Sophie Taieb

Phase II Trial of Weekly Paclitaxel for Unresectable Angiosarcoma: The ANGIOTAX Study

PURPOSE The objective of this phase II trial was to assess the efficacy and toxicity of weekly paclitaxel for patients with metastatic or unresectable angiosarcoma. PATIENTS AND METHODS Thirty patients were entered onto the study from April 2005 through October 2006. Paclitaxel was administered intravenously as a 60-minute infusion at a dose of 80 mg/m(2) on days 1, 8, and 15 of a 4-week cycle. The primary end point was the nonprogression rate after two cycles. RESULTS The progression-free survival rates after 2 and 4 months were 74% and 45%, respectively. With a median follow-up of 8 months, the median time to progression was 4 months and the median overall survival was 8 months. The progression-free survival rate was similar in patients pretreated with chemotherapy and in chemotherapy-naïve patients (77% v 71%). Three patients with locally advanced breast angiosarcoma presented partial response, which enabled a secondary curative-intent surgery with complete histologic response in two cases. One toxic death occurred as a result of a thrombocytopenia episode. Six patients presented with grade 3 toxicities and one patient presented with a grade 4 toxicity. Anemia and fatigue were the most frequently reported toxicities. CONCLUSION Weekly paclitaxel at the dose schedule used in the current study was well tolerated and demonstrated clinical benefit.

Safety and efficacy of regorafenib in patients with advanced soft tissue sarcoma (REGOSARC): a randomised, double-blind, placebo-controlled, phase 2 trial

BACKGROUND Regorafenib is a multikinase inhibitor with proven activity in refractory gastrointestinal stromal tumours and chemotherapy-refractory advanced colorectal cancers. We assessed this agents efficacy and safety in patients with metastatic soft tissue sarcomas previously treated with anthracycline. METHODS In this randomised, double-blind, phase 2 trial undertaken in France and Austria, we enrolled patients aged 18 years and older with advanced soft tissue sarcomas who had received previous doxorubicin or other anthracycline treatment. These patients were randomly assigned (1:1) into one of the following four cohorts: liposarcoma, leiomyosarcoma, synovial sarcoma, and other sarcomas. Participants were treated with oral regorafenib (160 mg per day 3 weeks on and 1 week off) or matched placebo. Patients receiving placebo were offered optional crossover in case of centrally confirmed disease progression. The random allocation schedule was computer-generated with permuted blocks of four patients, with two stratification factors: country (France or Austria) and previous exposure to pazopanib (yes or no). Eligibility criteria included patients with histologically proven advanced and inoperable soft tissue sarcomas with intolerance or failure to doxorubicin or other anthracycline-based chemotherapy and at least one unidimensionally or bidimensionally measurable lesion according to Response Evaluation Criteria in Solid Tumors (RECIST; version 1.1). The primary endpoint was RECIST-based progression-free survival after central radiological review in the intention-to-treat population. Patients, physicians, and radiologists of the panel were masked to treatment allocation. This study is still open for recruitment for an additional stratum (patients previously treated with pazopanib) and registered with ClinicalTrials.gov, NCT01900743. FINDINGS From Aug 5, 2013, to Nov 26, 2014, 182 patients were randomly assigned to one of four cohorts and included in the final analysis. At the cutoff date (Jan 7, 2016), the number of required events was reached for the four cohorts. In the liposarcoma cohort, progression-free survival was 1·1 months (95% CI 0·9-2·3) with regorafenib versus 1·7 months (0·9-1·8) with placebo (HR 0·89 [95% CI 0·48-1·64] p=0·70). In the leiomyosarcoma cohort, progression-free survival was 3·7 months (95% CI 2·5-5·0) with regorafenib versus 1·8 (1·0-2·8) months with placebo (HR 0·46 [95% CI 0·46-0·80] p=0·0045). In the synovial sarcoma cohort, progression-free survival was 5·6 months (95% CI 1·4-11·6) with regorafenib versus 1·0 (0·8-1·4) with placebo (HR 0·10 [95% CI 0·03-0·35] p<0·0001). In the other sarcoma cohort, progression-free survival was 2·9 months (95% CI 1·0-7·8) with regorafenib versus 1·0 (0·9-1·9) with placebo (HR 0·46 [95% CI 0·25-0·81] p=0·0061). Before crossover, the most common clinically significant grade 3 or higher adverse events were arterial hypertension (17 [19%] events in the 89 patients in the regorafenib group vs two [2%] events in the 92 patients in the placebo group), hand and foot skin reaction (14 [15%] vs no events) and asthenia (12 [13%] vs six [6%]). One treatment-related death occurred in the regorafenib group due to liver failure. INTERPRETATION Regorafenib has an important clinical antitumour effect in non-adipocytic soft tissue sarcomas, improving progression-free survival. Regorafenib should be further evaluated in this setting, and its therapeutic role has to be defined in the context of the growing therapeutic armamentarium, already including one approved multikinase inhibitor, pazopanib. FUNDING Bayer HealthCare.

Image-based response assessment of liver metastases following stereotactic body radiotherapy with respiratory tracking

ObjectiveTo describe post-CyberKnife® imaging characteristics of liver metastases as an aid in assessing response to treatment, and a novel set of combined criteria (CC) as an alternative to response according to change in size (RECIST).Subjects and MethodsImaging data and medical records of 28 patients with 40 liver metastases treated with stereotactic body radiotherapy (SBRT) were reviewed. Tumor size, CT attenuation coefficient, and contrast enhancement of lesions were evaluated up to 2 years post SBRT. Rates of local control, progression-free survival, time to progression, and overall survival according to RECIST and CC were estimated.ResultsComplete response (CR) was 3.6% (95% CI: 0.1–18%) and 18% (95% CI: 6–37%) according to RECIST and combined criteria, respectively. Two progressive diseases and two partial responses according to RECIST were classified as CR by the combined criteria and one stable response according to RECIST was classified as progressive by CC (Stuart-Maxwell test, p = 0.012). The disease control rate was 60.7% (95% CI: 41–78%) by RECIST and 64% (95% CI: 44%–81%) by CC.ConclusionUse of response criteria based on change in size alone in the interpretation of liver response to SBRT may be inadequate. We propose a simple algorithm with a combination of criteria to better assess tumor response. Further studies are needed to confirm their validity.

Surveillance de l'endomètre des femmes sous tamoxifène

Tamoxifen estrogenic action in the uterus induces several uterine diseases, benign and/or malignant ones. The risk of endometrial adenocarcinoma is multiplied by two to three in post-menopausal women. It is mainly linked with the doses and the length of the treatment. However, the global benefit of that drug is not questioned anymore. What matters now though is to find the best way to follow patients on tamoxifen. As a matter of fact, there is no such thing as a consensus that would include specific tests, nor a surveillance protocol in women on tamoxifen. Most teams do not propose any special follow-up. Some patients already show uterine anomalies prior to the beginning of tamoxifen treatment. A yearly gynecologic examination, together with a cervico-vaginal smear, is enough when there are no specific endometrial adenocarcinoma risk factors, nor anomalies detected during the pre-therapeutical evaluation, nor clinical symptomatology. In case of risk factors, or cervical stenosis, or again initial abnormalities though, a yearly transvaginal sonography may be proposed. There is no need for other exploratory examinations if the results are satisfying. In case of symptoms, anomalies in the cervico-vaginal smears, intra-uterine liquid retention with a stenosed cervix, or suspicious endometrial thickness, then an endometrial sampling must be carried out. MRI could be of interest in asymptomatic patients with unclear ultrasonography images. Follow-up must be continued after interruption of tamoxifen. It is important to inform patients about the additional risks of developing an endometrial cancer because of tamoxifen, while still being reassuring. Besides, it is absolutely necessary to recommend them to take quickly medical advice in case of gynecologic symptoms.

Report of Eight Recent Cases of Locally Advanced Primary Pulmonary Artery Sarcomas: Failure of Doxorubicin-Based Chemotherapy

Background: Case reports of primary pulmonary artery sarcomas are very rare. Methods: We described herein eight new cases diagnosed between December 2000 and December 2004. Results: There were four men and four women, with median age of 52 years. Presenting symptoms mimicked pulmonary emboli in all cases. There were six “intimal sarcomas” and two leiomyosarcomas. In six cases, we observed initial metastasis in lung (six cases), in bone (two cases), and in brain (two cases), and adrenal gland (one case). The palliative treatments included surgical desobstruction (six cases), conformational radiotherapy (four cases), and chemotherapy (seven cases). Doxorubicin-based regimen failed in seven cases. All patients died (median survival: 8 months, extremes 5–20 months). Conclusion: Those eight cases illustrate the high incidence of initial metastasis and the very poor outcome of primary pulmonary artery sarcomas despite classic doxorubicin-based chemotherapy.

A paradigm shift in tumour response evaluation of targeted therapy: the assessment of novel drugs in exploratory clinical trials.

Purpose of review To describe the difficulty in assessing the biological activity of a novel agent in phase II trials. Recent findings Two major fields of research provide interesting new potential endpoints: endpoints based on new imaging techniques (e.g. PET or spectral imaging that explore tumour metabolism, dynamic contrast enhanced (DCE) ultrasonography or DCE-MRI that explore tumour vascularization and tumour growth inhibition) and endpoints integrating assessment of tumour burden across time, such as the growth modulation index. Summary Most of the recently described techniques appear attractive, but require formal validation.

Soft tissue sarcomas or intramuscular haematomas

Haematomas are common and sarcomas are rare. However the absence of trauma or a light trauma should alert the clinician to the possibility that the abnormality may represent haemorrhage into a tumor and not just haematoma, even in a haemophilic patient. Clinical findings, sonography with Doppler assessment and magnetic resonance images with contrast administration will help in the differential diagnosis. The diagnosis of a high grade sarcoma must be considered in these patients and any doubt should be resolved with a biopsy to avoid tragic consequences of missed sarcoma.

Comparison of Response Evaluation Criteria in Solid Tumours and Choi criteria for response evaluation in patients with advanced soft tissue sarcoma treated with trabectedin: A retrospective analysis

BACKGROUND To assess the additional value of density measurement using contrast-enhancement sequences (Choi assessment) in a real-life cohort of adult soft tissue sarcoma patients treated with trabectedin. METHODS Eligibility criteria included adults (age ⩾18) treated between 01/2007 and 12/2011, with at least two trabectedin cycles after failure or intolerance to doxorubicin/ifosfamide. Baseline and first computed tomography (CT)-scans were centrally reviewed by an experienced radiologist. RESULTS The retrospective cohort consists of 134 (73 female) patients treated with trabectedin 1.5 mg/m(2) given as a 24-h infusion every 3 weeks. Patients received a median of five trabectedin cycles (range: 2-33) and the main cause of discontinuation was progressive disease (PD) (n = 105, 78.4%). Response Evaluation Criteria in Solid Tumours (RECIST) assessment was feasible in 128 (95.5%) patients, with Choi assessment performed in 92 (68.7%) patients, generally due to inadequate sequences or exclusive lung metastases. Concordance between both methods was fair (Kappa = 0.290). We identified five patients with false PD (i.e. PD according to RECIST but stable disease/partial response as per Choi). Univariate analysis did not identify any predictive factors for false PD. Median overall survival (OS) of patients with PD as per RECIST but stable disease/partial response (SD/PR) according to Choi was better than for patients with PD according to both RECIST and Choi (14 months versus 8 months; p = 0.052). CONCLUSIONS Choi assessment may identify patients with false PD who achieved improved efficacy outcomes, suggesting that trabectedin may delay tumour progression even in the case of non-dimensional response. Dual size and tumour density assessment may be more suitable to evaluate responses to trabectedin in sarcoma patients as well as to improve the decision-making strategies for the continuation of trabectedin therapy.

Standards, Options et Recommandations 2006. Prise en charge des patients adultes atteints de sarcome des tissus mous, de sarcome utérin ou de tumeur stromale gastro-intestinale

RésuméContexteLa mise à jour des recommandations pour la pratique clinique (RPC) pour la prise en charge des patients atteints d’un sarcome des tissus mous a été élaborée par la Fédération nationale des centres de lutte contre le cancer (FNCLCC), en collaboration avec le Groupe sarcome français et le Groupe d’étude des tumeurs osseuses (GSF-GETO), des partenaires des secteurs publics (CHU, CHG), privé et de l’Institut national du cancer sur la base de la méthodologie développée par les SOR.ObjectifsActualiser les recommandations SOR pour la prise en charge des patients atteints d’un sarcome des tissus mous validées en 1995.MéthodesLa méthodologie d’élaboration des RPC-SOR repose sur une revue et une analyse critique des données de la littérature scientifique par un groupe d’experts pluridisciplinaire, permettant de définir, sur la base du niveau de preuve scientifique et du jugement argumenté des experts, des « Standards » et des « Options ». Avant publication, les RPC-SOR sont revues par des experts indépendants.RésultatsFace à la complexité inhérente au diagnostic et au traitement des sarcomes, le caractère collégial de leur prise en charge apparaît comme une nécessité et ces recommandations SOR se veulent en être un instrument.AbstractContextThe French National Federation of Comprehensive Cancer Centres (FNCLCC) initiated the update of clinical practice guidelines (CPGs) for the management of patients with soft tissue sarcoma, in collaboration with the French National Cancer Institute and the French Sarcoma Group (GSF-GETO), specialists from French public universities, general hospitals and private clinics. This work was based on the methodology developed by the Standards, Options and Recommendations (SOR) project.ObjectivesTo update the SOR for the management of patients with soft tissue sarcoma, previously validated in 1995.MethodsThe methodology was based on a literature review and critical appraisal by a multidisciplinary group of experts who defined CPGs according to the definitions of the Standards, Options and Recommendations project. Once the guidelines were developed, they were reviewed by independent experts.ResultsBecause of the difficulties inherent in diagnosing and treating sarcoma, it is essential to set up cooperative consulting for the management of these tumours. The updated SOR can serve as a tool to achieve that goal.

Lobulated Enhancement Evaluation in the Follow-Up of Liver Metastases Treated by Stereotactic Body Radiation Therapy

OBJECTIVE The Response Evaluation Criteria in Solid Tumors (RECIST) can have limitations when used to evaluate local treatments for cancer, especially for liver malignancies treated by stereotactic body radiation therapy (SBRT). The aim of this study was to validate the relationship between the occurrence of lobulated enhancement (LE) and local relapse and to evaluate the utility of this relationship for predicting local progression. PATIENTS AND METHODS Imaging data of 59 lesions in 46 patients, including 281 computed tomographic (CT) scans, were retrospectively and blindly reviewed by 3 radiologists. One radiologist measured the lesion size, for each CT and overall, to classify responses using RECIST threshold criteria. The second studied LE occurrence. A third radiologist was later included and studied LE occurrence to evaluate the interobserver consistency for LE evaluation. RESULTS The mean duration of follow-up was 13.6 months. LE was observed in 16 of 18 progressive lesions, occurring before size-based progression in 50% of cases, and the median delay of LE detection was 3.2 months. The sensitivity of LE to predict progression was 89%, and its specificity was 100%. The positive predictive value was 100%, the negative predictive value was 95.3%, and the overall accuracy was 97%. The probability of local progression-free survival at 12 months was significantly higher for lesions without LE compared with all lesions: 0.80 (CI 95%: 0.65-0.89) versus 0.69 (CI 95%: 0.54-0.80), respectively. The overall concordance rate between the 2 readers of LE was 97.9%. CONCLUSION Response assessment of liver metastases treated by SBRT can be improved by including LE. This study demonstrates the diagnostic and predictive utility of LE for assessing local progression at a size still eligible for local salvage treatment.