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Background : Cisplatin-based combination chemotherapy before surgery is the standard of care for muscle-invasive bladder cancer. However, the optimal chemotherapy modalities have not been precisely defined to date. Patients and Methods : In the VESPER trial, patients received after randomization either gemcitabine and cisplatin (GC, 4 cycles) or methotrexate, vinblastine, doxorubicin and cisplatin (dose dense [dd]-MVAC, 6 cycles). Creatinine clearance (CrCl) was calculated before each cycle according to the Cockroft and Gault formula. Definition criteria for local control after neoadjuvant chemotherapy included pathological complete response (ypT0N0), pathological downstaging ( Results : A total of 2,128 cycles of chemotherapy were delivered, including 2,120 (99.6%) with cisplatin. Full doses of cisplatin were given in 1866 (88%) cycles. Twenty-three (4.7%) patients had to stop chemotherapy (12 GC, 11 dd-MVAC) because of renal failure. No difference in CrCl median values was observed between the two regimens during the first four cycles. A mild decrease occurred thereafter in patients treated with two additional cycles of dd-MVAC. A minimum total dose of 270 mg/m2 for cisplatin was mandatory to optimize pathological complete responses. Conclusion : At least 4 cycles of cisplatin-based chemotherapy should be delivered before cystectomy. Increasing the number of cycles beyond 4 cycles does not lead to a clinically significant deterioration in renal function but without obvious gain on local control. MicroAbstractCGC : A deep analysis of data from a randomized trial of perioperative chemotherapy in muscle-invasive bladder cancer shows that a minimum number of 4 cycles is required to optimize the chances of pathological complete response at cystectomy. Increasing the number beyond 4 cycles does not lead to a clinically significant deterioration in renal function without any obvious gain on pathological complete response.

This study looked at whether epidermal growth factor receptor inhibition by the monoclonal antibody panitumumab could increase the efficacy of standard chemotherapy in advanced urothelial cancer. Results were disappointing, with higher toxicity and no improvement in efficacy in the combination arm. Background: Epidermal growth factor receptor (EGFR) overexpression is frequent and associated with poor outcome in urothelial carcinoma. EGFR inhibition could improve the antitumor activity of chemotherapy. Patients and Methods: Patients with advanced, treatment-naive, histologically confirmed advanced urothelial carcinoma and no HRAS or KRAS mutation in the primary tumor received dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin (dd-MVAC) without or with the anti-EGFR monoclonal antibody panitumumab (Pmab). A randomized (1:2) phase II design was used with progression-free survival (PFS) as the primary endpoint. Results: Ninety-seven eligible patients were randomized; 96 patients were evaluable for toxicity and 87 for efficacy. The median PFS were 6.8 months (95% confidence interval [CI], 6.3-9.2) for dd-MVAC and 5.7 months (95% CI, 4.6-6.4 months) for dd-MVAC+Pmab. For both immunohistochemical and molecular definition of basal/squamous-like (BASQ) tumors, no difference was observed in objective response rates or PFS between the two arms in BASQ and non-BASQ tumors. Conclusion: dd-MVAC+Pmab was associated with more serious adverse events and no improvement in efficacy outcomes.

Administration of cytotoxic chemotherapy for patients with metastatic cancer and poor performance status is a daily clinical challenge. Guidelines only help to select a therapeutic regimen but do not offer a clear response whether or not the patients should be treated. We performed a prospective analysis in 139 metastatic patients with performance status > 1 according to the Eastern Cooperative Oncology Group scale. A decision was considered correct if patients treated with a medical anticancer treatment lived over 3 months or alternatively patients not treated had a survival under 3 months. The predominant tumor type was non-small cell lung cancer. Patients were chemotherapy naive in 87 cases (63 %). A new line of medical anticancer treatment was started in 107 cases (77 %). The median survival of the study population was 11 weeks (range, 1-53). 84 patients (60 %) died within 3 months while 55 patients (40 %) lived more than 3 months after decision. Treatment decisions were considered as appropriate in 81 cases (58 %). No patient was considered as undertreated. The analysis by pathology allowed to identify pathologies where decisions were correct in the majority of the cases (renal, urothelial and small cell lung cancers), pathologies where appropriate and inappropriate decisions were balanced (prostate, ovarian and breast cancers) and pathologies where decisions for treatment were excessive (non-small cell lung cancer and unknown primary). This prospective study was conducted as part of the evaluation of professional practices in our department. Administration of a medical anticancer treatment validated with patients with good performance status may be harmful for patients with poor performance status. The findings resulted in recommendations for daily practice in order to help physicians, especially for the "don't go" decisions. Until the identification of new prognostic factors for survival and/or the development of therapies making sensitive currently chemoresistant diseases, the initiation of a medical anticancer treatment outside standard situations should result from a consensual decision team or the inclusion in a clinical trial.

The microtubule inhibitor vinflunine is currently the only cytotoxic drug approved in Europe for the treatment of patients with metastatic transitional cell carcinoma who failed first-line platinum-based chemotherapy. Indeed, the only Phase III trial ever conducted in this setting demonstrated a benefit in progression-free and overall survival for patients receiving vinflunine plus best supportive care compared with best supportive care alone. Recent data from European studies performed in real life confirmed the efficacy of the drug, even in patient populations exhibiting adverse prognostic factors. Side effects were manageable, provided gastrointestinal prophylaxis is performed. The potential role of vinflunine in first-line treatment as maintenance therapy or as a partner in combination chemotherapy for patients unfit for cisplatin is currently being investigated.

Purpose: Response Evaluation Criteria in Solid Tumors (RECIST) may underestimate the efficacy of targeted therapies. In hepatocellular carcinoma (HCC) studies with sunitinib, RECIST-defined response rates are low, although hypodensity on computed tomography (CT) scans occurs more frequently. This exploratory analysis investigated tumor density as a surrogate endpoint of sunitinib activity in a phase II HCC study. Experimental Design: Patients received sunitinib 50 mg/d (4 weeks on/2 weeks off). Tumor size and density were assessed on CT scans by using RECIST and Choi criteria, the latter of which classify a partial response as a 15% or more reduction in tumor density or a 10% or more reduction in tumor size. The overall percentage volume of tumor necrosis was calculated with volumetric reconstruction. Tumor perfusion parameters were assessed by using perfusion CT scans with specific acquisition. Results: Among the 26 evaluable patients, 1 achieved a partial response and 22 had tumor stabilization by RECIST. In analysis of tumor density, 17 of 26 patients (65.4%) were responders by Choi criteria. Volumetric assessment showed major tumor necrosis (≥30% of tumor volume) in 10 of 21 patients (47.6%). Among four patients evaluated, tumor blood flow was reduced by 58.8% and blood volume by 68.4% after 4 weeks of treatment. The median time to progression (TTP) was 6.4 months. Patients with responses by Choi criteria had a significantly longer TTP (7.5 months) compared with nonresponders (4.8 months; HR = 0.33, two-sided P = 0.0182). Conclusions: Tumor density assessment suggested that radiologic endpoints in addition to RECIST may be considered to capture sunitinib activity in HCC. Clin Cancer Res; 17(13); 4504–12. ©2011 AACR.

The MET tyrosine-kinase receptor is implicated in embryonic development and tissue repair. It appears to be a key of tumour development since it drives cell migration and invasion and can induce the conversion from an epithelial to a mesenchymal phenotype. Aberrant signaling of the MET pathways is associated with an aggressive prognosis and a poor outcome. Preliminary clinical results of several MET inhibitors have been encouraging particularly in tumours in which MET was amplified or mutated. MET inhibition could be especially interesting in association with others drugs since activation of MET is a secondary event induced by hypoxia, inflammatory cytokines or HER inhibitors that could exacerbate the malignant properties of transformed cells. Molecular targeted therapies against MET could therefore be effective as a combination approach.

The management of patients with metastatic bladder cancer is mainly based on cytotoxic chemotherapy. The reference molecule is cisplatin. In 2014, first-line regimens include gemcitabine and cisplatin (GC protocol) or methotrexate, vinblastine, and cisplatin doxorubicin (MVAC protocol). When cisplatin is contra-indicated, another platinum Salt, carboplatin, is used in combination with gemcitabine. Vinflunine is the only molecule to have obtained a marketing approval for patients who failed first-line chemotherapy including a platinum salt. The overall prognosis of patients remains dismal, since the median overall survival is 12 to 14 months for patients being treated with cisplatin, whereas it is less than 1 year for patients receiving carboplatin. The identification of new effective drugs is a major challenge for the coming years.

Chemotherapy is currently used in metastatic, castrate-resistant prostate cancer. The key drugs are docetaxel and cabazitaxel since two large randomized trials have shown a survival benefit for docetaxel in first-line and cabazitaxel in second-line as compared to mitoxantrone during the last decade. Docetaxel and cabazitaxel belong to the taxane family and inhibit the polymerization dynamics of microtubules during the cell cycle. These are delivered every 3 weeks in an outpatient setting. The main side effects are neutropenia, alopecia, mucositis, diarrhea and peripheral neuropathy. The prophylactic use of hematopoietic growth factor (G-CSF) in patients older than 70 years reduces the risk of febrile neutropenia. Chemotherapy is primarily used in patients with symptomatic or rapidly progressive disease.

Among neuroendocrine carcinomas of the gut, well-differentiated tumors are highly vascularized, featuring specific characteristics on contrast-enhanced imaging. Well-differentiated neuroendocrine tumors spontaneously harbor hypervascular enhancement, coexisting with areas of necrosis mainly located at the center of tumor lesions. When exposed to vascular endothelial growth factor (VEGFR) inhibitors such as sunitinib, target lesions display few if any variation in tumor size, but rather detectable modifications in tumor density. In several patients treated with targeted therapy, a significant decrease of tumor density at first tumor evaluation can be detected as compared to baseline. Consistently, the two randomized trials leading to approval of sunitinib and everolimus in pancreatic neuroendocrine tumors report objective response rate below 10 %, emphasizing that Response Evaluation Criteria in Solid Tumors (RECIST), that focus only on the largest diameters of target lesions, may be insufficient to capture the full benefit of targeted therapies. Alternative criteria, such as those developed by Choi et al., consider both the size and the density of the tumor as parameters for response evaluation. Choi criteria have been recently proposed as a surrogate endpoint for efficacy and to identify patients that are good responders to VEGFR inhibitors such as sunitinib and sorafenib in advanced hepatocellular carcinoma, another disease highly addicted to angiogenesis. Preliminary data generated from patients included in the sunitinib phase III trial suggest that Choi criteria might also be considered as an alternative to RECIST to evaluate the effects of sunitinib in patients with advanced well-differentiated neuroendocrine tumors.

The MET tyrosine-kinase receptor is implicated in embryonic development and tissue repair. It appears to be a key of tumour development since it drives cell migration and invasion and can induce the conversion from an epithelial to a mesenchymal phenotype. Aberrant signaling of the MET pathways is associated with an aggressive prognosis and a poor outcome. Preliminary clinical results of several MET inhibitors have been encouraging particularly in tumours in which MET was amplified or mutated. MET inhibition could be especially interesting in association with others drugs since activation of MET is a secondary event induced by hypoxia, inflammatory cytokines or HER inhibitors that could exacerbate the malignant properties of transformed cells. Molecular targeted therapies against MET could therefore be effective as a combination approach.

La validation du sorafenib dans le carcinome hepatocellulaire (CHC) avance a permis un progres majeur dans la prise en charge des patients atteints de cette maladie et a entraine un deferlement d'investigations portant sur des agents cibles dans cette pathologie. Un concept important est que la tolerance et l'efficacite de cet agent reposent sur une selection optimale des patients. Cependant, plusieurs questions pertinentes restent non resolues concernant l'utilisation du sorafenib en routine clinique. En effet, si le sorafenib a permis une amelioration significative de la survie globale des patients atteints d'un CHC avance sur cirrhose Child A comparativement au placebo, ceci contraste avec de faibles taux de reponse obtenus par cette molecule selon les criteres RECIST. Ainsi, de nouveaux parametres integrant des modifications de densite intratumorale pourraient etre pris en compte en plus des criteres dimensionnels pour juger de l'efficacite objective de cette drogue. Actuellement, les recherches en cours doivent definir la place des antiangiogeniques en association avec les autres approches therapeutiques et identifier des biomarqueurs fiables predictifs de reponse.

Introduction: c-MET pathway is often deregulated in human cancer progression including hepatocellular carcinoma (HCC) and cholangiocarcinoma (CK). Moreover, high level of HGF, and c-MET have been correlated with poor prognosis, aggressiveness and metastasis in HCC and CK (Kaposi-Novak et al., 2006; Miyamoto et al., 2011). We aimed to characterize the expression pattern of MET in HCC/CK specimens, to evaluate the effects of MET inhibition on HCC/CK cell properties, and to identify potential biomarkers of sensitivity and resistance to SU11274. Methods: SU11274 is a specific inhibitor of overexpressed and activated MET. MET expression was assessed on human paraffin-embedded liver section by IHC. Antiproliferative effects of SU11274 and an EGFR/HER2 inhibitor (lapatinib) were evaluated in human HCC (Sk-Hep1 and its sunitinib-tolerant counterpart SK-Suni) and CK (Mz-ch-A1, Mz-ch-A2, and SK-CH) cell lines using MTT assay. mRNA expression and protein levels were assessed by qRT-PCR and Western blot, respectively. Cell motility was investigated by wound-healing and matrigel invasion assays. Results: MET expression level was higher in HCC and CK tumor samples than adjacent normal liver tissue. Characterization of cell lines showed that MET-protein and -mRNA expression were detectable in all cell lines, Mz-ch-A1, Mz-ch-A2 and SK-HEP1 expressing higher MET levels (high-MET) compared to the other cell lines (low-MET). HGF-induced MET activation was associated with differential pattern of p-METTyr1234/35, p-GAB1, p-ERK1/2, and p-AKTser473 between high-MET and low-MET cell lines. We showed that SU11274 inhibits HGF-induced downstream signaling in all HCC and CK cell lines at 0.5-2μM. However, antiproliferative effects were only observed in the high-MET cell lines; inhibition rates were 83%, 53% and 48% in Mz-chA-1, Mz-chA-2 and SK-Hep1, respectively. Interestingly, SU11274 also potently decreased HGF-dependent cell motility (75-90% inhibition) in high-MET cells but not in low-MET cells. Since cells with low-MET showed high EGFR expression, we tested the EGFR/HER2 inhibitor lapatinib on cell proliferation. In contrast to SU11274, lapatinib inhibited proliferation in low-MET/high-EGFR cells (64% and 60% inhibition rate in SK-CH and SK-Suni, respectively) but not in high-MET/low-EGFR cell lines. Complementary results with a sorafenib-tolerant cell line, SK-sora and two intra-hepatic cholangiocarcinoma cell lines will be added. Conclusion: In HCC and CK cells, inhibition of MET-signaling by SU11274 results in decreased cell proliferation, motility and invasion restricted to high-MET/low-EGFR cell lines. Thus, high-MET/low EGFR HCC and CK might be the candidate tumor types to evaluate novel MET inhibitors, whereas low-MET/high-EGFR HCC and CK may be preferentially tested for EGFR pathway inhibition. Citation Format: Annemilai Tijeras-Raballand, Camille Serrate, Maria E. Riveiro, Maria Serova, Cindy Neuzillet, Matthieu Martinet, Valérie Paradis, Ivan Bièche, Eric Raymond, Armand de Gramont, Sandrine Faivre. MET inhibition using SU11274 impairs cellular activities in hepatocellular and Cholangiocarcinomas with high levels of MET and low levels of EGFR expressions. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2178. doi:10.1158/1538-7445.AM2013-2178

Background: Hepatocellular carcinomas (HCC) and cholangiocarcinomas (CK) are the most common primary tumors of the liver and are recognized among the most difficult tumors to treat. Signaling mediated by hepatocyte growth factor (HGF)/MET promotes multiple biological activities, including cell proliferation, motility, invasion, angiogenesis, and morphogenesis. Advanced HCC and CK are often displaying aberrant MET signaling and MET overexpression was observed in many tumors resistant to tyrosine kinase inhibitors (TKI). The aim of present study was to evaluate the effects of MET inhibition by SU11274 on HCC and CK cell proliferation and invasion. Materials and Methods: SU11274 is a pyrrole indolinone that specifically inhibits overexpressed and oncogenic MET activation at nanomolar concentrations. MET expression was assessed on human paraffin-embedded liver section by immunohistochemistry. Antiproliferative effects of SU11274, were evaluated in human HCC (SK-Hep1 and its sunitinib-tolerant counterpart SK-Suni) and CK (Mz-chA-1, Mz-chA-2, SK-ch) cell lines using a MTT assay. mRNA expression and protein levels were respectively assessed by qRT-PCR and Western blot. Cell mobility was investigated by wound-healing and matrigel invasion assays. Results: Higher MET protein expression was observed in human HCC and CK samples respect to normal tissues. MET-protein and -mRNA expression were detectable in all tested cell lines, Mz-ChA-1 and Mz-ChA-2 expressing higher MET levels. HGF-induced MET activation was associated with increase of p-METTyr1234/35, p-GAB1, p-ERK1/2, and p-AKTser473 in SK-CH, Mz-chA-2, SK-Hep1 and SK-Suni cells. We show that SU11274 inhibited HGF-induced downstream signaling by reducing p-METTyr1234/35, p-GAB1, p-AKT473 and p-ERK1/2 in HCC and CK cells at concentrations ranging from 0.5 to 2μM. However, antiproliferative effects were only observed for concentration above 2 μM (2,5 and 5 μM), In SK-Suni cells that are tolerant to high dose of sunitinib, proliferation was not inhibited even at the higher SU11274 dose (5μM). Interestingly, SU11274 potently decreased the spontaneous and HGF-dependent cell motility and invasion of Mz-chA-2 cells. Conclusion: In HCC and CK cells, inhibition of MET-signaling by SU11274 resulted in inhibition of cell proliferation, motility and invasion. HCC and CK may be interesting tumor types to evaluate novel MET inhibitors either as single agents and/or in combination with other targeted therapies. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A188.