipoblasts were observed in both myoxid and myoxid/round cell variants. Seven patients had partial response according to RECIST (objective response rate of 24%; 95% CI, 10% to 44%). No disease progression was reported. Neoadjuvant trabectedin was usually well tolerated, with a safety profile similar to that described in patients with soft tissue sarcoma or other tumor types. CONCLUSION Trabectedin 1.5 mg/m(2) given as a 24-h i.v. infusion every 3 weeks is a therapeutic option in the neoadjuvant setting of ML.

Effect of adjuvant chemotherapy on survival in FNCLCC grade 3 soft tissue sarcomas: a multivariate analysis of the French Sarcoma Group Database

BACKGROUND The predictive value of grade for benefit from adjuvant chemotherapy (AC) in soft tissue sarcoma (STS) patients has never been explored. PATIENTS AND METHODS From 1980 to 1999, 1513 adult patients with non-metastatic STS were included prospectively in the French Sarcoma Group database. Grade was assessed according to the Fédération Nationale des Centres de Lutte Contre le Cancer (FNCLCC) system after central review. RESULTS AC was delivered to 13 grade 1 patients (3%), 145 grade 2 patients (35%) and 262 grade 3 patients (62%). Young age, non-well-differentiated liposarcoma histology, deep location, bone and/or neurovascular invasion and grade 2 or 3 were significantly associated with a higher likelihood to receive AC. Median follow-up was 9 years. On multivariate analysis, AC was significantly associated with improved metastasis-free survival (MFS) [5-year MFS: 58% versus 49%, hazard ratio (HR) 0.7 (95% confidence interval (CI) 0.6-0.9), P = 0.01] and overall survival (OS) [5-year OS: 58% versus 45%, HR 0.6 (95% CI 0.5-0.8), P = 0.0002] in grade 3 patients. This was not observed in grade 2 patients [5-year MFS: 76% versus 73%, HR 0.8 (95% CI 0.5-1.2), P = 0.27; 5-year OS: 75% versus 65%, HR 0.8 (95% CI 0.6-1.1), P = 0.15]. CONCLUSION This large cohort-based analysis with long-term follow-up indicates that patients with FNCLCC grade 3 disease may benefit from AC.

Sporadic desmoid-type fibromatosis: a stepwise approach to a non-metastasising neoplasm—a position paper from the Italian and the French Sarcoma Group

Desmoid-type fibromatosis (DF) is a rare locally aggressive monoclonal proliferation of myofibroblasts lacking metastatic capacity. It may be observed in nearly every part of the body. Considering the variable clinical presentations, anatomic locations, and biologic behaviors, an individualized treatment approach is required. The pathogenesis of DF is not completely understood even if a high prevalence (∼85%) of CTNNB1 mutations discovered in sporadic DF underlies the importance of the Wnt/&bgr;-catenin pathway. No established and evidence-based approach for the treatment of this neoplasm is available as of today. Considering the unpredictable behavior and the heterogeneity of this disease, we propose a treatment algorithm approved by the French and the Italian Sarcoma Group, based on a front-line wait and see approach and subsequent therapy in the case of progression. A careful counseling at a referral center is mandatory and should be offered to all patients affected by sporadic DF from the time of their diagnosis.Desmoid-type fibromatosis (DF) is a rare locally aggressive monoclonal proliferation of myofibroblasts lacking metastatic capacity. It may be observed in nearly every part of the body. Considering the variable clinical presentations, anatomic locations, and biologic behaviors, an individualized treatment approach is required. The pathogenesis of DF is not completely understood even if a high prevalence (∼85%) of CTNNB1 mutations discovered in sporadic DF underlies the importance of the Wnt/β-catenin pathway. No established and evidence-based approach for the treatment of this neoplasm is available as of today. Considering the unpredictable behavior and the heterogeneity of this disease, we propose a treatment algorithm approved by the French and the Italian Sarcoma Group, based on a front-line wait and see approach and subsequent therapy in the case of progression. A careful counseling at a referral center is mandatory and should be offered to all patients affected by sporadic DF from the time of their diagnosis.

High frequency of β -catenin heterozygous mutations in extra-abdominal fibromatosis: a potential molecular tool for disease management

Background:Fibromatosis comprises distinct clinical entities, including sporadic extra-abdominal fibromatosis, which have a high tendency for recurrence, even after adequate resection. There are no known molecular biomarkers of local recurrence. We searched for β-catenin mutations in a European multicentre series of fibromatosis tumours to relate β-catenin mutational status to disease outcome.Methods:Direct sequencing of exon 3 β-catenin gene was performed for 155 frozen fibromatosis tissues from all topographies. Correlation of outcome with mutation rate and type was performed on the extra-abdominal fibromatosis group (101 patients).Results:Mutations of β-catenin were detected in 83% of all cases. Among 101 extra-abdominal fibromatosis, similar mutation rates (87%) were observed, namely T41A (39.5%), S45P (9%), S45F (36.5%), and deletion (2%). None of the clinico-pathological parameters were found to be significantly associated with β-catenin mutational status. With a median follow-up of 62 months, 51 patients relapsed. Five-year recurrence-free survival was significantly worse in β-catenin-mutated tumours regardless of a specific genotype, compared with wild-type tumours (49 vs 75%, respectively, P=0.02).Conclusion:A high frequency (87%) of β-catenin mutation hallmarks extra-abdominal fibromatosis from a large multicentric retrospective study. Moreover, wild-type β-catenin seems to be an interesting prognostic marker that might be useful in the therapeutic management of extra-abdominal fibromatosis.

Management of Recurrent Retroperitoneal Sarcoma (RPS) in the Adult: A Consensus Approach from the Trans-Atlantic RPS Working Group

IntroductionRetroperitoneal soft tissue sarcomas (RPS) are rare tumors. Surgery is the mainstay of curative therapy, but local recurrence is common. No recommendations concerning the best management of recurring disease have been developed so far. Although every effort should be made to optimize the initial approach, recommendations to treat recurring RPS will be helpful to maximize disease control at recurrence.MethodsAn RPS transatlantic working group was established in 2013. The goals of the group were to share institutional experiences, build large multi-institutional case series, and develop consensus documents on the approach to this difficult disease. The outcome of this document applies to recurrent RPS that is nonvisceral in origin. Included are sarcomas of major veins, undifferentiated pleomorphic sarcoma of psoas, ureteric leiomyosarcoma (LMS). Excluded are desmoids-type fibromatosis, angiomyolipoma, gastrointestinal stromal tumors, sarcomas arising from the gut or its mesentery, uterine LMS, prostatic sarcoma, paratesticular/spermatic cord sarcoma, Ewing sarcoma, alveolar/embryonal rhabdomyosarcoma, sarcoma arising from teratoma, carcinosarcoma, sarcomatoid carcinoma, clear cell sarcoma, radiation-induced sarcoma, paraganglioma, and malignant pheochromocytoma.ResultsRecurrent RPS management was evaluated from diagnosis to follow-up. It is a rare and complex malignancy that is best managed by an experienced multidisciplinary team in a specialized referral center. The best chance of cure is at the time of primary presentation, but some patients may experience prolonged disease control also at recurrence, when the approach is optimized and follows the recommendations contained herein.ConclusionsInternational collaboration is critical for adding to the present knowledge. A transatlantic prospective registry has been established.

Can the MRI signal of aggressive fibromatosis be used to predict its behavior

PURPOSE Aggressive fibromatosis is an invasive non-metastasizing soft-tissue tumor. Until recently, the standard treatment combined surgery and radiation therapy, but new studies reported that conservative strategies with or without medical treatment could be the best management. The aim of this study was to analyze and correlate the size and MR imaging signal features of aggressive fibromatosis with its behavior in order to choose the best treatment. MATERIALS AND METHODS Between March 1985 and December 2005, 27 patients with at least 2 consecutive MRI examinations and no surgery or radiation therapy in between were recorded. There were 9 men and 18 women, and median age was 31 years. They underwent 107 MRI examinations of 47 lesions, 29 of which were medically treated, while the remaining 18 did not receive any drug administration. The size and signal changes of each lesion were studied over time on T2- and/or T1-weighted sequences after injection of contrast medium. RECIST criteria were used for size: only a 30% decrease or a 20% increase in the size of the main dimension was considered significant. We classified the appearance of the signal into six categories in order of increasing intensity and then we established the related variations over time. RESULTS The size of 79% of the lesions in the treated group and 82% in the untreated group remained stable. The initial signal of stable lesions or those exhibiting an increase in size was most frequently high. There was a high rate of signal stability over time, whatever the initial signal and size changes. Changes in size were not correlated with the initial MR signal. A decrease in size associated with a decreased signal was observed in three cases exclusively in the treated group. CONCLUSION Fibromatoses are a group of soft-tissue tumors with variable characteristics on MRI, but it is not possible to predict their behavior based on the MRI signal.

Recommandations pour la prise en charge des tumeurs stromales gastro-intestinales

Resume Contexte La prise en charge des tumeurs stromales gastro-intestinales (GIST) a considerablement evolue recemment, avec notamment la mise a disposition de l’imatinib. Les standards de prise en charge restaient mal definis. Nous rendons compte du travail d’un groupe d’experts francais sur l’adaptation francaise des recommandations de pratiques de l’Europeen Society of Medical Oncology (ESMO) recemment rapportees. Materiels et methodes Un groupe de vingt-deux experts francais s’est reuni pour analyser le document de consensus ESMO et l’adapter a la pratique francaise. Quatre groupes de travail ont ainsi revu les propositions concernant : l’anatomopathologie et la biologie moleculaire, l’imagerie en situation localisee ou metastatique et la prise en charge diagnostique des tumeurs de petite taille, la chirurgie des GIST localisees et metastatiques, le traitement systemique des GIST. Resultats L’examen histologique standard doit etre complete par une analyse immunohistochimique a l’aide des marqueurs CD117, CD34, PS100, Desmine et SMA. Le recours a la biologie moleculaire pour l’identification de la mutation des genes KIT et PDGFRA, est souhaitable pour les GIST presentant un immunomarquage negatif avec CD117 et pour predire la reponse au traitement, mais reste un examen de recherche. La chirurgie de la tumeur primaire doit comprendre une resection tumorale complete, incluant des marges tumorales negatives. L’administration d’imatinib en traitement adjuvant ou neoadjuvant est consideree comme une approche experimentale, a effectuer dans le cadre d’etudes cliniques prospectives. La resection des metastases est egalement consideree comme une procedure experimentale, avant, pendant ou apres echec d’un traitement par imatinib. Il est recommande d’instaurer l’imatinib des le diagnostic de recidive metastatique et de le poursuivre jusqu’a l’intolerance ou la progression multifocale de la maladie. Les criteres optimaux de reponse tumorale a l’imatinib font encore l’objet de travaux prospectifs. Ils peuvent inclure : une reduction de taille de la tumeur ou une stabilisation de la maladie, une diminution de la densite tumorale (unites Hounsfield) sur la TDM, une diminution de l’activite metabolique (mesuree par la captation de FDG sur TEP), la diminution de la vascularisation tumorale, mesuree par echo-Doppler avec injection de produit de contraste. Une augmentation de la taille de la tumeur ne traduit pas necessairement une progression et doit donc etre soigneusement evaluee, sans interrompre le traitement par imatinib avant confirmation definitive. Conclusion Les recommandations francaises pour la prise en charge des GIST adoptent la plupart des recommandations etablies par l’ESMO, et les completent du point de vue du gastroenterologue. Ce travail collegial a ete soumis a une revue de pathologie, de gastroenterologie et d’oncologie et son impact sur les pratiques sera evalue prospectivement.

Primary retroperitoneal soft tissue sarcoma: Imaging appearances, pitfalls and diagnostic algorithm.

Although retroperitoneal sarcomas are rare tumours, they can be encountered by a wide variety of clinicians as they can be incidental findings on imaging or present with non specific symptoms and signs. Surgical resection can offer hope of cure and patient outcomes are improved when patients are managed in high-volume specialist centers. Failure to recognize retroperitoneal sarcomas on imaging can lead to inappropriate management in inexperienced centers. Therefore it is critical that a diagnosis of retroperitoneal sarcoma should be considered in the differential diagnosis of a retroperitoneal mass with prompt referral to a soft tissue sarcoma unit. In particular, the most common retroperitoneal sarcoma subtypes, liposarcoma and leiomyosarcoma, have characteristic imaging appearances which are discussed. This review therefore aims to set the context and guide clinicians through a diagnostic pathway for retroperitoneal masses in adults which arise extrinsic to the solid abdominal viscera.