Patterns of care and outcomes of 417 patients with METAstatic SYNovial sarcoma (METASYN): real-life data from the French Sarcoma Group (FSG).

BACKGROUND: Synovial sarcoma (SS) occurs in both adult and pediatric patients. The primary aim of this study is to describe the outcomes, prognostic factors, and treatment of patients with metastatic SS within a nationwide cohort. PATIENTS AND METHODS: All pediatric and adult patients with metastatic SS are registered in the French Sarcoma Group database. Data were collected from the national database https://conticabase.sarcomabcb.org/ up to March 2020. Descriptive and comparative analyses were conducted using SAS 9.4 and Stata Special Edition 16.1 software. RESULTS: Between January 1981 and December 2019, 417 patients with metastatic SS from 17 French sarcoma centers were included, including 64 (15.3%) under the age of 26 years. Median age was 42.5 years (range 9-87 years). The metastases were synchronous (cohort 1) or metachronous (cohort 2) in 18.9% (N = 79) and 81.1% (N = 338) patients, respectively. Median overall survival (OS) from the date of metastasis was 22.3 months (95% confidence interval 19.7-24.1 months). First-line chemotherapy without ifosfamide and/or doxorubicin was unfavorable for progression-free survival and OS (P < 0.001). Concerning cohort 1, young age, surgery of the primary tumor, and single metastatic site were independent favorable prognostic factors for OS. In cohort 2, surgery within an expert French Sarcoma Group center, absence of chemotherapy in the perioperative setting, the lungs as a single metastatic site, time to first metastasis >12 months, local therapy, and ifosfamide in the first metastatic line were independent favorable prognostic factors. CONCLUSIONS: The outcome of patients with metastatic SS is influenced by local treatment, management in reference centers, and cytotoxic treatments given in the perioperative and metastatic setting.

A single-arm multicentre phase II trial of doxorubicin in combination with trabectedin in the first-line treatment for leiomyosarcoma with long-term follow-up and impact of cytoreductive surgery.

BACKGROUND: Uterine leiomyosarcomas (U-LMSs) and soft tissue leiomyosarcomas (ST-LMSs) are rare tumours with poor prognosis when locally advanced or metastatic, and with moderate chemosensitivity. In 2015 we reported very encouraging results of the LMS-02 study (NCT02131480) with manageable toxicity. Herein, we report the updated and long-term results of progression-free survival (PFS) and overall survival (OS). PATIENTS AND METHODS: Patients received 60 mg/m2 intravenous doxorubicin followed by trabectedin 1.1 mg/m2 as a 3-h infusion on day 1 and pegfilgrastim on day 2, every 3 weeks, up to six cycles. Surgery for residual disease was permitted. Patients were stratified into U-LMS and ST-LMS groups. RESULTS: One-hundred and eight patients were enrolled, mainly with metastatic disease (85%), and 20 patients (18.5%) had surgical resection of metastases after chemotherapy. With a median follow-up of 7.2 years [95% confidence interval (CI) 6.9-8.2 years], the median PFS was 10.1 months (95% CI 8.5-12.6 months) in the whole population, and 8.3 months (95% CI 7.4-10.3 months) and 12.9 months (95% CI 9.2-14.1 months) for U-LMSs and ST-LMSs, respectively. The median OS was 34.4 months (95% CI 26.9-42.7 months), 27.5 months (95% CI 17.9-38.2 months), and 38.7 months (95% CI 31.0-52.9 months) for the whole population, U-LMSs, and ST-LMSs, respectively. The median OS of the patients with resected metastases was not reached versus 31.6 months in the overall population without surgery (95% CI 23.9-35.4 months). CONCLUSIONS: These updated results confirm the impressive efficiency of the doxorubicin plus trabectedin combination given in first-line therapy for patients with locally advanced/metastatic LMS in terms of PFS and OS. Results of the LMS04 trial (NCT02997358), a randomized phase III study comparing the doxorubicin plus trabectedin combination versus doxorubicin alone in first-line therapy in metastatic LMSs, are pending.

A randomized phase III trial comparing trabectedin to best supportive care in patients with pre-treated soft tissue sarcoma: T-SAR, a French Sarcoma Group trial.

BACKGROUND: The French Sarcoma Group assessed the efficacy, safety, and quality of life (QoL) of trabectedin versus best supportive care (BSC) in patients with advanced soft tissue sarcoma (STS). PATIENTS AND METHODS: This randomized, multicenter, open-label, phase III study included adults with STS who progressed after 1-3 prior treatment lines. Patients were randomized (1 : 1) to receive trabectedin 1.5 mg/m2 every 3 weeks or BSC, stratified into L-STS (liposarcoma/leiomyosarcoma) and non-L-STS groups (other histotypes). Patients from the BSC arm were allowed to cross over to trabectedin at progression. The primary efficacy endpoint was progression-free survival (PFS) confirmed by blinded central review and analyzed in the intention-to-treat population. RESULTS: Between 26 January 2015 and 5 November 2015, 103 heavily pre-treated patients (60.2% with L-STS) from 16 French centers were allocated to receive trabectedin (n = 52) or BSC (n = 51). Median PFS was 3.1 months [95% confidence interval (CI) 1.8-5.9 months] in the trabectedin arm versus 1.5 months (0.9-2.6 months) in the BSC arm (hazard ratio = 0.39, 95% CI 0.24-0.64, P < 0.001) with benefits observed across almost all analyzed subgroups, but particularly in patients with L-STS (5.1 versus 1.4 months, P = 0.0001). Seven patients (13.7%) in the trabectedin arm (all with L-STS) achieved a partial response, while no objective responses were observed in the BSC arm (P = 0.004). The most common grade 3/4 adverse events were neutropenia (44.2% of patients), leukopenia (34.6%), and transaminase increase (32.7%). Health-related 30-item core European Organization for the Research and Treatment of Cancer Quality-of-Life Questionnaire evidenced no statistical differences between the arms for any domain and at any time point. After progression, 91.8% of patients crossed over from BSC to trabectedin. CONCLUSION: Trabectedin demonstrates superior disease control to BSC without impairing QoL in patients with recurrent STS of multiple histologies, with greater impact in patients with L-STS.

A phase II of gemcitabine combined with pazopanib followed by pazopanib maintenance, as second-line treatment in patients with advanced leiomyosarcomas: A unicancer French Sarcoma Group study (LMS03 study).

BACKGROUND: Options in second-line therapy after doxorubicin-based chemotherapy for metastatic/advanced leiomyosarcoma include gemcitabine (G), trabectedin and pazopanib (P) monotherapy. Currently, no combination therapy is better than monotherapy. LMS03 is an open-label multicentre single-group phase II study designed to assess the efficacy and tolerance of G + P in the second-line setting. PATIENTS AND METHODS: Patients (pts), ECOG ≤2, with metastatic leiomyosarcomas (LMS) after first-line doxorubicin chemotherapy failure were eligible. Pts were treated with G 1000 mg/m2 on days 1 and 8 of each 21 days (maximum eight cycles), in combination with oral daily P (800 mg), until disease progression/toxicity. 9-month progression-free survival (PFS) rate was the primary endpoint. Inacceptable and promising 9-month PFS rates were defined, in the intent-to-treat population, as 32% and 44%. RESULTS: 106 pts were included with a mean age of 59.8 years and an ECOG 0 in 63.5%; the primary tumour site was uterus in 61%. Pts were treated with P + G for a median of 3.8 mo, and P for a median of 4.2 mo. The 9-month PFS rate was 32.1% (95% CI 23.1-41.1). After a median follow-up of 14.2 months, the PFS was 6.5 months (95% CI 5.6-8.2), and the overall survival was 22.4 months (95% CI 16.9-26.5). The best response was 23.8%. The most frequent reported grade 3-4 adverse events were haematological. CONCLUSIONS: LMS03 failed to show that second-line therapy, with gemcitabine combined with pazopanib, followed by pazopanib alone, was beneficial for advanced LMS patients. Eudract N°2011-001308-36 and NCT01442662.

Prediction of local and metastatic recurrence in solitary fibrous tumor: construction of a risk calculator in a multicenter cohort from the French Sarcoma Group (FSG) database.

BACKGROUND: Solitary fibrous tumors (SFT) are rare unusual ubiquitous soft tissue tumors that are presumed to be of fibroblastic differentiation. At present, the challenge is to establish accurate prognostic factors. PATIENTS AND METHODS: A total of 214 consecutive patients with SFT diagnosed in 24 participating cancer centers were entered into the European database (www.conticabase.org) to perform univariate and multivariate analysis for overall survival (OS), local recurrence incidence (LRI) and metastatic recurrence incidence (MRI) by taking competing risks into account. A prognostic model was constructed for LRI and MRI. Internal and external validations of the prognostic models were carried out. An individual risk calculator was carried out to quantify the risk of both local and metastatic recurrence. RESULTS: We restricted our analysis to 162 patients with local disease. Twenty patients (12.3%) were deceased at the time of analysis and the median OS was not reached. The LRI rates at 10 and 20 years were 19.2% and 38.6%, respectively. The MRI rates at 10 and 20 years were 31.4% and 49.8%, respectively. Multivariate analysis retained age and mitotic count tended to significance for predicting OS. The factors influencing LRI were viscera localization, radiotherapy and age. Mitotic count, tumor localization other than limb and age had independent values for MRI. Three prognostic groups for OS were defined based on the number of unfavorable prognostic factors and calculations were carried out to predict the risk of local and metastatic recurrence for individual patients. CONCLUSION: LRI and MRI rates increased between 10 and 20 years so relapses were delayed, suggesting that long-term monitoring is useful. This study also shows that different prognostic SFT sub-groups could benefit from different therapeutic strategies and that use of a survival calculator could become standard practice in SFTs to individualize treatment based on the clinical situation.

Sorafenib in metastatic uveal melanoma: efficacy, toxicity and health-related quality of life in a multicentre phase II study.

BACKGROUND: The aim of the study was to analyse efficacy, safety, and health-related quality of life (HRQoL) for sorafenib treatment in patients with metastatic uveal melanoma. METHODS: A multicentre, single-arm phase II trial was conducted. The primary objective was to determine the non-progression rate (RECIST) at 24 weeks for patients receiving sorafenib at a dose of 800 mg per day. Secondary endpoints included progression-free survival (PFS), overall survival (OS), toxicity, and HRQoL. RESULTS: Thirty-two patients were included. Ten patients showed non-progression at 24 weeks (31.2%) without objective tumour responses. The estimated 24-week PFS was 31.2% (95% CI: 14.8%-47.6%) and the estimated 24-week OS was 62.5% (95% CI: 45.4%-79.6%). Ten patients (34.3%) had at least one grade 3 or 4 adverse reaction and 12 patients (41.4%) required dose modifications due to toxicity. At 24 weeks, no patient had an improvement in global HRQoL and 87.5% experienced a permanent increase in physical fatigue. CONCLUSIONS: Sorafenib demonstrated non-progression at 24 weeks in 31.2% of patients. However, 41.4% of patients required dose modifications due to toxicity and no improvement in HRQoL was demonstrated.

Role of physical activity and sport in oncology: scientific commission of the National Federation Sport and Cancer CAMI.

This overview reports published data about the interaction between physical activity and sport during and after cancer on one hand and improvement in psychological parameters, survival and biological mechanisms underlying this effect on the other hand. Practising physical activity and sport during cancer modifies parameters assessing fatigue and quality of life and reduces symptoms of depression. An association also exists between the practise of physical activity and sport and overall and cancer-specific survivals, especially after breast cancer, colon cancer and prostate cancer. These benefits seem to be mediated by a modification of circulating levels of estrogens, insulin, IGF-1 and by a decrease in insulin-resistance, by alterations in the secretion of adipokines, and by a reduction in chronic inflammation through decreased levels of cytokines. There exist some obstacles to the practise of physical activity. These obstacles are mainly related to a fear of pain induced by physical activity and to overweight. These programmes of physical activity and sport cannot be offered to all patients since there are several contra-indications, with some being present since the initial visit and others appearing during cancer management either due to disease progression or related to iatrogenic effects. Whereas benefits from physical activity and sport among cancer patients seem obvious, there are still several pending clinical and biological issues.

Site-Specific Conjugation of Monomethyl Auristatin E to Anti-CD30 Antibodies Improves Their Pharmacokinetics and Therapeutic Index in Rodent Models.

Antibody-drug conjugates (ADCs) have demonstrated clinical benefits that have led to the recent FDA approval of KADCYLA and ADCETRIS. Most ADCs that are currently in clinical use or development, including ADCETRIS, are produced by chemical conjugation of a toxin via either lysine or cysteine residues, inevitably leading to heterogeneous products with variable drug-to-antibody ratios (DARs). Here, we describe the in vitro and in vivo characterization of four novel ADCs that are based on the anti-CD30 antibody cAC10, which has the same polypeptide backbone as ADCETRIS, and compare the results with the latter. Bacterial transglutaminase (BTG) was exploited to site-specifically conjugate derivatives of monomethyl auristatin E (all comprising a cleavable linker) to the glutamine at positions 295 and 297 of cAC10, thereby yielding homogeneous ADCs with a DAR of 4. In vitro cell toxicity experiments using two different CD30-positive cell lines (Karpas 299 and Raji-CD30(+)) revealed comparable EC50 values for ADCETRIS (1.8 ± 0.4 and 3.6 ± 0.6 ng/mL, respectively) and the four cAC10-based ADCs (2.0 ± 0.4 to 4.9 ± 1.0 ng/mL). Quantitative time-dependent in vivo biodistribution studies (3-96 h p.i.) in normal and xenografted (Karpas 299 cells) SCID mice were performed with a selected (125)I-radioiodinated cAC10 ADC and compared with that of (125)I-ADCETRIS. The chemo-enzymatically conjugated, radioiodinated ADC showed higher tumor uptake (17.84 ± 2.2% ID/g 24 h p.i.) than (125)I-ADCETRIS (10.5 ± 1.8% ID/g 24 h p.i.). Moreover, (125)I-ADCETRIS exhibited higher nontargeted liver and spleen uptake. In line with these results, the maximum tolerated dose of the BTG-coupled ADC (>60 mg/kg) was significantly higher than that of ADCETRIS (18 mg/kg) in rats. These results suggest that homogeneous ADCs display improved pharmacokinetics and better therapeutic indexes compared to those of chemically modified ADCs with variable DARs.

Adjuvant radiotherapy for extremity and trunk wall atypical lipomatous tumor/well-differentiated LPS (ALT/WD-LPS): a French Sarcoma Group (GSF-GETO) study.

BACKGROUND: The role of adjuvant radiotherapy (RT) in the management of atypical lipomatous tumor/well-differentiated liposarcoma (ALT/WD-LPS) remains controversial. METHODS: Two hundred eighty-three patients with operable ALT/WD-LPS, no history of previous cancer, chemotherapy (CT) or RT, treated between 1984 and 2011 registered in the Conticabase database were included and described. Overall (OS), progression-free survival (PFS) and time to local relapse (TTLR) were evaluated from the time of first treatment. RESULTS: Three of 20 centers enrolled 58% of the patients. Median age at diagnosis was 61 (range 25-94) years, 147 patients (52%) were males, 222 (78%) patients had their primary tumor located in an extremity while 36 (13%) and 25 (9%) had tumors involving the girdle and the trunk wall, respectively. The median size of primary tumors was 17 cm (range 2-48 cm). Adjuvant RT was given to 132 patients (47%). Patients who received adjuvant RT had larger tumors (P = 0.005), involving more often the distal limbs (P < 0.001). Use of adjuvant RT varied across centers and along the study period. Other characteristics were balanced between the two groups. Median follow-up was 61.7 months. None of the patients developed metastasis during follow-up. The 5-year local relapse-free survival rates were 98.3% versus 80.3% with and without adjuvant RT, respectively (P < 0.001). Once stratified on time period (before/after 2003), adjuvant RT, tumor site and margin status (R0 versus other) were independently associated with TTLR. No OS difference was observed (P = 0.105). CONCLUSION: In this study, adjuvant RT following resection of ALT/WD-LPS was associated with a reduction of LR risk.

A randomized clinical trial of adjuvant chemotherapy with doxorubicin, ifosfamide, and cisplatin followed by radiotherapy versus radiotherapy alone in patients with localized uterine sarcomas (SARCGYN study). A study of the French Sarcoma Group.

BACKGROUND: There is no proven benefit of adjuvant treatment of uterine sarcoma (US). SARCGYN phase III study compared adjuvant polychemotherapy followed by pelvic radiotherapy (RT) (arm A) versus RT alone (arm B) conducted to detect an increase ≥ 20% of 3-year PFS. METHODS: Patients with FIGO stage ≤ III US, physiological age ≤ 65 years; chemotherapy: four cycles of doxorubicin 50 mg/m² d1, ifosfamide 3 g/m²/day d1-2, cisplatin 75 mg/m² d3, (API) + G-CSF q 3 weeks. Study was stopped because of lack of recruitment. RESULTS: Eighty-one patients were included: 39 in arm A and 42 in arm B; 52 stage I, 16 stage II, 13 stage III; 53 leiomyosarcomas, 9 undifferenciated sarcomas, 19 carcinosarcomas. Gr 3-4 toxicity during API (/37 patients): thrombopenia (76%), febrile neutropenia (22%) with two toxic deaths; renal gr 3 (1 patient). After a median follow-up of 4.3 years, 41/81 patients recurred, 15 in arm A, 26 in arm B. The 3 years DFS is 55% in arm A, 41% in arm B (P = 0.048). The 3-year overall survival (OS) is 81% in arm A and 69% in arm B (P = 0.41). CONCLUSION: API adjuvant CT statistically increases the 3 year-DFS of patients with US.

Metastatic angiosarcomas: doxorubicin-based regimens, weekly paclitaxel and metastasectomy significantly improve the outcome.

BACKGROUND: Angiosarcomas are a rare but aggressive form of soft tissue sarcoma. At metastatic stage, the clinical benefit of therapeutic intervention remains debatable. PATIENTS AND METHODS: We have carried a retrospective analysis of 149 cases treated between 1996 and 2009 in the French Sarcoma Group. RESULTS: The median age was 60; the sex ratio was 0.80. Sixty-two percentage of cases presented with metastasis at the diagnosis. About 20% arose in irradiated fields. The median overall survival was 11 months. Treatment consisted in metastasectomy (5.4%), doxorubicin-based regimen (46.9%), weekly paclitaxel (Taxol) (31.5%), other chemotherapy regimens (10.7%) or exclusive palliative care (10.9%). Clinical prognostic factors identified by univariate analysis were presence of bone metastasis (P = 0.0107), presence of other metastasis (P = 0.0327) and performance status (P < 0.0001). The Cox model retained a performance status of two or more as the sole independent prognostic factor (HR [hazard ratio] = 2.49, P < 0.0001). After adjustment to the performance status and compared with exclusive palliative care, the following treatments significantly improve the outcome: doxorubicin-based regimen as first-line chemotherapy (HR = 0.38, P = 0.0165), weekly paclitaxel as first-line regimen (HR = 0.36, P = 0.0146) and metastasectomy (HR = 0.09, P = 0.0221). CONCLUSIONS: This retrospective analysis indicates that some therapeutic interventions may significantly improve the outcome of this aggressive disease. Doxorubicin-based regimens and weekly paclitaxel seem to provide the same range of efficacy.

Localized squamous-cell cancer of the esophagus: retrospective analysis of three treatment schedules.

BACKGROUND AND PURPOSE: A retrospective study comparing chemotherapy and radiation, esophagectomy alone versus preoperative radiochemotherapy and surgery in localized squamous-cell esophageal carcinoma. MATERIALS AND METHODS: Between 1989 and 1995, 139 patients (40 stage I, 77 stage IIA and 22 stage IIB according to the UICC 78 TNM classification) were treated in two different institutions. They were divided into three groups according to the treatment proposed: E group (treatment by esophagectomy; n = 30), RCT+E group (treatment by preoperative radiochemotherapy and esophagectomy; n = 46), RCT group (treatment by radiochemotherapy; n = 63). Factors like age, tumor localization and stage were similar in all groups. An intention to treat analysis was made. RESULTS: The E group showed no postoperative mortality, while in the RCT+E group, the surgery mortality was 12.8%. The mortality after RCT was 1.7%. After preoperative radiochemotherapy, a pathological complete response was observed in 25% of cases and the curative resection rate was higher (82% after RCT + E versus 60% after E). The 5-year survival difference between the three groups was not relevant (E group, 12.6%; RCT group, 25.8%; RCT + E group, 38.7%). The median survival was 29, 24 and 28.5 months, respectively. The event-free survival was identical for the E group and the RCT group. For patients treated by radiochemotherapy, local and/or distant relapses were significantly reduced by esophagectomy (relapses occurred in 51% of patients in the RCT + E group versus 75% in the RCT group, P = 0.017). Palliative care (dilatations, prosthesis, gastrostomy or jejunostomy) to improve dysphagia was necessary for 38% of patients treated by exclusive radiochemotherapy versus 11% of patients treated by surgery (P = 0.001). CONCLUSIONS: Treatments by esophagectomy or radiochemotherapy were not significantly different. Preoperative radiochemotherapy and surgery lead to a higher survival rate than exclusive radiochemotherapy, however, with a high postoperative mortality rate. This study suggests the relevance of a prospective randomized trial to compare RCT+E and RCT alone.

Clinical relevance of gallium-67 scintigraphy in lymphoma before and after therapy.

The clinical impact of gallium-67 scintigraphy before and after therapy for lymphoma remains controversial. The aims of this study were: (1) to compare the staging of lymphoma by 67Ga scintigraphy only with staging by clinical examination and conventional imaging (CI), and (2) to analyse the clinical relevance of both 67Ga imaging and CI after treatment. From March 1995 to November 1998, 86 67Ga scintigraphy studies were performed in 62 patients with Hodgkin's disease (n=52) or non-Hodgkin's lymphoma (n=10). 67Ga scintigraphy was performed at diagnosis (n=44) or after therapy (n=42) using 185-220 MBq 67Ga citrate and planar and single-photon emission tomography (SPET) studies. Treatment comprised radiotherapy, chemotherapy or combined modalities. CI included plain chest radiography, computed tomography (CT) of the chest and abdomen/pelvis, ultrasound of the abdomen, lymphography, bone marrow biopsy and, when necessary, magnetic resonance imaging (MRI) and bone scintigraphy. For individual suspected sites of disease before treatment, complete agreement between clinical examination and CI on the one hand and 67Ga scintigraphy on the other hand was observed in 25/44 patients (57%; 95% confidence interval 41%-72%). Clinical examination and CI showed more sites than did 67Ga scintigraphy in 12/44 patients (27%) and 67Ga imaging demonstrated more sites than CI in 6/44 patients (11%). The clinical stage of the disease as assessed using 67Ga scintigraphy only was in agreement with that using all diagnostic procedures in 34/44 patients (77%; 95% confidence interval 62%-89%). Compared with CI staging, 67Ga scintigraphy downstaged seven patients (16%) and upstaged three (7%). 67Ga scintigraphy downstaged mainly because of the limited value of the technique below the diaphragm and upstaged owing to the good sensitivity in the lung. After therapy, both CI and 67Ga scintigraphy were normal in 11 patients. All but one of these patients were in complete remission after a median follow-up of 31 months. In contrast, radiological residual mass was observed in 31/42 patients. 67Ga imaging was normal in 22/31 (71%); 17 of these 22 patients, including nine with a large residual mass (> or =2 cm), were in complete remission after a median follow-up of 32 months, while four suffered relapses 8-45 months later. The cause of death remained unknown in one patient. 67Ga scintigraphy showed abnormal uptake in 9 of the 31 patients with a large residual mass. Active disease was demonstrated in eight patients and one patient was in complete remission 30 months thereafter. Our data show that 67Ga imaging cannot replace CI in initial staging but can demonstrate additional individual sites of disease in more than 10% of patients and can lead to clinical upstaging with potential prognostic and therapeutic consequences. After therapy, 67Ga scintigraphy has a clinical impact when radiological abnormalities persist because it can either avoid unnecessary complementary treatment or confirm the need to change treatment modalities.

Successful delivery of mature twins after a ruptured interstitial heterotopic pregnancy. A case report.

A 31-year-old primigravida had a combined pregnancy consisting of intrauterine twins and an interstitial ectopic after in vitro fertilization/embryo transfer. The patient underwent repair of the ectopic pregnancy at 15 weeks of gestation, with subsequent delivery of mature twins close to term.