Improved nationwide survival of sarcoma patients with a network of reference centers.

BACKGROUND: We investigated the impact of the implementation of a network of reference centers for sarcomas (NETSARC) on the care and survival of sarcoma patients in France since 2010. PATIENTS AND METHODS: NETSARC (netsarc.org) is a network of 26 reference sarcoma centers with specialized multidisciplinary tumor boards (MDTBs), funded by the French National Cancer Institute (INCa) since 2010. Its aims are to improve the quality of diagnosis and care of sarcoma patients. Patients' characteristics, treatments, and outcomes are collected in a nationwide database. The objective of this analysis was to compare the survival of patients in three periods: 2010-2012 (non-exhaustive), 2013-2015, and 2016-2020. RESULTS: A total of 43 975 patients with sarcomas, gastrointestinal stromal tumors (GISTs), or connective tissue tumors of intermediate malignancy were included in the NETSARC+ database since 2010 (n = 9266 before 2013, n = 12 274 between 2013 and 2015, n = 22 435 in 2016-2020). Median age was 56 years, 50.5% were women, and 13.2% had metastasis at diagnosis. Overall survival was significantly superior in the period 2016-2020 versus 2013-2015 versus 2010-2012 for the entire population, for patients >18 years of age, and for both metastatic and non-metastatic patients in univariate and multivariate analyses (P < 0.0001). Over the three periods, we observed a significantly improved compliance to clinical practice guidelines (CPGs) nationwide: the proportion of patients biopsied before surgery increased from 62.9% to 72.6%; the percentage of patients presented to NETSARC MDTBs before first surgery increased from 31.7% to 44.4% (P < 0.0001). The proportion of patients with R0 resection on first surgery increased (from 36.1% to 46.6%), while R2 resection rate decreased (from 10.9% to 7.9%), with a better compliance and improvement in NETSARC centers. CONCLUSIONS: The implementation of the national reference network for sarcoma was associated with an improvement of overall survival and compliance to guidelines nationwide in sarcoma patients. Referral to expert networks for sarcoma patients should be encouraged, though a better compliance to CPGs can still be achieved.

Association between recent pregnancy or hormonal contraceptive exposure and outcome of desmoid-type fibromatosis.

BACKGROUND: The role of both hormonal contraception and pregnancy on the outcomes of desmoid-type fibromatosis (DF) is debatable. MATERIALS AND METHODS: In the present study, we selected female patients of childbearing age from the prospective ALTITUDES cohort. The primary study endpoint was event-free survival (EFS), with an event defined as relapse or progression. We estimated the risk of events according to the use of hormonal contraception [estrogen-progestin (EP) and progestin] and pregnancy status using multivariate time-dependent models, controlling for major confounders. RESULTS: A total of 242 patients (median age, 34.7 years) were included in the present study. The abdominal wall was the most common tumor site (51%). Patients were managed by active surveillance (80%) or surgery (20%). Pregnancy occurred within 24 months before, at the time of, and after DF diagnosis in 33%, 5%, and 10% of the cases, respectively. Exposure to hormonal contraception was documented within 24 months before, at the time of, and after diagnosis in 44%, 34%, and 39% of the cases, respectively. The 2-year EFS was 75%. After adjusting for DF location, tumor size, front-line treatment strategy, and hormonal contraception, we observed an increased risk of events occurring at 24 months after pregnancy [hazard ratio (HR) = 2.09, P = 0.018]. We observed no statistically significant association between the risk of events and current EP exposure (HR = 1.28, P = 0.65), recent EP exposure (within 1-24 months, HR = 1.38, P = 0.39), current progestin exposure (HR = 0.81, P = 0.66), or recent progestin exposure (HR = 1.05, P = 0.91). CONCLUSIONS: In our study, a recent history of pregnancy was associated with an increased risk of progression/relapse in patients with newly diagnosed DF, whereas hormonal contraception did not demonstrate an association with progression/relapse.

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.

Need for risk-adapted therapy for malignant ovarian germ cell tumors: A large multicenter analysis of germ cell tumors' patients from French TMRG network.

BACKGROUND: Malignant ovarian germ cell tumors are rare tumors, affecting young women with a generally favorable prognosis. The French reference network for Rare Malignant Gynecological Tumors (TMRG) aims to improve their management. The purpose of this study is to report clinicopathological features and long-term outcomes, to explore prognostic parameters and to help in considering adjuvant strategy for stage I patients. PATIENTS AND METHODS: Data from patients with MOGCT registered among 13 of the largest centers of the TMRG network were analyzed. We report clinicopathological features, estimated 5-year event-free survival (5y-EFS) and 5-year overall survival (5y-OS) of MOGCT patients. RESULTS: We collected data from 147 patients including 101 (68.7%) FIGO stage I patients. Histology identifies 40 dysgerminomas, 52 immature teratomas, 32 yolk sac tumors, 2 choriocarcinomas and 21 mixed tumors. Surgery was performed in 140 (95.2%) patients and 106 (72.1%) received first line chemotherapy. Twenty-two stage I patients did not receive chemotherapy. Relapse occurred in 24 patients: 13 were exclusively treated with upfront surgery and 11 received surgery and chemotherapy. 5y-EFS was 82% and 5y-OS was 92.4%. Stage I patients who underwent surgery alone had an estimated 5y-EFS of 54.6% and patients receiving adjuvant chemotherapy 94.4% (P < .001). However, no impact on estimated 5y-OS was observed: 96.3% versus 97.8% respectively (P = .62). FIGO stage, complete primary surgery and post-operative alpha fetoprotein level significantly correlated with survival. CONCLUSION: Adjuvant chemotherapy does not seem to improve survival in stage I patients. Active surveillance can be proposed for selected patients with a complete surgical staging.

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.

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.

Imatinib for progressive and recurrent aggressive fibromatosis (desmoid tumors): an FNCLCC/French Sarcoma Group phase II trial with a long-term follow-up.

BACKGROUND: Imatinib evaluated as a new treatment option in patients with recurrent or established progressive aggressive fibromatosis/desmoid tumor (AF/DT). PATIENTS AND METHODS: Forty patients with unresectable and progressive symptomatic AF/DT were treated with imatinib (400 mg/day for 1 year) in a Simon's optimal two-stage phase II study (P(0) = 10%, P(1) = 30%, α = 5%, ß = 10%). The primary end point was non-progressive at 3 months (RECIST). RESULTS: The study population consisted of 28 women and 12 men, with a mean age of 41 (range 20-72 years). Most of the primary sites were extra-abdominal (24, 54.5%). Familial adenomatous polyposis was observed in six (15%) cases. The median follow-up was 34 months. Imatinib toxicity was similar to that previously reported in literature. Tumor assessment was validated by a central independent radiology committee for 35 patients At 3 months, one (3%) complete and three (9%) partial confirmed responses were observed. The non-progression rates at 3, 6 and 12 months were, respectively, 91%, 80% and 67%. The 2-year progression-free and overall survival rates were 55% and 95%, respectively. Two patients with mesenteric AF/DT died from progressive disease. CONCLUSION: Imatinib is active in the treatment of recurrent and progressive AF/DT, providing objective response and long-term stable disease in a large proportion of patients.

Optimal treatment with systemic chemotherapy, complete surgical excision and hyperthermic intraperitoneal chemotherapy for a desmoplastic small round cell tumor in an adult male patient.

Desmoplastic small round cell tumor (DSRCT) is a very rare but aggressive malignancy. It is usually observed in males during adolescent and early adulthood. The tumor primarily affects the intra-abdominal serosal and is characterized by distinctive histological and immunophenotypic features and by the specific reciprocal translocation EWS-WT1. Prognosis is mainly poor with a mean survival approximately of 2.5 years. However, long-term survivals have been reported using aggressive multimodal therapy based on complete surgical excision, systemic chemotherapy and radiotherapy. The addition of hyperthermic intraperitoneal chemotherapy in the multimodal approach has been reported in very few cases but no effect on survival has been clearly demonstrated. We report a case of a 51-year old adult patient presenting with a DSRCT treated with aggressive therapy based on systemic chemotherapy, complete cytoreductive surgery associated with hyperthermic intraperitoneal chemotherapy, resulting in a long term survival of 4 years.

[Pneumocystis pneumonia in two breast cancer patients treated with docetaxel: an unusual adverse event of chemotherapy]. / Deux observations de pneumocystose chez des patientes traitées par docétaxel pour un cancer du sein : une complication inhabituelle de la chimiothérapie.

We report two cases of pneumocystis pneumonia in patients receiving chemotherapy for breast cancer. These case series emphasize the frailty of the patients as the causative role for occurrence of this uncommon complication of chemotherapy in breast cancer. We remind the importance of screening for unusual adverse events in frail patients receiving chemotherapy.

Cetuximab, topotecan and cisplatin for the treatment of advanced cervical cancer: A phase II GINECO trial.

OBJECTIVE: Cisplatin (Cp) plus topotecan (Tc) is the first combination chemotherapy to demonstrate a survival advantage over cisplatin alone in advanced cervical cancer. Combining Cp and Tc with an epidermal growth factor receptor (EGFR) inhibitor such as cetuximab (Ce) may increase the activity of chemotherapy. METHODS: Patients with advanced cervical squamous cell cancer or adenocarcinoma and at least one measurable target received intravenous Cp 50 mg/m(2) on day 1 plus Tc 0.75 mg/m(2)/day from days 1 to 3 every 3 weeks combined with Ce (initial dose of 400 mg/m(2) followed by subsequent weekly dose of 250 mg/m(2)). Objective response rate according to RECIST criteria was the primary end point; safety, progression free survival (PFS) and overall survival (OS) were secondary end points. RESULTS: Between April and July 2007, 19 out of the 44 planned patients were accrued before the study was stopped early due to excessive toxicity. The most frequent adverse event was severe myelosuppression with grades 3-4 neutropenia (72%), grades 3-4 thrombocytopenia (61%), and grade 3 anemia (44.5%). The main grades 3-4 non-hematologic toxicities were infection (39%) and febrile neutropenia (28%), skin reactions (22%), renal toxicity (11%), and pulmonary embolism (11%). Five (28%) patients died during the treatment including 3 deaths related to treatment toxicity. Six (32%) evaluable patients achieved a partial response. The median times of PFS and OS were 172 and 220 days, respectively. CONCLUSION: In this phase II trial, the combination Cp-Tc-Ce induced a high rate of serious adverse and/or fatal events at standard dose and schedule. Cetuximab plus platinum-based combination chemotherapy should be further explored with caution in the future in advanced cervix cancer.

[Carcinosarcoma of the ovary]. / Le carcinosarcome ovarien.

Ovarian carcinosarcoma, also called malignant mixed mesodermal tumour, is a rare ovarian tumour representing less than two per cent of ovarian cancers. Carcinosarcoma is an aggressive tumour, which associates some epithelial elements (carcinoma) with a stromal component (sarcoma). This tumour can be found in the female genital tractus, mostly in the uterus. It can be found even more rarely on the ovaries. The initial stage of the disease at the diagnostic is considered as the only prognostic factor. There is no existing consensus concerning treatment. Nevertheless, surgical treatment is paramount for the survival of patients. Response rates to chemotherapy are about 20%.

[Diagnosis and treatment of soft-tissue tumors]. / Prise en charge des tumeurs des parties molles de l'appareil locomoteur de l'adulte.

The diagnostic and therapeutic management of patients with soft-tissue tumors would be similar to the approach used for bone tumors if it were not for one crucial factor: the absolute necessity to recognize a sarcoma. The predominant features are the size of the tumor and its superficial or deep localization. If the tumor is small and superficial, biopsy can be associated with immediate resection without risk of dissemination to the deep tissues: this is the biopsy-resection approach. If the tumor is deep or superficial but large sized, search for locoregional spread with MRI is necessary before undertaking any surgical procedure. MRI can help guide the biopsy and plan resection if the tumor is a sarcoma. A first biopsy is necessary to establish the histological diagnosis and elaborate the therapeutic strategy. Samples should be sent immediately to the pathology lab which should examine sterile fresh tissue. Experience has demonstrated that proper rules for diagnosis and treatment are not necessarily applied initially in approximately one-fourth of all subjects with a malignant soft-tissue tumor. Besides the medical problems caused by this situation, the patient loses a chance for cure. When the tumor is a sarcoma, surgery is the basis of treatment. Complementary radiation therapy may be necessary, particularly for high-grade tumors or if the surgical margin was insufficient. Systemic or locoregional chemotherapy can also be used for high-grade or non-resectable tumors.