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Background The initial management of patients with sarcoma is a critical issue. We used the nationwide French National Cancer Institute-funded prospective sarcoma database NETSARC to report the management and oncologic outcomes in adolescents and young adults (AYAs) patients with sarcoma at the national level. Patients and methods NETSARC database gathers regularly monitored and updated data from patients with sarcoma. NETSARC was queried for patients (15–30 years) with sarcoma diagnosed from 2010 to 2017 for whom tumor resection had been performed. We reported management, locoregional recurrence-free survival (LRFS), progression-free survival (PFS), and overall survival (OS) in AYA treated in French reference sarcoma centers (RSC) and outside RSC (non-RSC) and conducted multivariable survival analyses adjusted for classical prognostic factors. Results Among 3,227 patients aged 15–30 years with sarcoma diagnosed between 2010 and 2017, the study included 2,227 patients with surgery data available, among whom 1,290 AYAs had been operated in RSC, and 937 AYAs in non-RSC. Significant differences in compliance to guidelines were observed including pre-treatment biopsy (RSC: 85.9%; non-RSC 48.1%), pre-treatment imaging (RSC: 86.8%; non-RSC: 56.5%) and R0 margins (RSC 57.6%; non-RSC: 20.2%) (p Conclusions This study highlights the importance for AYA patients with sarcoma to be managed in national sarcoma reference centers involving multidisciplinary medical teams with paediatric and adult oncologists.

Metastatic phyllodes tumors have poor prognosis with median overall survival of 11.5 months. The objective of this study is to identify prognostic factors and the best options for management of metastatic malignant phyllode tumors (MMPTs). A multicentric retrospective study, including cases of MMPT from 10 sarcoma centers, was conducted. The primary end-point was overall survival (OS), and the secondary end-point was the clinical benefit of chemotherapy (CBCT) rate. 51 MMPT patients were included. Median time from diagnosis to metastatic recurrence was 13 months. Management of MMPT consisted in surgery of the metastatic disease for 16 patients (31.3%), radiation therapy of the metastatic disease for 15 patients (31.9%), and chemotherapy for 37 patients (72.5%). Median follow-up was 62.1 months [95% confidence interval (CI) 31–80 months]. Median OS was 11.5 months (95% CI 7.5–18.7 months). On multivariate analysis, two or more metastatic sites [hazard ratio (HR) 2.81, 95% CI 1.27–6.19; p = 0.01] and surgery of metastasis (HR 0.33, 95% CI 0.14–0.78; p = 0.01) were independently associated with OS. The CBCT rate was 31.4% and 16.7% for the first and second lines. Polychemotherapy was not superior to single-agent therapy. Alkylating-agent-based chemotherapy, possibly associated with anthracyclines, was associated with a better CBCT rate than anthracyclines alone (p = 0.049). The results of this study emphasize the impact of the number of metastatic sites on survival of MMPT patients and the leading role of metastasis surgery in MMPT management. If systemic therapy is used, it should include alkylating agents, which are associated with a better clinical benefit.

BackgroundFrench legislation about sedation in palliative medicine evolved in 2016 with the introduction of a right to deep and continuous sedation, maintained until death. The objective was to describe midazolam sedation at the COL (Centre Oscar Lambret[Oscar Lambret Center], French regional center for cancer control), in order to establish a current overview before the final legislative changes.MethodsDescriptive, retrospective and single-center study, concerning major patients in palliative care hospitalized from 01/01/2014 to 12/31/2015, who had been sedated by midazolam. The proven sedations (explicitly named) and the probable sedations were distinguished.ResultsA total of 54 sedations were identified (48 proven, 6 probable). Refractory symptoms accounted for 48.1% of indications, complications with immediate risk of death 46.3%, existential suffering 5.6%. Titration was performed in 44.4% of cases. Sedation was continuous until death for 98.1% of the cases. Probable sedation had a higher failure rate than proven sedation. Significant differences existed for the palliative care unit compared to other units regarding information to the patient, their consent, anticipation, mention by correspondence and carrying out titrations. When patients had already been treated with midazolam, the induction doses, initial maintenance doses, and doses at the time of death were significantly higher. For those receiving opioids, the maintenance dose at the time of death was higher. No comparison found a difference in overall survival.ConclusionsAfter a sufficient follow-up has enabled teams to familiarize with this new legislation, reflection on sedation should be conducted to adapt to final recommendations.

The purpose of this study is to assess the efficacy of 153Sm-EDTMP (Quadramet®) in a clinical setting. We have conducted a retrospective study of all consecutive patients (pts) treated with 153Sm-EDTMP for painful bone metastases. At each visit (before and after treatment), four parameters were collected: (i) pain assessment according to the 10-step visual analogue scale (VAS), (ii) sleep disturbance related to pain, (iii) dose of analgesic medication, and (iv) answer to the following closed question “Do you think you obtained a benefit from treatment?” Success of treatment was defined by the combination of these four parameters. Three hundred seventy consecutive 153Sm-EDTMP treatments for painful bone metastases were given. Patients had the following primary tumors: breast carcinoma (153), prostate carcinoma (155), lung carcinoma (27), or other cancers (35). Fifty-eight percent of the patients had received previous external osseous radiotherapy. Ninety-seven percent of the patients were treated with concomitant analgesics and 61% were treated with diphosphonates. A clinical benefit was described in 55.0% of cases at D30. Treatment was more effective in cases of breast and prostate cancers compared with other types of primary cancers. Patients described a benefit at D30 in 62, 58, 6, and 38% of cases of breast, prostate, lung, and other cancers. The subjective efficacy was accompanied by a decrease in analgesic intake in 35.0% of cases. 153Sm-EDTMP therapy is an effective supportive treatment in patients who suffer from bone metastases, especially in patients with breast or prostate cancer.

Background There is substantial evidence that classically used toxicity-driven dose-escalating phase I trials are not optimal for defining the recommended phase II dose for molecular-targeted therapies.

The selection of patients for phase I cancer trials remains challenging. Patients who dropout of the trial before completion need to be replaced and this can result in significant delays to trial completion. The objective of this study was to identify patients enrolled in phase I oncology trials who were unable to complete the minimum evaluation period of the trial, and to use these data to develop a predictive model of risk factors for patient replacement. We retrospectively reviewed all consecutive patients who were enrolled in dose-escalating phase I cancer trials at four medical centers in France between May 2003 and May 2013. Replacement was defined as trial discontinuation before 6 weeks, without the occurrence of dose-limiting toxicity. Using logistic regression and decision-tree analyses, we developed a predictive model to identify patients who were at high risk for replacement, and also their common risk factors. This model was designed to provide maximum specificity and a negative predictive value. Of 332 patients enrolled in the study, 16 had to be replaced (4.8 %). The median overall survival time was 45 days for the patients who were replaced versus 480 days for the patients who were not replaced (p

We have carried out a stratified phase II study of sorafenib (So) in patients with advanced angiosarcoma (n = 32) and epithelioid hemangioendothelioma (n = 13). This report concerns the correlative analysis of the predictive values of circulating pro/anti-angiogenetic biomarkers. Using the ELISA method (R&D Systems), circulating biomarkers (VEGF-A, in picograms per milliliter), thrombospondin-1 (TSP1, in micrograms per milliliter), stem cell factor (SCF, in picograms per milliliter), placental growth factor (PlGF, in picograms per milliliter), VEGF-C (in picograms per milliliter), and E-selectin (in nanograms per milliliter) were measured before So treatment and after 7 days. VEGF-A (mean value 475 vs. 541, p = 0.002), TSP1 (16 vs. 24, p = 0.0002), and PlGF (20.9 vs. 40.7, p = 0.0001) significantly increased during the treatment. Treatment did not affect the levels of SCF, VEGF-C, and E-selectin. Only two biomarkers were associated with better outcome as follows: VEGF-A and PlGF. Best objective response and non-progression at 180 days were associated with low level of VEGF-A at baseline (p = 0.04 and 0.03, respectively). There was a correlation between the circulating level of VEGF-A and time to progression (TTP) (r = −0.47, p = 0.001). Best objective response and non-progression at 180 days were not associated with baseline level of PIGF, but there was a correlation between the circulating level of PIGF at baseline and TTP. Low level of VEGF-A at baseline (

Background: Preclinical findings suggest that imatinib mesylate (IM) and metronomic cyclophosphamide (MC) combination provides synergistic antiangiogenic activity on both pericytes and endothelial cells. Methods: We have designed a 3+3 dose-escalating phase I trial with a fixed dose of MC (50 mg two times daily) plus IM (400 mg per day; 300 and 400 mg two times daily). Enrolled patients had IM- and sutininib-refractory advanced gastrointestinal stromal tumours (GIST) (n=17), chordoma (n=7) and mucosal melanoma (n=2). Dose-limiting toxicities were monitored for the first 6 weeks. Progression-free survival (PFS) and response assessment are based on RECIST 1.0 guidelines. Pharmacokinetics of IM were measured before and after exposure to MC. Results: No dose-limiting toxicity was observed. Fourteen patients of the expanded cohort received 400 mg two times daily of IM with MC. Apart from a case of possibly related acute leukaemia occurring after 4 years of treatment, we did not see unexpected toxicity. No drug–drug pharmacokinetic interaction was observed. There was no objective response. We have observed long-lasting stable disease in chordoma patients (median PFS=10.2 months; range, 4.2–18+) and short-term stable disease in heavily GIST pretreated patients (median PFS=2.3 months; range, 2.1–6.6). Conclusion: This combination is feasible and may warrant further exploration in refractory GIST or chordoma patients.

Background: Soft tissue sarcomas (STS) are rare tumours for which treatment options are limited in the advanced setting. Histone deacetylase inhibitors have shown activity in preclinical models of STS. Methods: We conducted a single-arm, open-label, multicentre phase II study to assess the efficacy and tolerability of panobinostat given orally, 40 mg thrice weekly in patients with advanced pretreated STS. The primary endpoint was the 3-month progression-free rate. Results: Forty-seven STS patients were enrolled between January 2010 and December 2010. Median age was 59 (range 21–79) years, 22 (47%) patients were males. Panobinostat dose was lowered to 20 mg thrice weekly after nine patients were enrolled, based on the recommendation of an independent safety committee. The most common grade 3/4 adverse events were thrombocytopenia, fatigue, lymphopenia and anaemia. Forty-five patients were evaluable for the primary endpoint. Among them, nine patients (20%, 95% CI (10–35%)) were progression-free at 3 months. No partial response was seen, but 17 patients (36%) had stable disease (SD) as their best response. Six patients were progression-free at 6 months. Conclusion: Panobinostat was poorly tolerated at 40 mg thrice a week. Efficacy in unselected advanced STS was limited, although some patients had prolonged SD.

Background: Imatinib induces responses and disease stabilisations in non-resectable patients with aggressive fibromatosis (AF). The precise target of imatinib in AF and predictive factors for response to treatment are unknown. Methods: We investigated factors potentially predictive of response to imatinib in a series of 40 patients with progressive AF included in a phase II trial of imatinib: we tested the presence of KIT exon 10 variant (M541L), the expression of imatinib-sensitive kinases and cell cycle proteins by immunohistochemistry (IHC), and other clinical and biological factors. Results: Of 10 patients for whom DNA could be extracted, 3 had a KIT exon 10 variant (30%), with no correlation with response or progression-free survival (PFS). The expression of other imatinib targets (PDGFRA/B, macrophage colony-stimulating factor receptor (M-CSFR)) and of downstream components of the cell cycle, cell proliferation and proliferation pathway (cyclin D1, ERK, MEK 1–2) did not correlate with PFS. Pre-treatment lymphopenia (120 mm correlated with shorter PFS in univariate and multivariate analyses. Conclusion: Our findings show that a baseline biological characteristic of the patient is the major parameter influencing response to imatinib in aggressive fibromatosis. Tumour characteristics, including the presence of a KIT exon 10 M541L variant, may influence tumour control but this needs to be confirmed and better explained.

Dose-limiting toxicity (DLT) remains the preferred metric in dose-finding phase 1 trials. Nevertheless, this primary endpoint appears unsuitable for investigating non-cytotoxic drugs. We reviewed 201 recent dose-finding phase 1 trials and compared the DLT defined with cytotoxic (119 trials) and non-cytotoxic drugs (molecular-targeted therapies and immune-stimulant agents; 82 trials). DLT was less frequently identified with non-cytotoxic drugs (52 vs. 89%, p = 0.00005). Myelotoxicity remains the most frequent DLT in studies investigating cytotoxic agents (51%). Myelotoxicity was significantly less frequent in studies investigating non-cytotoxic drugs (14%, p = 0.00003). Skin toxicities (p = 0.038), coagulation perturbation (p = 0.025) and fever (p = 0.025) were the most frequent DLTs in studies investigating non-cytotoxic drugs. Moreover, DLTs identified with non-cytotoxic drugs were less frequently objectively measurable as they were based on biological anomalies (30 vs. 63%, p = 0.0026). Approximately 50% of dose-finding phase 1 trials investigating non-cytotoxic drugs led to DLT and then the maximum tolerated dose being found. However, the nature of these DLTs is different from those described with cytotoxic drugs and less objectively measurable in many cases.

Background: To evaluate the antitumour activity and safety of metronomic cyclophosphamide vs megestrol acetate in progressive and advanced cancer patients having exhausted all effective therapies under standard care. Methods: Patients were randomly assigned to receive orally metronomic cyclophosphamide (50 mg b.i.d) or megestrol acetate (160 mg only daily) until intolerance or progression (RECIST 1.0). The primary efficacy end point was a 2-month progression-free rate (PFR2m). According to Optimal Simon's design and the following assumptions, namely, P0=5%, P1=20%, α=β=10%, the treatment is considered as effective if atleast 5 out of 44 patients achieved PFR2m. Results: Between September 2006 and January 2009, 88 patients were enrolled. Two patients experienced grade 3–4 toxicities in each arm (4%). One toxic death occurred in the megestrol acetate arm as a consequence of thrombosis. The metronomic cyclophosphamide arm reached the predefined level of efficacy with a PFR2m rate of 9 out of 44 and a PFR4m rate of 5 out of 44. The MA arm failed to achieve the level of efficacy with a PFR2m of 4 out of 44 and a PFR4m of 1 out of 44. The median overall survival was 195 and 144 days in the metronomic cyclophosphamide arm and megestrol acetate arm, respectively. Conclusion: Metronomic cyclophosphamide is well tolerated and provides stable disease in such vulnerable and poor-prognosis cancer patients. This regimen warrants further evaluations.

Superficial soft-tissue sarcomas are malignant mesenchymal tumors located within the cutaneous and/or subcutaneous layers. Most superficial soft-tissue sarcomas are low-grade tumors; yet, the risk of local recurrence is high, and initial wide surgery is the main prognostic factor. Some of these superficial sarcomas may grow, following an infiltrative pattern, and their real extent may be underestimated clinically. Imaging techniques are useful to determine precisely the real margins of the tumor, especially in cases of clinically doubtful or recurrent or large superficial lesions. Imaging tools enable one to determine the relationship with the superficial fascia separating the subcutaneous layer from the underlying muscle. In our institution ultrasonographic examination is followed by magnetic resonance (MR) imaging when the size of the lesion exceeds 3-5 cm. Imaging assessment is performed prior to biopsy, enabling optimal surgical management. Imaging features of the main superficial sarcomas are detailed in the following article, according to their major locations: those arising in the epidermis and/or dermis, which are most often diagnosed by dermatologists, and the subcutaneous sarcomas.

Background The management of carcinoma of unknown primary site remains debatable. The literature data consists of about 29 phase-II studies investigating 38 regimens, providing a broad range of response rates (RR). Methods We performed a pooled published data analysis to identify the factors influencing RR in these 29 studies. Results In front-line treatment, the overall RR was 31% (430/1,380). At least nine factors significantly influenced the reported RR, excluding drugs under investigation, such as the impact factor of the journal, single-centre study, some eligibility criteria, central radiological review, sample size calculation based on statistical hypothesis and stratification. Two drugs seem to improve RR: cisplatin and doxorubicin. Two drugs seem to be associated with a worse RR: irinotecan and carboplatin. Conclusions This pooled data analysis illustrates that in a phase II trial setting, it is impossible to attribute the variation in RR solely to the modification of drugs under investigation.

Multidrug chemotherapy increases responses in advanced soft tissues sarcoma. Can a 20% increase of relative dose intensity of the MAID regimen, more improve responses? From 1994 to 1997, 162 patients were randomized in a phase III study to the conventional drug combination (6 cycles of MAID: 60, 7,500, 900 mg/m(2) for doxorubicin, ifosfamide and dacarbazine respectively), or at doses 20-33% higher per cycle (5 cycles of intensified MAID for similar cumulative doses) with systematic G-CSF. Primary endpoint was response rate; secondary were toxicity, event-free and overall survival. The objective response rate in assessable patients was 38% with intensified MAID and 35% with MAID (p = 0.72). Event-free and overall survivals were similar in both arms. Only grade 3-4 thrombocytopenia and anemia were significantly higher in intensified arm. Treatment with intensified MAID did not improve response rate neither survival and cannot be recommended for advanced or metastatic soft tissue sarcoma.

The number of patients treated at each dose-level in dose seeking phase I trials is arbitrarily established. The most frequently used design is the "classical 3 + 3 design (3 + 3D)". Recently, Simon et al. had introduced several "accelerated titration designs (ATD)". In the present analysis, we compared the performance of these two types of designs in 270 recently (1997-2008) published phase I trials. ATD had been used in only 10% of the recent studies. ATD had permitted to explore significantly more dose levels (seven versus five, p = 0.0001) and reduced the rate of patients treated at doses below phase-2 recommended dose (46% versus 56%, p = 0.0001). Nevertheless, ATD did not allow a reduction in the number of enrolled patients, shorten the accrual time nor increase the efficacy of phase I trials. These data support that ATD as an effective clinical trial design over a standard 3 + 3 dose escalation design.

Background: Nowadays, there is no consensual and effective treatment in metastatic uveal melanoma (MUM). Numerous preclinical data (for example, 75% of MUM express c-kit) suggest that imatinib mesylate (IM) may be a potential treatment of UMM. Methods: The primary objective of this phase II trial was to determine the non-progression rate at 3 months for patients receiving IM at dose of 400 mg twice per day orally. The study was based on a Simon’s optimal design, which allows entry a total of 29 patients, if at least two non-progressions among ten first patients were observed. Result: Thirteen patients including ten assessable patients were enrolled in 12 months. No objective response and only one stable disease with duration of 5 months were noted. Five and one out of 13 enrolled patients experienced grade 3 and grade 4 toxicities, respectively. The most common severe adverse events were abdominal pain. The overall survival was 10.8 months. Conclusions: Despite promising preclinical data, IM is an inactive single agent in MUM. This phase II clinical trial has been stopped at the first step.

Bone metastases revealing solid tumors require a multidisciplinary treatment that may include aggressive surgery. Nevertheless, decision making is very difficult because of lack of reliable guidance for life expectancy. Therefore, we had conducted a retrospective study to analyze prognostic factors in this vulnerable population.We reviewed the medical charts of 119 consecutive patients with solid tumors treated between August 1999 and December 2007. Survival was estimated using Kaplan-Meier method. Prognostic factors were assessed with Log-rank test and Cox model. There were 77 men and 42 women.The median age was 57 (range, 29-84). The most frequent primaries were lung (51 cases), unknown primary (42 cases), and breast (six cases). The median overall survival was 118 days (1-2,815). Six independent prognostic factors were identified by multivariate analysis: Karnosky index80% (HR = 1.92), albuminemia38 g/l (HR = 2.60), natremia135 mEq/l (HR = 2.78), platelet count500,000/mm(3) (HR = 2.71), cutaneous metastasis (HR = 4.6), and pleural metastasis (HR = 4.76). For example, patients withor =2 of these prognostic factors experienced a median overall survival of 196 days (1-2,875) and their risk of death within the 90 days was 15/77. On the contrary, the patients with more than two poor prognostic factors experienced a median overall survival of about 80 days (1-834) and their risk of early death was 22/32. We had proposed an easily obtained at bedside score that needs further validation on independent cohort.

Squamous cell carcinomas (SCC) localized at the lateral buccopharyngeal junction are frequent occurrences in our experience. This anatomical site gives the tumor ample space to spread in different directions, making tumor management all the more difficult. We focused our study on this localization to underline their specificities and evaluate our practices. In the Department of Head and Neck Oncology at the Centre Oscar Lambret, 57 patients with lateral bucco-pharyngeal junction SCC were treated from 1995 to 2000. Epidemiological data were extracted from the medical chart. Description of the tumor was based on clinical and imaging data. Treatment modalities frequently combined surgery, radiotherapy and chemotherapy. Protocol was adapted with the health status and the aggressiveness of the disease. Follow-up and survival rates are outlined below. Fifty men and seven women with a mean age of 57 years constitute the patient population. Forty-nine out of 57 presented a history of smoking, and 44 out of 46 presented a history of alcoholism. Patient overall clinical status, social and family background were also discussed. Thirty-one of fifty-seven tumors were categorized as T1 or T2. Forty-five out of fifty-seven presented limited lymph-node involvement. Tumor extension, growth pathology and degree of differentiation were described. Twenty-eight out of fifty-seven had undergone primary surgery. Primary radiotherapy with or without chemotherapy was delivered to the others. The modality of the different treatments and their results were specified. The 3-year disease-free survival rate was 52.7% and the 3-year overall survival rate was 48.2%. The mean survival rate was 3 years. Univariate analysis was performed on all occasions. Gender (P = 0.008), surgery first versus non-surgical treatment first (P = 0.03), spread beyond the midline (P = 0.03), and small tumors T1 T2 versus T3 T4 (P = 0.003) were predictive factors of overall survival. A Multivariate analysis showed that the type of treatment (surgery first versus no primary surgery P = 0.006), and the T (T1, T2 versus T3, T4 P = 0.005) were the two predictive factors of the overall survival. Because of the small size of the population studied, the retrospective nature of the study and the scarcity of the publications on the subject, results must be carefully interpreted. For example, surgery must be proposed whenever deemed possible. It is in an independent factor in our series. All the statuses linked to the population type, tumor extension and tumor differentiation are also discussed.

Selecting patients for phase I trials in order to investigate cytotoxic agents is challenging, since there is no clear and reliable guidance to estimate life expectancy among these patients. We retrospectively assessed prognostic factors in cancer patients screened for Phase1 trials between October 1997 and October 2002.148 consecutive patients, screened for inclusion in phase I trials investigating cytotoxic agents, were included in the present study. 70 out of them actually received phase I trial regimens. Univariate and multivariate analysis were undertaken to determine the prognostic factors for overall survival (OS) from the date of screening.The median OS of the 148 patients was 5.7 months. Ninety-two percent of them had PSor=1. The Cox model identified serum albumin38 g/l [HR 2.51 (1.51-4.18), p=0.0001] and lymphocyte count700/mm3 [HR 2.27 (1.13-4.62), p=0.024] as independent prognostic for overall survival. All patients presenting both prognostic factors died within 90 days.We propose a simple model, easily obtained at the bedside, which can discriminate patients who are likely to be alive at 3 months and thus could be included in a phase 1 anti-cancer trial. This model now needs to be validated on an independent cohort.

Cancer-associated hypercalcemia (CAH) is the most frequent metabolic disorder in cancer patients. We retrospectively reviewed the outcome and prognostic factors for patients with CAH being treated with standard intravenous disphosphonates.Two hundred sixty patients were reviewed. Overall survival and prognostic factors were analyzed. Relative risks (RR) for early death (within 60 days) were assessed (Fischer exact test and logistic regression model).Median survival was 64 days (range, 12-1,955+). Multivariate analysis identified the following factors as poor survival predictors: serum corrected calcium2.83 mmol/l [hazard ratio (HR) = HR 2.21], albuminemia35.5 (HR 2.41), squamous cell carcinoma (HR 2.64), bone metastasis (HR 1.44), and liver metastasis (HR 2..22). One hundred twenty-one patients died within 60 days. For those patients, the logistic regression model identified four independent predicting factors for early death: calcemia2.83 mmol/l (RR 5.07), hypoalbuminemia (RR 7.42), liver metastasis (RR 4.34), and squamous cell carcinomas (RR 2.21).Despite intravenous diphosphonate, CAH is still associated with poor outcome. Simple bedside parameters may estimate the risk of early deaths.

Background Advanced malignant solitary fibrous tumors (SFTs) are rare soft-tissue sarcomas with a poor prognosis. Several treatment options have been reported, but with uncertain rates of efficacy. Our aim is to describe the activity of trabectedin in a retrospective, multi-center French series of patients with SFTs. Methods Patients were mainly identified through the French RetrospectYon database and were treated between January 2008 and May 2013. Trabectedin was administered at an initial dose of 1.5 mg/m2, q3 weeks. The best tumor response was assessed according to the Response Evaluation Criteria In Solid Tumors 1.1. The Kaplan–Meier method was used to estimate median progression-free survival (PFS) and overall survival (OS). The growth-modulation index (GMI) was defined as the ratio between the time to progression with trabectedin (TTPn) and the TTP with the immediately prior line of treatment (TTPn-1). Results Eleven patients treated with trabectedin for advanced SFT were identified. Trabectedin had been used as second-line treatment in 8 patients (72.7 %) and as at least third-line therapy in a further 3 (27.3 %). The best RECIST response was a partial response (PR) in one patient (9.1 %) and stable disease (SD) in eight patients (72.7 %). Disease-control rate (DCR = PR + SD) was 81.8 %. After a median follow-up of 29.2 months, the median PFS was 11.6 months (95 % CI = 2.0; 15.2 months) and the median OS was 22.3 months (95 % CI = 9.1 months; not reached). The median GMI was 1.49 (range: 0.11–4.12). Conclusion Trabectedin is a very promising treatment for advanced SFTs. Further investigations are needed.

The aims of our retrospective study were to study first the causes of 245 febrile episodes in cancer patients and then the value of procalcitonin (PCT) and C-reactive protein (CRP) in differentiating infections from paraneoplastic fever.The causes of fever were studied in 245 consecutive cases observed between January and December 2002, and PCT and CRP diagnostic value in 155 cases (114 infections and 41 paraneoplastic fever).The two main causes of fever were infection (121 cases) and paraneoplastic fever (43 cases); 77 infections were microbiologically documented. Cocci gram positive caused 41 out of 77 documented infections. Paraneoplastic fever was more frequent in metastatic disease ( p=6.10(-6)). CRP and PCT serum levels at admission did not differ significantly in the infection group and paraneoplastic fever group (respectively p=0.39 and p=0.14 with Mann-Whitney test). The PCT and CRP levels had poor prognostic value in infection (respectively 0.04 and 0.0003 with Mann-Whitney test).Causes of fever are very numerous in cancer patients (more than 75 different causes in this study). Bacterial infection is the most frequent cause. PCT and CRP failed to discriminate infection, but both had pejorative prognostic value in infected patients.

Background Few targeted therapies (TTs) are registered for sarcoma treatment despite numerous phase II studies and yet there are potential treatment options for patients after standard treatment escape. The French Sarcoma Group - Bone Tumor Study Group (GSF-GETO) created a national registry to evaluate the outcome of patients treated with off-label TTs. Methods Every consecutive sarcoma-patient receiving an off-label TT outside a clinical trial was included. The objective was to describe this patient efficacy and safety data in routine practice. Results From October 2008 to October 2011, 249 patients in 24 centers received 278 treatment lines with TTs. Twenty-five histological subtypes were included: most frequent were leiomyosarcoma (n = 48, receiving sorafenib in 63%, and sunitinib in 27%), GIST (n = 39, receiving sorafenib in 79%), and angiosarcoma (n =18, receiving sorafenib in 78%). The overall response rate to TTs was 15% (95% CI [10,6-20,2]), the disease control rate at 2 months was 59%. The median progression-free survival was 4,1 months (IC 95% [3,2-4,8]). Three complete responses were observed. No toxic death occurred, grade 3 and 4 toxicities were reported in 74 (27%) and 14 patients (5%) respectively. Conclusion Off-label TTs can be used for sarcoma patients in routine practice with an acceptable toxicity profile and efficacy similar to that reported in non-randomized clinical trials. Electronic supplementary material The online version of this article (doi:10.1186/1471-2407-14-870) contains supplementary material, which is available to authorized users.

Purpose Most current dose-seeking phase 1 trials include an expanded cohort at phase-2-recommended dose (P2RD) to better characterize the drug safety or to obtain a better estimate of secondary endpoints. Nevertheless, the sample size of this expanded cohort has generally not been justified. Materials and methods We reviewed 330 phase 1 trials (1998–2008). We estimated the rate of patients experiencing dose-limiting toxicity (DLT) at P2RD. Next, we estimated the probability of observing 1, 2 or 3 DLT in different fictive cohorts (from 8 to 22 patients). Results In the literature, the rate of patients experiencing DLT at P2RD was 367/2433, or 15.0%. We drew a table estimating the probability of observing 1, 2 or 3 DLTs in the different fictive cohorts. For example, in a cohort of 16 patients, the probabilities of observing 1, 2 or 3 DLTs are about 92.6%, 91.3 and 91.1% respectively. Conclusion This simple tool could provide a justification for the sample size of an expanded cohort when DLT remains the metric for dose-seeking.

Until now, there was no validated and reliable tool to estimate life expectancy among patients with cancer-associated hypercalcemia (CAH). This study aimed to validate a prognostic score previously published. We studied a new cohort of 252 patients with CAH. Our prognostic score based on the four poor-prognosis factors (liver metastasis, squamous cell carcinoma, hypoalbuminemia, and calcemia >2.83 mmol) was implemented to this cohort. The accuracy of this score for the prediction of 90-day mortality was estimated with area under the curve of the receiver operator curve (AUC-ROC). Among this validation cohort, patients with score = 0 experienced a median overall survival of 797 days; whereas, patients with score ≥1 (at least one poor-prognosis factor) had median overall survival of 49 days (p

Background Current guidelines recommend anthracycline-based chemotherapy primarily with doxorubicin either as monotherapy or in combination with ifosfamide as the first-line treatment for most advanced STS subtypes. Therapeutic options after failure of doxorubicin and/or ifosfamide are limited. This study aimed to comprehensively review available data on the activity and safety of interventions in second- or later-line treatment of advanced STS. Methods Electronic literature databases (Embase®, MEDLINE®, MEDLINE® In-Process, Cochrane Central Register of Controlled Trials, and Cochrane Database of Systematic Reviews) were searched from 1980 to 01 March 2012 to identify randomised controlled trials (RCTs) and non-randomised studies (both prospective and retrospective) evaluating pharmacological interventions in patients with advanced STS pre-treated with anthracycline- and/or ifosfamide-based therapy. Results The review identified six RCTs (one phase III and five phase II trials) and 94 non-randomised studies. Based on the primary trial endpoints, RCTs demonstrated favourable efficacy for pazopanib over placebo (PFS: 4.6 months vs. 1.6 months), gemcitabine plus dacarbazine over dacarbazine monotherapy (3-month PFS rate: 54.2% vs. 35.2%), and trabectedin 3-weekly schedule over weekly schedule (TTP: 3.7 months vs. 2.3 months. The non-randomised studies demonstrated heterogeneity in efficacy and safety results. Conclusions Across the RCTs, pazopanib over placebo, gemcitabine-dacarbazine over dacarbazine, and trabectedin 3-weekly over weekly regimen clearly demonstrated a PFS advantage in the second- and later-line treatment of advanced STS. With only one phase III trial in this setting, there is a clear need for additional comparative trials to better understand the risk: benefit ratios of available agents and combinations.

International audience; Background: The long term outcome of advanced sarcoma patients treated with trabectedin outside of clinical trials and the utility of maintenance treatment has not been reported.Methods: Between 2003 and 2008, patients with advanced sarcoma failing doxorubicin could be treated within a compassionate use program (ATU, Temporary Use Authorization) of trabectedin in France using the standard 3-weekly regimen. Data from 181 patients (55%) were collected from 11 centres and analyzed.Results: Trabectedin was given in first, second, third or fourth line in metastatic phase in 6%, 37%, 33% and 23% of patients respectively. With a median follow-up of 6 years, median PFS and OS were 3.6 months and 16.1 months respectively. The median number of cycles was 3 (range 1-19). Best response were partial response (PR, n = 18, 10%), stable disease (SD, n = 69, 39%) and progressive disease (PD, n = 83, 46%), non evaluable (NE, n = 9, 5%). Thirty patients (17%) had to be hospitalized for treatment- related side effects. Independent prognostic factors in multivariate analysis (Cox model) were myxoid LPS and line of trabectedin for PFS, and myxoid LPS and retroperitoneal sarcomas for OS. Patients in PR or SD after 6 cycles continuing treatment had a better PFS (median 5.3 vs 10.5 months, p = 0.001) and OS (median 13.9 vs 33.4 months, p = 0.009) as compared to patients who stopped after 6 cycles.Conclusions: In this compassionate use program, trabectedin yielded similar or better PFS and OS than in clinical trials. Maintenance treatment beyond 6 cycles was associated with an improved survival.

Background In most phase I oncology trials, it is often stated that the dose increments follow a “modified-Fibonacci sequence”. This term, however, is vague. Methods To better characterize this sequence, we reviewed 81 phase I trials based on this concept. Results Out of 198 phase I oncology trials, 81 (41%) are based on modified-Fibonacci series. Actual incremental ratios varied in a large range from 0.80 to 2.08. The median of actual increments was about 2.00, 1.50, 1.33, 1.33, 1.33, 1.33, 1.30, 1.35…. The “modified Fibonacci-sequence” gathers heterogeneous variation of the genuine sequence, which does not tend to a constant number at higher dose-levels. Conclusion This confusing term should be avoided.

Malignant solitary fibrous tumors are rare soft-tissue sarcomas. They are considered as low-grade malignancies, but may display metastatic potential in 20% of the cases. In case of metastatic or locally advanced, unresectable disease, standard treatments, like anthracycline-based regimens, are poorly effective. Previous studies suggested that antiangiogenic drugs, such as sorafenib, could be efficient to treat vascular sarcomas and solitary fibrous tumors. Five patients with progressive SFT were included in this phase 2 study, and treated with sorafenib at a dose of 800 mg daily. Two patients out of the five achieved a 9 months disease control with sorafenib, while their disease had progressed within the month preceding their inclusion. Consequently, our data suggest a potential efficacy of sorafenib in SFT, Further investigation is needed to confirm these data.