Morbidity of Staging Inframesenteric Paraaortic Lymphadenectomy in Locally Advanced Cervical Cancer Compared With Infrarenal Lymphadenectomy

International audienceObjective: Extended-field chemoradiation is typically used for the management of patients with locally advanced cervical cancer. Given the low rate of skipped metastases above the inferior mesenteric artery, ilioinframesenteric dissection seems to be an acceptable pattern of paraaortic lymph node dissection (LND). Our objective is to compare the surgical morbidity of inframesenteric LND (IM-LND) with infrarenal LND (IR-LND).Methods: In our center, all of the patients with locally advanced cervical cancer and negative magnetic resonance imaging and positron emission tomography-computed tomography imaging at the paraaortic level were offered laparoscopic staging including a diagnostic laparoscopy followed, if negative, by an extraperitoneal paraaortic lymphadenectomy. From January 2011 to September 2015, we included patients who had paraaortic LND from both common iliac bifurcations and divided them into 2 groups according to dissection pattern: to the inferior mesenteric artery (IM-LND) level or to the left renal vein (IR-LND) level. The perioperative and postoperative data were retrospectively recorded.Results: A total of 119 women were included in our study: 56 in the IM-LND group and 63 in the IR-LND group. There was no difference in the patients' characteristics between groups. Regarding the surgical procedure, the operating time was shorter in the IM-LND group than the IR-LND group, 174 ± 50 minutes versus 209 ± 61 minutes (P = 0.001), respectively. There was no significant difference in intra- and postoperative complications, overall survival, or progression-free survival.Conclusions: In our series, exclusive IM-LND surgery is faster than IR-LND and results in similar morbidity and survival rates. These results confirm the feasibility and the applicability of IM-LND to simplify the surgical procedure without impacting survival. More patients should be included in the study to demonstrate the lower rate of morbidity

Pretherapeutic staging of locally advanced cervical cancer: Inframesenteric paraaortic lymphadenectomy accuracy to detect paraaortic metastases in comparison with infrarenal paraaortic lymphadenectomy

International audienceBackground: Extended-field chemoradiation therapy is usually performed in patients with locally advanced cervical cancer (LACC) and paraaortic (PA) node metastases. Considering the very low rate of skip metastases above inferior mesenteric artery, ilio-inframesenteric paraaortic lymph node dissection (IM-PALND) seems to be an adequate pattern of PALND. Our objective was to assess the accuracy of this management to determine PA nodal status in comparison with infrarenal paraaortic lymphadenectomy (IR-PALND) in case of squamous or glandular cervical cancer.Methods: All patients with LACC and negative MRI and PET/CT imaging at paraaortic level had laparoscopic staging (followed, if negative, by extraperitoneal paraaortic lymphadenectomy). From January 2011 to September 2015, patients who had IM-PALND were included and were compared to a previous historical series of IR-PALND patients. The two groups differed only at the upper level of dissection. Characteristics of nodal involvement at paraaortic level depending on level of dissection, PET/CT imaging and histology were studied.Results: 119 women were included in our study, with 56 patients in the IM-PALND group and 63 in the IR-PALND group. In the IM-PALND group, fewer nodes were resected (p<0.001). There was no difference between the two groups regarding nodal status at paraaortic level (p=0.77). Patterns of nodal involvement were similar whichever the histological subtype of cervical cancer (squamous or glandular).Conclusion: IM-PALND appears to be equally effective to assess paraaortic nodal involvement in LACC for both histological subtypes - glandular and squamous carcinomas - and to select patients for extended-field chemoradiation therapy

Circulating vascular endothelial growth factor (VEGF) as predictive factor of progression-free survival in patients with advanced chordoma receiving sorafenib: an analysis from a phase II trial of the french sarcoma group (GSF/GETO)

International audienceBackground: Patients with advanced chordoma are often treated with tyrosine kinase inhibitors without any predictive factor to guide decision. We report herein an ancillary analysis of the the Angionext phase II trial (NCT 00874874). Results: From May 2011 to January 2014, 26 were sampled. The 9-month PFS rate was 72.9% (95%-CI: 45.9-87.9). During sorafenib treatment, a significant increase in PlGF (18.4 vs 43.8 pg/mL, p1.04 ng/mL (HR=12.5, 95%-CI: 1.37-114, p=0.025) and VEGF at D7 >1.36 ng/mL (HR=10.7, 95%-CI: 1.16-98, p= 0.037) were associated with shorter PFS. The 9-month PFS rate was 92.3% (95%-CI: 56.6-98.9) when VEGF at D1 was 1.04 ng/mL. Patients and Methods: Chordoma patients were treated with sorafenib 800 mg/day for 9 months, unless earlier occurrence of progression or toxicities. Six biomarkers (sE-Selectin, VEGF, VEGF-C, placental growth factor (PlGF), Thrombospondin, Stem Cell Factor (SCF)) were measured at baseline (day 1: D1) and day 7 (D7). Conclusion: High levels of VEGF was associated with poor outcome

Study protocol of regosarc trial: activity and safety of regorafenib in advanced soft tissue sarcoma: a multinational, randomized, placebo-controlled, phase ii trial

International audienceBACKGROUND: Angiogenesis, among other signaling pathways, plays a key-role in sarcoma biology. Regorafenib (RE) has recently been shown to be effective in imatinib and sunitinib-refractory GIST in a phase III trial.METHODS: We are conducting an international trial (France, Austria and Germany) consisting in 4 parallel double-blind placebo-controlled randomized (1/1) phase II trials to assess the activity and safety of RE in doxorubicin-refractory STS (ClinicalTrials.gov: NCT01900743). Each phase II trial is dedicated to one of the 4 following histological subgroups: liposarcoma, leiomyosarcoma, synovial sarcoma and other sarcoma. Within each randomized trial the following stratification factors will be applied: countries and prior exposure to pazopanib. Key-eligibility criteria are: measurable disease, age ≥18, not > 3 previous systemic treatment lines for metastatic disease, metastatic disease not amenable to surgical resection. The primary endpoint is progression-free survival (PFS) according to central radiological review. Secondary endpoints are: Toxicity (NCI-CTC AE V4.0); time to progression; Growth modulation index in pts receiving RE after randomization; 3 and 6 months PFS-Rates, best response rate and overall survival. Each phase II trial will be separately analyzed. In 3 trials, statistical assumptions are: PFS0 = 1.6 & PFS1 = 4.6 months; 1-sided α = 0.1; β = 0.05 with a total sample size of 192 pts. To take into account the rarity of synovial sarcoma, the statistical assumptions are: PFS0 = 1.6 & PFS1 = 4.6 months; 1-sided α = 0.1; β = 0.2 Tumor assessment is done monthly during the 4 first months, and every 3 months thereafter. After central radiological confirmation of tumor progression, an optional open-label option is offered to eligible patients.CONCLUSIONS: The design of this trial allows an assessment of regorafenib activity over placebo in four sarcoma strata and might provide evidence for launching a phase III trial. This study includes both integrative and exploratory translational research program. The study is enrolling since June 2013 (TRIAL REGISTRATION NUMBER: EudraCT N°: 2012-005743-24, on the 15(th) February 2012)

Prognostic and predictive factors for angiosarcoma patients receiving paclitaxel once weekly plus or minus bevacizumab: an ancillary study derived from a randomized clinical trial

Abstract Background We report here a correlation analysis conducted along with a phase II trial assessing bevacizumab in combination with weekly paclitaxel. Methods Circulating pro/anti-angiogenic factors were assessed on day 1 (D1) and day 8 (D8). The prognostic value for progression-free survival (PFS) was evaluated using a Cox model with biomarkers as continuous variables. Results Among the 51 patients enrolled and treated in this trial, biomarker analysis was performed for 42: 18 in Arm A (single-agent) and 24 in Arm B (combination). With a median follow-up of 46 months, PFS was 5.5 versus 5.7 months, respectively (p = 0.75). According to univariate analysis, factors associated with a poor PFS were as follows: visceral angiosarcoma, de novo angiosarcoma, and high PlGF and low VEGF-C baseline values. In multivariate analysis, de novo angiosarcoma (HR = 2.5; p = 0.024) and baseline VEGF-C value (HR = 0.7; p = 0.003) were significant prognostic factors. We observed a significant increase in circulating PlGF (< 0.001) and a decrease in VEGF (< 0.001) during bevacizumab treatment. An increase in FGF was associated with a poor outcome. Conclusions De novo angiosarcoma and a low baseline level of VEGF-C were found to be associated with a poor prognosis. Addition of bevacizumab induces major changes in circulating biomarkers (VEGF and PlGF) in a short timeframe without impacting PFS. Trial registration Retrospectively registered on EudraCT N° 2009–017020-59 and NCT01303497 (February 24, 2011)

Pharmacokinetics of oral vinorelbine in French children with recurrent or progressive primary low‐grade glioma

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Paclitaxel Given Once Per Week With or Without Bevacizumab in Patients With Advanced Angiosarcoma: A Randomized Phase II Trial

International audiencePurpose The aim of this randomized, phase II trial was to explore the activity and safety of adding bevacizumab to paclitaxel once per week in treatment of angiosarcomas (AS). Methods Patients were treated with paclitaxel alone (90 mg/m 2 per week for six cycles of 28 days each; arm A) or with paclitaxel combined with bevacizumab (10 mg/kg once every 2 weeks; arm B). In the combination treatment arm, bevacizumab was administered after the six cycles of chemotherapy as maintenance therapy (15 mg/kg once every 3 weeks) until intolerance or progression occurred. Stratification factors were superficial versus visceral AS and de novo versus radiation-induced AS. The primary end point was the 6-month progression-free survival (PFS) rate, which was based on RECIST, version 1.1. Statistical assumptions were P0 = 20%, P1 = 40%, a = 10%, and b = 20%. P0 was the PFS rate at 6 months defining inactive drug, and P1 was the PFS rate at 6 months defining promising drug. Results A total of 52 patients were enrolled, and 50 were randomly assigned in 14 centers. The most common primary sites were the breast (49%) and skin (12%). There were 17 (34%) visceral and 24 (49%) radiation-induced AS. The performance status was 0 in 24 patients (49%) and 1 in the remaining 25 patients (51%). The median follow-up time was 14.5 months. Both treatment regimens were considered active, with 6-month PFS rates of 54% (14 of 26) in arm A and 57% (14 of 24) in arm B. The median overall survival rates were 19.5 months in arm A and 15.9 months in arm B. Toxicity was higher with the combination arm and included one fatal drug-related toxicity (intestinal occlusion). Conclusion The primary objective was met in both treatment arms. However, the present data do not support additional clinical investigation of combined paclitaxel/bevacizumab for the treatment of advanced AS

Impact of pharmacogenetics on variability in exposure to oral vinorelbine among pediatric patients: a model‐based population pharmacokinetic analysis

International audienceBetter understanding of pharmacokinetics of oral vinorelbine (VNR) in children would help predicting drug exposure and, beyond, clinical outcome. Here, we have characterized the population pharmacokinetics of oral VNR and studied the factors likely to explain the variability observed in VNR exposure among young patients

Phase I Study of a Combination of Fluvastatin and Celecoxib in Children with Relapsing/Refractory Low-Grade or High-Grade Glioma (FLUVABREX)

Preclinical data support the activity of celecoxib and fluvastatin in high-grade (HGG) and low-grade gliomas (LGG). A phase I trial (NCT02115074) was designed to evaluate the safety of this combination in children with refractory/relapsed HGG and LGG using four dose levels of fluvastatin with a fixed daily dose of celecoxib. A Continual Reassessment Method was used for fluvastatin dose escalation. Dose-limiting toxicities (DLT) were determined on the first treatment cycle. Twenty patients were included. Ten LGG and ten HGG patients received a median of 3.5 treatment cycles. Two DLTs were reported: one grade 3 maculopapular rash (4 mg/kg dose level) and one grade 4 increase of Creatine Phospho-Kinase (6 mg/kg dose level). We identified the dose of 6 mg/kg/day as the recommended phase II dose (RP2D) of fluvastatin with celecoxib. Four patients with LGG continued treatment beyond 12 cycles because of stable disease, including one patient who received 23 treatment cycles. In children with refractory/relapsed glioma, the RP2D of fluvastatin with celecoxib is 6 mg/kg/day. The long-term stable diseases observed in LGG suggest a possible role of the combination in a maintenance setting, given its good tolerance and low cost for children living in low- and middle-income countries