Molecular screening program to select molecular-based recommended therapies for metastatic cancer patients: analysis from the ProfiLER trial.

BACKGROUND: Antitumor activity of molecular-targeted agents is guided by the presence of documented genomic alteration in specific histological subtypes. We aim to explore the feasibility, efficacy and therapeutic impact of molecular profiling in routine setting. PATIENTS AND METHODS: This multicentric prospective study enrolled adult or pediatric patients with solid or hematological advanced cancer previously treated in advanced/metastatic setting and noneligible to curative treatment. Each molecular profile was established on tumor, relapse or biopsies, and reviewed by a molecular tumor board (MTB) to identify molecular-based recommended therapies (MBRT). The main outcome was to assess the incidence rate of genomic mutations in routine setting, across specific histological types. Secondary objectives included a description of patients with actionable alterations and for whom MBRT was initiated, and overall response rate. RESULTS: Four centers included 2579 patients from February 2013 to February 2017, and the MTB reviewed the molecular profiles achieved for 1980 (76.8%) patients. The most frequently altered genes were CDKN2A (N = 181, 7%), KRAS (N = 177, 7%), PIK3CA (N = 185, 7%), and CCND1 (N = 104, 4%). An MBRT was recommended for 699/2579 patients (27%), and only 163/2579 patients (6%) received at least one MBRT. Out of the 182 lines of MBRT initiated, 23 (13%) partial responses were observed. However, only 0.9% of the whole cohort experienced an objective response. CONCLUSION: An MBRT was provided for 27% of patients in our study, but only 6% of patients actually received matched therapy with an overall response rate of 0.9%. Molecular screening should not be used at present to guide decision-making in routine clinical practice outside of clinical trials.This trial is registered with ClinicalTrials.gov, number NCT01774409.

Surgery in reference centers improves survival of sarcoma patients: a nationwide study.

BACKGROUND: NETSARC (netsarc.org) is a network of 26 sarcoma reference centers with specialized multidisciplinary tumor boards (MDTB) aiming to improve the outcome of sarcoma patients. Since 2010, presentation to an MDTB and expert pathological review are mandatory for sarcoma patients nationwide. In the present work, the impact of surgery in a reference center on the survival of sarcoma patients investigated using this national NETSARC registry. PATIENTS AND METHODS: Patients' characteristics and follow-up are prospectively collected and data monitored. Descriptive, uni- and multivariate analysis of prognostic factors were conducted in the entire series (N = 35 784) and in the subgroup of incident patient population (N = 29 497). RESULTS: Among the 35 784 patients, 155 different histological subtypes were reported. 4310 (11.6%) patients were metastatic at diagnosis. Previous cancer, previous radiotherapy, neurofibromatosis type 1 (NF1), and Li-Fraumeni syndrome were reported in 12.5%, 3.6%, 0.7%, and 0.1% of patients respectively. Among the 29 497 incident patients, 25 851 (87.6%) patients had surgical removal of the sarcoma, including 9949 (33.7%) operated in a NETSARC center. Location, grade, age, size, depth, histotypes, gender, NF1, and surgery outside a NETSARC center all correlated to overall survival (OS), local relapse free survival (LRFS), and event-free survival (EFS) in the incident patient population. NF1 history was one of the strongest adverse prognostic factors for LRFS, EFS, and OS. Presentation to an MDTB was associated with an improved LRFS and EFS, but was an adverse prognostic factor for OS if surgery was not carried out in a reference center. In multivariate analysis, surgery in a NETSARC center was positively correlated with LRFS, EFS, and OS [P < 0.001 for all, with a hazard ratio of 0.681 (95% CI 0.618-0.749) for OS]. CONCLUSION: This nationwide registry of sarcoma patients shows that surgical treatment in a reference center reduces the risk of relapse and death.

Sorafenib in patients with locally advanced and metastatic chordomas: a phase II trial of the French Sarcoma Group (GSF/GETO).

BACKGROUND: There is no consensual treatment of locally advanced or metastatic chordomas. PATIENTS AND METHODS: We conducted a multicenter, open-label, uncontrolled phase II trial of sorafenib (800 mg/day). The primary end point was the 9-month progression-free rate according to RECIST 1.1. All patients had documented progressive disease at the time of study entry. RESULTS: Twenty-seven patients were enrolled between May 2011 and January 2014. The median age was 64 (range, 30-86) years. There were 17 men and 10 women. Twelve patients had been previously treated with chemotherapy and molecularly targeted agents. The maximum toxicity grade per patient was grade 3 in 21 cases (77.8%) and grade 4 in 4 cases (14.8%). Sorafenib provided an intent-to-treat best objective response of 1/27 [3.7%; 95% confidence interval (CI) 0.1% to 19.0%], a 9-month progression-free rate of 73.0% (95% CI 46.1-88.0) and a 12-month overall survival rate of 86.5% (95% CI 55.8-96.5). Survival curves were similar in pretreated and not pretreated patients. DISCUSSION: Additional clinical trials further exploring sorafenib as a treatment of locally advanced or metastatic chordomas are warranted.

Advanced chondrosarcomas: role of chemotherapy and survival.

BACKGROUND: There are limited data about the role of chemotherapy in patients with advanced chondrosarcomas. METHODS: The medical charts of 180 patients with advanced chondrosarcomas having received chemotherapy in 15 participating institutions between 1988 and 2011 were reviewed. RESULTS: Median age was 52 years. Sixty-three percent of patients had conventional chondrosarcoma and 88% had metastatic disease. Combination chemotherapy was delivered in 98 cases (54.5%). One hundred and thirty-one patients (73%) received an anthracycline-containing regimen. Using RECIST, the objective response rate was significantly different according to histological subtype, being 31% for mesenchymal chondrosarcoma, 20.5% for dedifferentiated chondrosarcoma, 11.5% for conventional chondrosarcoma and 0% for clear-cell chondrosarcoma (P = 0.04). Median progression-free survival (PFS) was 4.7 months [95% confidence interval (CI) 3-6.5]. Performance status (PS) ≥2, number of metastatic sites ≥1 and single-agent regimen were independently associated with poor PFS. Median overall survival (OS) was 18 months (95% CI 14.5-21.6). PS, number of metastatic sites and palliative surgery were independently associated with OS. CONCLUSIONS: Conventional chemotherapy have very limited efficacy in patients with advanced chondrosarcoma, the highest benefit being observed in mesenchymal and dedifferentiated chondrosarcoma. These data should be used as a reference for response and outcome in the assessment of investigational drugs in advanced chondrosarcoma.

Chemotherapy in patients with desmoid tumors: a study from the French Sarcoma Group (FSG).

BACKGROUND: Data regarding the role of chemotherapy (CT) in patients with recurrent and/or unresectable desmoid tumors (DTs) are scarce. PATIENTS AND METHODS: Records of patients with DT who were treated with CT in centers from the French Sarcoma Group were reviewed. RESULTS: Sixty-two patients entered the study. The two most common locations were extremities (35.5%) and internal trunk (32.5%). Twelve patients (19.5%) were diagnosed with Gardner syndrome. Thirty-seven patients (54.7%) received previously one or more lines of systemic therapies (nonsteroidal anti-inflammatory drugs: 43.5%, antiestrogens: 43.5% and imatinib: 30.5%). Combination CT was delivered in 44 cases (71%) and single agent in 18 patients (29%), respectively. Thirteen patients (21%) received an anthracycline-containing regimen. The most frequent nonanthracycline regimen was the methotrexate-vinblastine combination (n=27). Complete response, partial response, stable disease and progressive disease were observed in 1 (1.6%), 12 (19.4%), 37 (59.6%) and 12 (19.4%) patients, respectively. The response rate was higher with anthracycline-containing regimens: 54% versus 12%, P=0.0011. Median progression-free survival (PFS) was 40.8 months. The sole factor associated with improved PFS was the nonlimb location: 12.1 months (95% confidence interval 5.6-18.7) versus not reached, P=0.03. CONCLUSIONS: CT has significant activity in DT. Anthracycline-containing regimens appear to be associated with a higher response rate.

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.

Clinical management of adolescents and young adults suffering from sarcoma in the French Rhône-Alpes region: A prospective exhaustive cohort with 10 years follow up.

INTRODUCTION: Survival of adolescents and young adults (AYA) with sarcoma is lower than in younger patients. The objective of this study was to describe the regional healthcare circuits, the differences in the management between adult, paediatric and mixed units and to assess the prognostic impact of compliance with clinical practice guidelines (CPGs) on overall survival (OS) and on relapse free survival (RFS). MATERIALS AND METHODS: Retrospective analysis of the management and long term follow-up of all 13-25 year old patients with a sarcoma diagnosed in the Rhône-Alpes area between 2000 and 2005. RESULTS: 140 patients satisfied inclusion criteria and were selected. The majority of 13-25 year old patients were treated in paediatric units. Joint management resulted in a higher rate of discussion in multidisciplinary tumour board, inclusion in clinical trials, and fertility preservation. Non-compliance with guidelines was observed in 65% of cases. Overall compliance was not reported to correlate to survival. Compliance of radiotherapy with CPG's seemed associated with a better prognosis for OS (HR = 0.20, 95% CI = [0.10-0.40]; p < 0.0001) and RFS (HR = 0.18, 95% CI = [0.09-0.37; p < 0.0001) as well as compliance of surgery for OS (HR = 0.43, 95% CI = [0.23-0.81]; p = 0.01). Multivariate Cox regression analysis revealed other independent predictors of OS like age at diagnosis, stage and histological subtype. CONCLUSIONS: Management of AYA in joint units seems to improve the quality of care. Compliance of surgery and radiotherapy with CGP's seems to improve survival.

Relationship between nutritional status and quality of life in patients with cancer.

Patients with cancer frequently suffer a deteriorated quality of life and this is an important factor in the therapeutic decision. The correlation between quality of life and malnutrition seems obvious and bidirectional. The aim of our study was to describe the global quality of life and its various dimensions in patients with cancer, as a function of the nutritional status. A transversal observational study was performed in wards in hospitals in Clermont-Ferrand and Saint Etienne on 907 patients. The EORTC questionnaire, QLQ-C30, was used to assess the quality of life. The mean global quality of life score was 48.8 for patients who had a weight loss of more than 10% since the beginning of their illness, compared with 62.8 for the other patients (p<0.001). A significant association with weight was observed for the main dimensions of the quality of life: physical, functional, cognitive, social, fatigue, nausea, pain, loss of appetite, constipation and diarrhoea. This strong relation between quality of life and weight loss shows the importance of dietary management in patients with cancer.

Liver abscess due to clostridium septicum. A case report and review of the literature.

The onset of liver abscess due to Clostridium septicum -an anaerobic gram-positive bacillus- is a rare condition, generally arising in cancer patients. The radiological picture is that of gas-containing pyogenic abscess, that predominates within preexisting liver metastases. We report a case of a 50-year-old patient with metastatic colon cancer who was referred with multiple Clostridium septicum liver abscesses. The patient underwent parenteral antibiotherapy as well as transcutaneous drainage of the largest liver abscess. However the outcome was unfavorable in a clinical picture of liver failure that was likely due to disease progression rather than sepsis. Clostridium septicum liver abscess is a life-threatening condition that occurs in fragile patients, mostly with metastatic cancers. A review of the reported cases is presented and treatment options are discussed.

Conservative surgery vs. duodeneopancreatectomy in primary duodenal gastrointestinal stromal tumors (GIST): a retrospective review of 114 patients from the French sarcoma group (FSG).

BACKGROUND: Duodenal GISTs represent 3-5% of all GISTs with limited understanding of patient outcomes. We conducted a retrospective analysis of primary localized duodenal GISTs. METHODS: Patients were identified via a survey from 16 FSG centers (n = 105), and a group of 9 patients enrolled in the BFR14 trial. Data were collected from the original database and patient files, in agreement with French legislation. RESULTS: 114 patients were included, with a median age of 57. Tumors originated mainly in D2 (33%), or D3 (24%), with a median size of 5 cm. 109 patients had resection of the primary tumor; with a Local Resection (LR, n = 82), a pancreaticoduodenectomy (PD, n = 23), and data were missing for 4 patients. Resections were R0 (n = 87, 79%), R1 (n = 8, 7%), R2 (n = 6). Tumor characteristics were: KIT+ (n = 104), CD34+ (n = 58). Miettinen risk was low (n = 43), and high (n = 52). Imatinib was administered preoperatively (n = 11) and post-operatively (n = 20). With a median follow-up of 36 months (2-250), 98 patients are alive, and 33 relapsed. The 5-year OS and EFS rates are 86.5% and 54.5%. EFS was similar for patients in the LR and the PD groups (P > 0.05). In multivariate analysis, ECOG PS, and CD34 expression are independent prognostic factors on OS. Miettinen risk and spindle cell type are independent predictive factors for relapse. CONCLUSIONS: Patients with resected duodenal GIST have a reasonably favorable prognosis. This study favors a preservation of pancreas when there are no anatomical constraints. LR exhibit similar survival and smaller morbidity then PD.

Treatment of advanced gastrointestinal stromal tumors in patients over 75 years old: clinical and pharmacological implications.

Data about the patterns of care and the specific outcome of elderly patients with advanced gastrointestinal stromal tumors (GISTs) are almost nonexistent. Between 2001 and 2009, 44 patients ≥75 years old with advanced GISTs started first-line imatinib (400 mg/day) in seven participating institutions. Clinical data were collected by reviewing medical records and were entered in a comprehensive database. During the same period, 160 patients with advanced GIST (136 patients <75 years old, 24 patients ≥75 years old) had access to an imatinib blood level testing program. Imatinib plasma concentration (patient dose 400 mg/day) tests were centralized in a single laboratory. Median age was 78 years old (range 75-86). Thirty-six patients (82 %) experienced at least one adverse event (Table 2). Drug-related adverse events were mainly of grades 1 and 2 and were medically manageable. Permanent dose reduction (200-300 mg/day) was required for 20 patients (45.5 %) and was significantly more frequent for patients with performance status (PS) ≥2: 33.5 versus 8.5 %, p = 0.04. Eight patients (18 %) required imatinib interruption for intolerance. Median PFS was 34.4 months (95 % CI 11.5-57.4) (Fig. 1). Median overall survival (OS) was 50.3 months (95 % CI 37-63.5). Performance status <2 was the sole pre-therapeutic factor associated with improved OS. No correlation was found between comorbidities and tolerance or outcome. Imatinib trough plasma concentrations increase with age, although this correlation did not reach statistical significance. First-line imatinib is a feasible and effective treatment in patients with advanced GISTs ≥75 years. Aging seems to have only a moderate impact on imatinib pharmacokinetics. Overall survival is similar to that of younger patients. Comorbidities did not result in increased incidence of toxicity. Careful follow-up regarding tolerance issues should be considered in elderly patients with poor PS.