Kirsten Sundby Hall

One vs Three Years of Adjuvant Imatinib for Operable Gastrointestinal Stromal Tumor A Randomized Trial

CONTEXT Adjuvant imatinib administered for 12 months after surgery has improved recurrence-free survival (RFS) of patients with operable gastrointestinal stromal tumor (GIST) compared with placebo. OBJECTIVE To investigate the role of imatinib administration duration as adjuvant treatment of patients who have a high estimated risk for GIST recurrence after surgery. DESIGN, SETTING, AND PATIENTS Patients with KIT-positive GIST removed at surgery were entered between February 2004 and September 2008 to this randomized, open-label phase 3 study conducted in 24 hospitals in Finland, Germany, Norway, and Sweden. The risk of GIST recurrence was estimated using the modified National Institutes of Health Consensus Criteria. INTERVENTION Imatinib, 400 mg per day, orally for either 12 months or 36 months, started within 12 weeks of surgery. MAIN OUTCOME MEASURES The primary end point was RFS; the secondary end points included overall survival and treatment safety. RESULTS Two hundred patients were allocated to each group. The median follow-up time after randomization was 54 months in December 2010. Diagnosis of GIST was confirmed in 382 of 397 patients (96%) in the intention-to-treat population at a central pathology review. KIT or PDGFRA mutation was detected in 333 of 366 tumors (91%) available for testing. Patients assigned for 36 months of imatinib had longer RFS compared with those assigned for 12 months (hazard ratio [HR], 0.46; 95% CI, 0.32-0.65; P < .001; 5-year RFS, 65.6% vs 47.9%, respectively) and longer overall survival (HR, 0.45; 95% CI, 0.22-0.89; P = .02; 5-year survival, 92.0% vs 81.7%). Imatinib was generally well tolerated, but 12.6% and 25.8% of patients assigned to the 12- and 36-month groups, respectively, discontinued imatinib for a reason other than GIST recurrence. CONCLUSION Compared with 12 months of adjuvant imatinib, 36 months of imatinib improved RFS and overall survival of GIST patients with a high risk of GIST recurrence. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00116935.

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

Ewing Sarcoma: Current Management and Future Approaches Through Collaboration

Ewing sarcoma (ES) is an aggressive sarcoma of bone and soft tissue occurring at any age with a peak incidence in adolescents and young adults. The treatment of ES relies on a multidisciplinary approach, coupling risk-adapted intensive neoadjuvant and adjuvant chemotherapies with surgery and/or radiotherapy for control of the primary site and possible metastatic disease. The optimization of ES multimodality therapeutic strategies has resulted from the efforts of several national and international groups in Europe and North America and from cooperation between pediatric and medical oncologists. Successive first-line trials addressed the efficacy of various cyclic combinations of drugs incorporating doxorubicin, vincristine, cyclophosphamide, ifosfamide, etoposide, and dactinomycin and identified prognostic factors now used to tailor therapies. The role of high-dose chemotherapy is still debated. Current 5-year overall survival for patients with localized disease is 65% to 75%. Patients with metastases have a 5-year overall survival < 30%, except for those with isolated pulmonary metastasis (approximately 50%). Patients with recurrence have a dismal prognosis. The many insights into the biology of the EWS-FLI1 protein in the initiation and progression of ES remain to be translated into novel therapeutic strategies. Current options and future approaches will be discussed.

EURAMOS-1, an international randomised study for osteosarcoma: results from pre-randomisation treatment.

This manuscript describes the experience from registration until randomisation for a cohort of 2260 patients with osteosarcoma who joined the EURAMOS-1 trial. This includes pre-operative chemotherapy and surgery. It sets out the practical issues in collaboration and in achieving randomisation.

Methotrexate, Doxorubicin, and Cisplatin (MAP) Plus Maintenance Pegylated Interferon Alfa-2b Versus MAP Alone in Patients With Resectable High-Grade Osteosarcoma and Good Histologic Response to Preoperative MAP: First Results of the EURAMOS-1 Good Response Randomized Controlled Trial

Purpose EURAMOS-1, an international randomized controlled trial, investigated maintenance therapy with pegylated interferon alfa-2b (IFN-α-2b) in patients whose osteosarcoma showed good histologic response (good response) to induction chemotherapy. Patients and Methods At diagnosis, patients age ≤ 40 years with resectable high-grade osteosarcoma were registered. Eligibility after surgery for good response random assignment included ≥ two cycles of preoperative MAP (methotrexate, doxorubicin, and cisplatin), macroscopically complete surgery of primary tumor, < 10% viable tumor, and no disease progression. These patients were randomly assigned to four additional cycles MAP with or without IFN-α-2b (0.5 to 1.0 μg/kg per week subcutaneously, after chemotherapy until 2 years postregistration). Outcome measures were event-free survival (EFS; primary) and overall survival and toxicity (secondary). Results Good response was reported in 1,041 of 2,260 registered patients; 716 consented to random assignment (MAP, n = 359; MAP plus IFN-α-2b, n = 357), with baseline characteristics balanced by arm. A total of 271 of 357 started IFN-α-2b; 105 stopped early, and 38 continued to receive treatment at data freeze. Refusal and toxicity were the main reasons for never starting IFN-α-2b and for stopping prematurely, respectively. Median IFN-α-2b duration, if started, was 67 weeks. A total of 133 of 268 patients who started IFN-α-2b and provided toxicity information reported grade ≥ 3 toxicity during IFN-α-2b treatment. With median follow-up of 44 months, 3-year EFS for all 716 randomly assigned patients was 76% (95% CI, 72% to 79%); 174 EFS events were reported (MAP, n = 93; MAP plus IFN-α-2b, n = 81). Hazard ratio was 0.83 (95% CI, 0.61 to 1.12; P = .214) from an adjusted Cox model. Conclusion At the preplanned analysis time, MAP plus IFN-α-2b was not statistically different from MAP alone. A considerable proportion of patients never started IFN-α-2b or stopped prematurely. Long-term follow-up for events and survival continues.

Radiotherapy to Improve Local Control Regardless of Surgical Margin and Malignancy Grade in Extremity and Trunk Wall Soft Tissue Sarcoma: A Scandinavian Sarcoma Group Study

PURPOSE Adjuvant radiotherapy has during the past decades become increasingly used in the treatment of localized soft tissue sarcoma. We evaluated the effect of radiotherapy (RT) on local recurrence rates (LRRs) in Scandinavia between 1986 and 2005. METHODS AND MATERIALS A total of 1,093 adult patients with extremity or trunk wall soft tissue sarcoma treated at four Scandinavian sarcoma centers were stratified according to the treatment period (1986-1991, 1992-1997, and 1998-2005). The use of adjuvant RT, quality of the surgical margin, interval between surgery and RT, and LRR were analyzed. The median follow-up was 5 years. RESULTS The use of RT (77% treated postoperatively) increased from 28% to 53%, and the 5-year LRR decreased from 27% to 15%. The rate of wide surgical margins did not increase. The risk factors for local recurrence were histologic high-grade malignancy (hazard ratio [HR], 5), an intralesional (HR, 6) or marginal (HR, 3) surgical margin, and no RT (HR, 3). The effect of RT on the LRR was also significant after a wide margin resection and in low-grade malignant tumors. The LRR was the same after preoperative and postoperative RT. The median interval from surgery to the start of RT was 7 weeks, and 98% started RT within 4 months. The LRR was the same in patients who started treatment before and after 7 weeks. CONCLUSION The results of our study have shown that adjuvant RT effectively prevents local recurrence in soft tissue sarcoma, irrespective of the tumor depth, malignancy grade, and surgical margin status. The effect was most pronounced in deep-seated, high-grade tumors, even when removed with a wide surgical margin.

Survival meta-analyses for >1800 malignant peripheral nerve sheath tumor patients with and without neurofibromatosis type 1

There are conflicting reports as to whether malignant peripheral nerve sheath tumor (MPNST) patients with neurofibromatosis type 1 (NF1) have worse prognosis than non-NF1 MPNST patients. Large clinical studies to address this problem are lacking due to the rareness of MPNST. We have performed meta-analyses testing the effect of NF1 status on MPNST survival based on publications from the last 50 years, including only nonoverlapping patients reported from each institution. In addition, we analyzed survival characteristics for 179 MPNST patients from 3 European sarcoma centers. The meta-analyses including data from a total of 48 studies and >1800 patients revealed a significantly higher odds ratio for overall survival (OROS) and disease-specific survival (ORDSS) in the non-NF1 group (OROS = 1.75, 95% confidence interval [CI] = 1.28–2.39, and ORDSS = 1.68, 95% CI = 1.18–2.40). However, in studies published in the last decade, survival in the 2 patient groups has been converging, as especially the NF1 group has shown improved prognosis. For our own MPNST patients, NF1 status had no effect on overall or disease-specific survival. The compiled literature from 1963 to the present indicates a significantly worse outcome of MPNST in patients with NF1 syndrome compared with non-NF1 patients. However, survival for the NF1 patients has improved in the last decade, and the survival difference is diminishing. These observations support the hypothesis that MPNSTs arising in NF1 and non-NF1 patients are not different per se. Consequently, we suggest that the choice of treatment for MPNST should be independent of NF1 status.

Clinical course of nonvisceral soft tissue leiomyosarcoma in 225 patients from the Scandinavian Sarcoma Group.

Leiomyosarcoma of nonvisceral soft tissues is an uncommon malignant tumor; thus, only small numbers of cases have been reported. This study was based on a large series of patients from the Scandinavian Sarcoma Group Register acquired during a 15‐year period (from 1986 to 2001). Follow‐up information was available for all patients.

Adjuvant Imatinib for High-Risk GI Stromal Tumor: Analysis of a Randomized Trial

PURPOSE Three years of adjuvant imatinib therapy are recommended for patients with GI stromal tumor (GIST) with high-risk features, according to survival findings in the Scandinavian Sarcoma Group XVIII/AIO (Arbeitsgemeinschaft Internistische Onkologie) trial. To investigate whether the survival benefits have persisted, we performed the second planned analysis of the trial. PATIENTS AND METHODS Eligible patients had macroscopically completely excised, KIT-positive GIST with a high risk of recurrence, as determined by using the modified National Institutes of Health criteria. After surgery, the patients were randomly assigned to receive imatinib for either 1 or 3 years. The primary objective was recurrence-free survival (RFS), and the secondary objectives included survival. RESULTS A total of 400 patients were entered onto this open-label study between February 4, 2004, and September 29, 2008. During a median follow-up of 90 months, 171 recurrences and 69 deaths were detected. Patients assigned to the 3-year group had longer RFS than those assigned to the 1- year group; 5-year RFS was 71.1% versus 52.3%, respectively (hazard ratio [HR], 0.60; 95% CI 0.44 to 0.81; P < .001), and survival was 91.9% versus 85.3% (HR, 0.60; 95% CI, 0.37 to 0.97; P = .036). Patients in the 3-year group survived longer in the subset with centrally confirmed GIST and without macroscopic metastases at study entry (93.4% v 86.8%; HR, 0.53; 95% CI, 0.30 to 0.93; P = .024). Similar numbers of cardiac events and second cancers were recorded in the groups. CONCLUSION Three years of adjuvant imatinib therapy results in longer survival than 1 year of imatinib. High 5-year survival rates are achievable in patient populations with high-risk GIST.

Comparison of MAPIE versus MAP in patients with a poor response to preoperative chemotherapy for newly diagnosed high-grade osteosarcoma (EURAMOS-1): an open-label, international, randomised controlled trial

Summary Background We designed the EURAMOS-1 trial to investigate whether intensified postoperative chemotherapy for patients whose tumour showed a poor response to preoperative chemotherapy (≥10% viable tumour) improved event-free survival in patients with high-grade osteosarcoma. Methods EURAMOS-1 was an open-label, international, phase 3 randomised, controlled trial. Consenting patients with newly diagnosed, resectable, high-grade osteosarcoma aged 40 years or younger were eligible for randomisation. Patients were randomly assigned (1:1) to receive either postoperative cisplatin, doxorubicin, and methotrexate (MAP) or MAP plus ifosfamide and etoposide (MAPIE) using concealed permuted blocks with three stratification factors: trial group; location of tumour (proximal femur or proximal humerus vs other limb vs axial skeleton); and presence of metastases (no vs yes or possible). The MAP regimen consisted of cisplatin 120 mg/m2, doxorubicin 37·5 mg/m2 per day on days 1 and 2 (on weeks 1 and 6) followed 3 weeks later by high-dose methotrexate 12 g/m2 over 4 h. The MAPIE regimen consisted of MAP as a base regimen, with the addition of high-dose ifosfamide (14 g/m2) at 2·8 g/m2 per day with equidose mesna uroprotection, followed by etoposide 100 mg/m2 per day over 1 h on days 1–5. The primary outcome measure was event-free survival measured in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT00134030. Findings Between April 14, 2005, and June 30, 2011, 2260 patients were registered from 325 sites in 17 countries. 618 patients with poor response were randomly assigned; 310 to receive MAP and 308 to receive MAPIE. Median follow-up was 62·1 months (IQR 46·6–76·6); 62·3 months (IQR 46·9–77·1) for the MAP group and 61·1 months (IQR 46·5–75·3) for the MAPIE group. 307 event-free survival events were reported (153 in the MAP group vs 154 in the MAPIE group). 193 deaths were reported (101 in the MAP group vs 92 in the MAPIE group). Event-free survival did not differ between treatment groups (hazard ratio [HR] 0·98 [95% CI 0·78–1·23]); hazards were non-proportional (p=0·0003). The most common grade 3–4 adverse events were neutropenia (268 [89%] patients in MAP vs 268 [90%] in MAPIE), thrombocytopenia (231 [78% in MAP vs 248 [83%] in MAPIE), and febrile neutropenia without documented infection (149 [50%] in MAP vs 217 [73%] in MAPIE). MAPIE was associated with more frequent grade 4 non-haematological toxicity than MAP (35 [12%] of 301 in the MAP group vs 71 [24%] of 298 in the MAPIE group). Two patients died during postoperative therapy, one from infection (although their absolute neutrophil count was normal), which was definitely related to their MAP treatment (specifically doxorubicin and cisplatin), and one from left ventricular systolic dysfunction, which was probably related to MAPIE treatment (specifically doxorubicin). One suspected unexpected serious adverse reaction was reported in the MAP group: bone marrow infarction due to methotrexate. Interpretation EURAMOS-1 results do not support the addition of ifosfamide and etoposide to postoperative chemotherapy in patients with poorly responding osteosarcoma because its administration was associated with increased toxicity without improving event-free survival. The results define standard of care for this population. New strategies are required to improve outcomes in this setting. Funding UK Medical Research Council, National Cancer Institute, European Science Foundation, St Anna Kinderkrebsforschung, Fonds National de la Recherche Scientifique, Fonds voor Wetenschappelijk Onderzoek-Vlaanderen, Parents Organization, Danish Medical Research Council, Academy of Finland, Deutsche Forschungsgemeinschaft, Deutsche Krebshilfe, Federal Ministry of Education and Research, Semmelweis Foundation, ZonMw (Council for Medical Research), Research Council of Norway, Scandinavian Sarcoma Group, Swiss Paediatric Oncology Group, Cancer Research UK, National Institute for Health Research, University College London Hospitals, and Biomedical Research Centre.