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Introduction et but de l’etude Environ 30 % des 3,5 millions de nouveaux cas de cancer recenses en Europe en 2012 concernaient les personnes âgees de plus de 75 ans. Or, le cancer et le vieillissement sont deux situations s’accompagnant frequemment d’une denutrition, facteur de mauvais pronostic. Les modifications du metabolisme energetique liees au vieillissement pourraient majorer le risque de denutrition liee au cancer. Une etude menee au sein du service de cancerologie de notre hopital a montre une augmentation de la depense energetique de repos chez environ 50 % des patients atteints de cancer [1] . Les donnees concernant la reponse a l’agression chez la personne âgee sont rares, voire inexistantes dans le cas du cancer. L’objectif principal de notre travail etait d’etudier l’influence de l’âge sur la depense energetique de repos du patient atteint de cancer et les objectifs secondaires de mettre en evidence des determinants hormonaux et inflammatoires influencant cette depense energetique. Materiel et methodes Nous avons conduit une etude transversale cas/temoins dans deux groupes de patients âges respectivement de moins et de plus de 75 ans, tous atteints d’un cancer broncho-pulmonaire. Les patients ont ete soumis a une determination de la depense energetique de repos par calorimetrie indirecte et de la composition corporelle par extrapolation a partir du scanner en L3. Un bilan biologique hormonal (TSH, insuline, IGF1), inflammatoire (CRP, orosomucoide, TNFα, IL-1β, IL-4, IL-6, IL-10), nutritionnel (albumine, transthyretine) et metabolique (glucose, lactate, acides amines plasmatiques) a egalement ete realise. Analyse statistique : verification de la normalite (Shapiro-Wilk) et tests parametriques (Student, Pearson) ou non (Mann-Whitney, Spearman) ; seuil de significativite : p Resultats Entre janvier et juin 2016, nous avons pu inclure 20 patients âges de moins de 75 ans et sept patients âges de plus de 75 ans. La depense energetique de repos tendait a etre plus faible dans le groupe des patients les plus âges (1370 ± 424 kcal/j contre 1589 ± 328 kcal/j respectivement ; p = 0,16) mais cette difference disparaissait apres correction par la masse maigre (37,9 ± 10,1 kcal/j/kg contre 38,2 ± 6,1 kcal/j/kg ; p = 0,921). En ce qui concerne les objectifs secondaires, nous n’avons pas mis en evidence de correlation entre les parametres etudies et la depense energetique de repos en dehors d’une correlation negative entre la depense energetique de repos rapportee a la masse maigre et la concentration plasmatique en tryptophane (r = –0,509 ; p Conclusion Avec les reserves imposees par le manque de puissance statistique de notre etude, il semble que la variation de depense energetique de repos accompagnant le vieillissement chez le patient atteint d’un cancer bronchopulmonaire soit liee a celle de la composition corporelle associee au vieillissement. La relation negative existant entre tryptophane plasmatique et depense energetique de repos pourrait etre liee au role de la depletion en tryptophane dans la tolerance immunitaire au cancer.

Background Intra-patient variability in sorafenib pharmacokinetics has been poorly investigated to date. We hypothesized that sorafenib clearance could decrease over time, as seen with imatinib. Patients and methods Sorafenib plasma concentrations were determined by liquid chromatography, every 2 weeks, in consecutive hepatocellular carcinoma patients treated with sorafenib. Sorafenib dose-normalized area under the concentration-time curve (AUC) was determined from a population pharmacokinetics model, and its kinetics was analyzed in order to identify possible alterations of exposure over time. Results Fifteen hepatocellular carcinoma patients with Child-Pugh A cirrhosis, in whom sorafenib dosing remained unchanged from initiation of treatment to disease progression, were eligible for this analysis. Sorafenib AUC significantly decreased over time: the median AUC during the third month of treatment was lower than that observed after one month of treatment (43.0 vs. 60.3 mg/L.h, p = 0.008). Most importantly, median sorafenib AUC at the time of progression was almost two-fold lower than that observed after one month of therapy (33.2 vs. 60.3 mg/L.h, p = 0.007). These findings suggest an induction of expression of efflux transporters in the gut wall, or an induction of sorafenib metabolism. Conclusions In patients with progressive disease in whom exposure markedly decreased from baseline, sorafenib dose escalation could be considered, aiming to restore an adequate drug exposure and possibly anti-tumor activity.

Background: BIBF 1120 is an oral, potent, tyrosine kinase inhibitor that simultaneously targets vascular endothelial growth factor receptors 1–3, platelet-derived growth factor receptors α and β, and fibroblast growth factor receptors 1–3, as well as FLT3 and Src. Currently, the molecule is in phase III development for second-line non-small cell lung cancer and first-line ovarian cancer patients. Methods: This phase I dose-escalation study assessed the safety and maximum tolerated dose of continuous daily treatment with BIBF 1120 plus standard-dose docetaxel (75 mg m−2, every 3 weeks) and prednisone (5 mg BID) in patients with metastatic, chemo-naive, hormone-refractory prostate cancer (HRPC). Secondary objectives were characterisation of BIBF 1120 and docetaxel pharmacokinetics (PK), and preliminary antitumour activity. Results: Patients received BIBF 1120 100 mg BID (n=3), 150 mg BID (n=3), 200 mg BID (n=3), and 250 mg BID (n=12). The most frequent drug-related adverse events were diarrhoea (71.4%), asthenia (61.9%), nausea (28.6%), vomiting (28.6%), and alopecia (23.8%). The maximum tolerated dose was 250 mg BID of BIBF 1120. Overall, reversible grade 3/4 liver enzyme elevations occurred in six of twelve patients at this dose level. Among 19 assessable patients, 13 (68.4%) showed a ⩾50% reduction in prostate serum antigen levels from baseline and among 6 evaluable patients with measurable lesions 1 patient experienced a partial response by Response Evaluation Criteria In Solid Tumours criteria. Pharmacokinetic analysis showed no interactions between BIBF 1120 and docetaxel/prednisone. Conclusion: Based on the overall safety profile, 200 mg BID was the recommended dose for the combination of BIBF 1120 with the standard dose of 75 mg m−2 of docetaxel and prednisone that might be further investigated in HRPC patients. This combination was well tolerated, with preliminary signs of efficacy and no indication of PK interaction between BIBF 1120 and docetaxel.

Gefitinib and erlotinib are two oral tyrosine kinase inhibitors (TKI) approved for the treatment of advanced non-small cell lung cancer (NSCLC). Published methods for simultaneous analysis of erlotinib and gefitinib in plasma are exclusively based on mass spectrometry. The purpose of this study was to develop a simple and sensitive HPLC-UV method to simultaneously quantify these two TKI in plasma. Following liquid-liquid extraction, gefitinib, erlotinib and sorafenib (internal standard), were separated with gradient elution (on a C8+ Satisfaction(®) using a mobile phase of acetonitrile/20mM ammonium acetate pH 4.5). Samples were eluted at a flow rate of 0.4 ml/min throughout the 15-min run. Dual UV wavelength mode was used, with gefitinib and erlotinib monitored at 331 nm, and sorafenib at 249 nm. The calibration was linear in the range 20-1000 ng/ml and 80-4000 ng/ml for gefitinib and erlotinib, respectively. Inter- and intra-day imprecision were less than 7.2% and 7.6% for gefitinib and erlotinib, respectively. This analytical method was successfully applied to assess the steady state plasma exposure to these TKI in NSCLC patients. This simple, sensitive, accurate and cost-effective method can be used in routine clinical practice to monitor gefitinib or erlotinib concentrations in plasma from NSCLC patients.

Sorafenib, an oral multitargeted tyrosine kinase inhibitor, is highly bound to plasma proteins (99.5%). Little is known about the influence of variations in sorafenib protein binding on its disposition. The aims of this study were to characterize in vitro sorafenib binding properties to albumin using the quenching fluorescence method and investigate the influence of albuminemia and bilirubinemia on sorafenib disposition in 54 adult cancer patients.In vitro estimate of sorafenib dissociation constant (Kd) for albumin was 0.22 μM [CI95 0.20-0.23]. In physiological conditions, sorafenib unbound fraction would increase 1.7-fold as albuminemia decreased from 45 g/L (680 μM) to 30 g/L (453 μM). In presence of bilirubin, apparent Kd of sorafenib was ~1.5-fold greater for bilirubin/albumin molar ratio of 1:4. In clinical settings, median sorafenib clearance (CL) was 1.42 L/h (0.75-2.13 L/h). In univariate analysis, sex, body mass index, and albuminemia were associated with CL (p = 0.04, 0.048, and 0.008, respectively). In multivariate analysis, albuminemia (p = 0.0036) was the single parameter independently associated with CL.These findings highlight the major influence of albuminemia on sorafenib clearance and its disposition in cancer patients.

Use of complementary and alternative medicine (CAM) has been reported to be more and more frequent among cancer patients in USA. The aim of this study was to analyze among French cancer patients the prevalence of CAM use, focusing on antioxidants (AO) that could interfere with antitumor agents. Seventy-nine patients, treated by antitumor chemotherapy in oncology day care unit, participated to an interview (medium age = 60 years old). CAM use was reported by 42% of patients: mostly AO (24%) (selenium, green tea and vitamins ACE, more specifically), but also relaxation, acupuncture, hypnosis (19%) and homeopathy (15%). Among patients using CAM, 66% of them indicated that their physicians were not aware of this use and 47% of them thought that CAM use was safe. Nevertheless, for seven patients who have taken AO, previous in vitro and preclinical studies suggested interactions with antitumor chemotherapy. Therefore, CAM use and, more specifically, AO use is common among cancer patients treated by antitumor chemotherapy in France. Nevertheless, AO could generate interactions with conventional treatment. Clinical studies are warranted to evaluate these interactions, and adequate communication with patients is needed.

Background Bevacizumab is a humanized IgG1 monoclonal antibody against VEGF. Because infusion-related hypersensitivity reactions (HSRs) are a concern with monoclonal antibodies, initial phase 1 trials used a 90-, 60-, then 30-min initial infusion sequence. We evaluated the impact of a shortened bevacizumab infusion (10 min) on toxicity in nonsmall cell lung cancer (NSCLC) patients. Patients and methods Consecutive patients with stage IV NSCLC eligible for anti-VEGF therapy received a platinum doublet plus bevacizumab 7.5 mg/kg infused over 10 min, every 3 weeks, in the outpatient setting. Blood pressure was monitored at home twice daily, and other toxicities (HSRs and proteinuria) were monitored at each treatment administration. Results Bevacizumab was given as a 10 min infusion in 55 patients (group A), and using the standard sequence in another 36 patients (group B). Hypertension (grade ≥2) was observed in 18/55 (32.7%) patients in group A and 13/36 (38.9%) patients in group B (p = 0.77). Similarly, no difference was seen regarding the incidence of grade ≥2 proteinuria (12.7% vs. 19.4%, p = 0.39), arterial thrombo-embolic events (0 in each group) or venous thromboembolic events (1.8% vs. 8.3%, p = 0.29). Conclusions Our data suggest that bevacizumab 7.5 mg/kg can be safely infused over 10 min in unselected NSCLC patients despite their cardio-vascular and respiratory comorbidities, saving time for both patients and caregivers.

Oncologists often overestimate survival of advanced cancer patients. This study aimed to validate a score for survival prediction in terminally ill cancer patients.Between 2004 and 2008, a prospective study was performed in 500 consecutive advanced cancer patients referred to a palliative care unit. Evaluation at admission included physical examination and routine blood tests. On a randomly selected training set, independent factors assessable at inclusion predicting 2-week survival by a multiple logistic regression were assigned integer-rounded weights to develop a risk index score, which was tested on a validation set.On the training set (334 patients), predictive factors were: urea12 mmol/L (weight = 5, odds ratio (OR) = 3.72, 95% confidence interval (95%CI) = [1.59; 8.71], p = 0.002), Karnofsky Performance Status ≤30% (weight = 4, OR = 3.28, 95%CI = [1.80; 6.01], p 0.001), leucocytes15 g/L (weight = 3, OR = 2.49, 95%CI = [1.18; 5.25], p = 0.017), transthyretin ≤0.05 g/L (weight = 3, OR = 2.42, 95%CI = [1.16; 5.04], p = 0.019) and male gender (weight = 2, OR = 2.25, 95%CI = [1.28; 3.97], p = 0.005). On the validation set (166 patients), the Cochin Risk Index Score (CRIS) ≥ 7 identified high-risk patients, with a positive predictive value of 78%.We validated the CRIS for survival prediction in terminally ill cancer patients.

Introduction Bien que moins frequents qu’avec les anti-CTLA4, des effets secondaires graves peuvent survenir sous anti-PD1. Ces traitements etant prescrits en mg/kg, les patients ayant une composition corporelle anormale et un volume de distribution reduit pourraient etre surexposes. Cette etude a pour but d’evaluer si la sarcopenie associee a un indice de masse corporelle (IMC) eleve est un facteur de risque de toxicite sous anti-PD1. Materiel et methodes Les dossiers des patients du service de dermatologie de l’hopital Cochin ayant recu des anti-PD1 pour un melanome ont ete revus retrospectivement. Une toxicite severe precoce etait definie comme toute toxicite survenant dans les 3 premiers mois de traitement faisant interrompre l’anti-PD1 de maniere definitive ou temporaire. Pour chaque patient etaient notes l’âge, le sexe, le type de melanome, le statut BRAF, les traitements anterieurs, l’IMC et l’index de muscle squelettique (calcule avec la masse musculaire mesuree en L3 sur le scanner de debut du traitement). Les patients ayant un index inferieur a la mediane de la population etudiee de meme sexe etaient definis comme sarcopeniques. Resultats Sur les 81 patients traites par anti-PD1 entre aout 2014 et fevrier 2016, 71 ont ete inclus (33 femmes, âge median 65 ans [22–91 ans]). Soixante-huit pour cent des patients ont recu du pembrolizumab (2 mg/kg/3 semaines), 32 % du nivolumab (3 mg/kg/2 semaines). Trente-six pour cent etaient naifs de traitement. Trente-neuf pour cent des melanomes etaient des SSM et 30 % etaient mutes BRAF V600. Quarante-deux (59 %) des patients avaient un IMC > 25 kg/m 2 et 10 (14 %) combinaient une sarcopenie et un IMC > 25. Onze patients (15 %) ont presente une toxicite severe precoce : 1 pneumonie, 1 nephrite, 1 polymyosite, 2 hepatites, 1 uveite, 3 cytopenies et 2 polyarthrites. Tous les patients ont ete traites par corticotherapie. Il n’y a pas eu de deces toxique. Soixante-douze pour cent de ces toxicites sont survenues apres la 1 re ou la 2 e perfusion. L’anti-PD1 a ete definitivement arrete chez 9 patients et repris chez 2. Ces effets secondaires graves sont survenus plus souvent chez les sarcopeniques avec un IMC > 25 kg/m 2 (40 % [ n = 4]) que chez les autres patients (11 % [ n = 7]), p = 0,04. Les patients ayant presente une toxicite severe avaient un taux de reponse objective de 40 % soit comparable au reste de la population dans cette etude. La sarcopenie n’etait pas predictive d’une meilleure reponse aux anti-PD1. Discussion La sarcopenie est un facteur de risque de toxicite demontre pour de nombreux anticancereux. La survenue precoce des effets secondaires dans cette etude renforce l’hypothese d’une surexposition. Une etude prospective avec des dosages sanguins des anti-PD1 est en cours pour confirmer ces resultats. Conclusion Les patients sarcopeniques avec un IMC > 25 kg/m 2 ont presente, dans cette etude, significativement plus de toxicite severe precoce sous anti-PD1, suggerant une surexposition. Une attention particuliere doit leur etre portee.

Purpose The only drug that improves survival in hepatocellular carcinoma is sorafenib. FOLFOX-4 regimen is safe and widely used in patients with colorectal cancer, yielding interesting results with little toxicity. We conducted a retrospective study to evaluate the safety and the effectiveness of FOLFOX-4 in cirrhotic or liver transplanted patients with hepatocellular carcinoma ineligible for sorafenib. Methods Thirty seven patients were enrolled in the study. The medical record of either cirrhotic patients or liver transplanted patients with advanced hepatocellular carcinoma receiving FOLFOX-4 regimen between November 1999 and March 2006 were retrospectively analyzed. Patients received oxaliplatin 85 mg/m2 as a 2-hour infusion on day one, and leucovorin 200 mg/m2 as a 2-hour infusion followed by bolus 5-fluorouracil 400 mg/m2 and a 48-hours infusion of 5-fluorouracil 2400 mg/m2. Treatment was repeated every 2 weeks until disease progression or unacceptable adverse effects occurred. Results Patients had a Child-Pugh class A (n = 16), class B cirrhosis (n = 10) or a liver transplant (n = 11) and received 2 to 37 cycles of chemotherapy (total of 310 cycles). Two (5.4%) cirrhotic patients developed neutropenic sepsis and one (2.7%) toxic death occurred. At first assessment, five patients from Child-Pugh class A (33%) and two from Child-Pugh class B group (20%) achieved a radiological response and/or alpha foeto-protein decrease, and no patient achieved a complete response. Conclusions In conclusion, with a manageable toxicity profile in cirrhotic Child-Pugh class A-B or liver transplanted patients, the FOLFOX-4 regimen appears to be a feasible treatment option for patients with advanced hepatocellular carcinoma unfit for sorafenib. These data need to be confirmed in a prospective study.

Purpose of the study : The 18-gene Tumor Inflammation Signature (TIS) (Ayers et al, J Clin Invest 2017; 127:2930) is a clinical research assay that enriches for clinical response to immune checkpoint blockade. In this work, the performance of the TIS was evaluated on standard tumor specimens for its ability to predict clinical benefit of immunotherapy in a cohort of cancer patients treated with PD1 checkpoint inhibitors in routine clinical care. Experimental procedures : Consecutive metastatic cancer patients treated with anti-PD1 in the outpatient monocentric CERTIM cohort with available formalin fixed paraffin embedded tumor specimen were selected for analysis. RNA were extracted from tissue samples with High Pure FFPET RNA Isolation Kit (Roche) and 25-100 ng RNA was hybridized to a pilot version of the NanoString® PanCancer Immuno-oncology 360 Panel. The association between individual gene expression (GE), TIS and other GE signatures with outcome (response to therapy and overall survival) was assessed with logistic resgression model, LogRank tests and Cox model. Results : A total of 69 patients with non-small cell lung carcinoma (NSCLC, n=42), small cell lung carcinoma (n=2), melanoma (n=9), renal cell carcinoma (n=10), urothelial carcinoma (n=5) or colorectal carcinoma (n=1), who had received nivolumab (n=59) or pembrolizumab (n=10) were analyzed. All samples but one SCLC could be successfully analyzed, demonstrating the feasibility of the testing even in small biopsy samples with little available RNA (>30 ng). In the whole cohort, clinical response (PR or CR versus SD or progression) was significantly associated with TIS score [OR=2.002, 95%CI=(1.123,3.977), p =0.029] as well as with the individual expression of PDL1, CTLA4, IDO1 or GE scores characterizing Th1, cytotoxic, NK cells infiltration, immuno-proteasome or antigen processing machinery. Receiver operating characteristics for response status demonstrated the high discriminatory ability of the TIS signature in this unselected series of patients (area under the ROC curve 0.71). Patients with a high TIS score (> 9.39) showed a longer OS (median OS 20.2 months) compared to those with lower scores (median OS 5.6 months, p value = 0.0017). A high TIS score was also significantly associated with clinical response when the analysis was limited to the NSCLC (n=42, [OR=3.156, 95%CI=(1.168,11.455), p-value=0.042] - or showed a strong trend in lung adenocarcinoma (n=29 [OR=11.251, 95%CI=(0.962,131.534), p-value=0.054] patients. Conclusion : Due to costs and toxicity, it is mandatory to identify the patients who benefit of immune checkpoint inhibitors. Here we demonstrate that the Tumor Inflammation Signature, that reflects key processes involved in anti-tumor immune response, may be used in routine samples to predict clinical benefit and prolonged survival of cancer patients. Citation Format: diane damotte, jennifer arrondeau, pascaline boudou-rouquette, audrey lupo, jerome biton, hanane ouakrim, Marco Alifano, Gervais Claire, Audrey Bellesoeur, Nora Kramkimel, Angeline Duche, Franck Letourneur, Xing Ren, Pascale Morel, Alessandra Cesano, Sarah Warren, François Goldwasser, Karen Leroy. The tumor inflammation signature is predictive of anti-PD1 treatment benefit in the CERTIM pan-cancer cohort [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4546.

Background: Immune evasion and deregulation of energy metabolism play a pivotal role in cancer progression. Immunosuppression in the tumor microenvironment can be based on the mutual metabolic requirements of immune and tumor cells. We evaluated the value of resting energy expenditure (REE) as a predictor of outcome, in mNSCLC patients under Nivolumab, an immune checkpoint inhibitor. Methods: We studied the relation between REE, clinical and biological markers of cachexia and inflammation, and response to Nivolumab in 82 consecutive mNSCLC patients. Efficacy was assessed every 2 months according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria. REE was measured using indirect calorimetry, before the initiation of Nivolumab. According to their REE and with the use of Boothby's standard, patients were categorized as hypermetabolic, normometabolic and hypometabolic. Body mass index (BMI), performance status (PS), C-reactive protein (CRP), albumin, Neutrophil Lymphocyte R Ratio (NLR) and PD-L1 tumor expression were also recorded. Results: Patients characteristics were: 62% males, median age of 65 years (range 37-78), 61% PS 0-1, median BMI of 24 kg.m-² (range 17-39), 78% nonsquamous NSCLC. The analysis of REE was available for 69 out of 82 consecutive pts: 37.7% were hypermetabolic, 47.8% were normometabolic, and 14.5% were hypometabolic. In univariate analysis, hypometabolism was a strong predictive marker of disease progression (Table 1), with positive and negative predictive values of 0.80 and 0.52 respectively. In multivariate analysis, independent parameters associated with disease progression were baseline hypometabolism (vs normometabolism: OR 1.77 [1.31-2.39] p= 0.0004) and albumin (per 1pt increase: OR 0.96 [0.94-0.99] p= 0.005). Conclusion: Rest energy expenditure assessed by calorimetry appears as a biomarker of nivolumab clinical activity independently of PD1/PDL1 status. Table 1Disease control (best response) n (%)115% calculated REE n=26 (37.7%) Hypermetabolicunivariate OR (Hypometabolic vs normometabolic)pProgression8 (80%)11 (33%)17 (65%)8 [1.4-44.2]0.0007Disease control rate2 (20%)22 (67%)9 (35%) Citation Format: Claire Gervais, Pascaline Boudou-Rouquette, Anne Jouinot, Jeanne Chapron, Jennifer Arrondeau, Marco Alifano, Frédérique Giraud, Olivier Huillard, Jérôme Alexandre, Clara Vazeille, Jean-Philippe Durand, Karen Leroy, Marie-Pierre Revel, Jean-Pascal de Bandt, Luc Cynober, Diane Damotte, Audrey Lupo-Mansuet, François Goldwasser. Prediction of the efficacy of nivolumab using resting energy expenditure in metastatic non-small cell lung cancer (mNSCLC) patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1693.

Background NRF2 is a major transcription factor regulating the expression of antioxidative/detoxifying enzymes. Its activation, due to mutations or activation of signaling pathways, has been associated with chemoresistance and poor prognosis in several tumors. NRF2 status remains unclear in endometrial carcinoma (EC). We aimed to identify molecular alterations associated with NRF2 activation in the four molecular subgroups of EC described by the Cancer Genome Atlas (TCGA), and explored its impact on EC prognosis. Methods Ninety patients treated in Cochin Hospital (2012 to 2017) for EC were included. Formalin-fixed paraffin-embedded tissue samples were processed for histopathological analysis and DNA and RNA extractions. Next generation sequencing (NGS) of NFE2L2 (encoding NRF2), KEAP1 and CUL3 genes and a panel of 15 genes significantly mutated in EC was performed using AmpliseqTM panels on Ion TorrentTM PGM (Thermo Fisher). The nuclear expression of mismatch repair (MMR) and NRF2 proteins were analyzed by immunochemistry (IHC). NRF2 activity was assessed by NQO1, GCLC, and AKR1C3 mRNA expressions, normalized to MRPL19 and TBP housekeeping genes, using TaqManTM assays and quantitative RT-PCR. Clinical event of interest was event-free survival (EFS) (progression, relapse, or death). Results Tumors were classified according to NGS and IHC data as POLE exonuclease domain mutated (N=3, 3%), MMR-deficient (dMMR) (N=28, 31%), TP53 mutated (N=23, 25%), and MMR-proficient tumors (N=32, 36%). NRF2 nuclear immunostaining was not correlated to NRF2 activity. The 3 tumors with highest NRF2 target genes expression harbored known NRF2 pathway activating mutations (NFE2L2 p.W24G, KEAP1 p.R336*, KEAP1 p.D422N). In addition, 2 dMMR tumors showed intermediate/high (1st quartile) NRF2 target genes expression and low allele ratio NFE2L2 mutations, suggesting NRF2 subclonal activation. No correlation was observed between NRF2 activity and PI3K or KRAS pathways mutations. The TP53 subgroup showed a strikingly lower NQO1 expression compared to dMMR or pMMR tumors (ANOVA p Conclusion In contrast with previous reports based on IHC, NRF2 activation is a rare event in EC, associated with NFE2L2 or KEAP1 mutations. NQO1 downregulation in the TP53-mutated subgroup might be explained by the interaction of NRF2 with TP53 missense mutants, which has been shown to impair its anti-oxidant transcriptional activity while enhancing proteasome expression (Walerych et al. Nat Cell Biol 2016). Very low levels of NQO1 expression identifies a subset of EC with a poor prognosis, which might be sensitive to specific combination therapies (Liu et al. Nat Commun. 2017). Citation Format: Guillaume Beinse, Pierre-Alexandre Just, Bastien Rance, Brigitte Izac, Franck Letourneur, Nathaniel Edward Saidu, Sandrine Chouzenoux, François Goldwasser, Eric Pasmant, Frederic Batteux, Bruno Borghese, Karen Leroy, Jérome Alexandre. High-grade TP53-mutated endometrial carcinomas have decreased NRF2 antioxidant activity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4609.

Recently, pneumatosis intestinalis has been described in patients receiving bevacizumab, a monoclonal antibody to VEGF-A. Pneumatosis intestinalis is a condition characterized by subserosal and submucosal gas-filled cysts in the gastrointestinal tract. We report on pneumatosis intestinalis in patients receiving oral anti-VEGF agents. Patients shared the following characteristics: long-term (> 4 months) exposure to anti-VEGF agents, lack of other factors predisposing to pneumatosis intestinalis, and lack of recent surgical intervention. Taken together, these observations suggest that pneumatosis intestinalis is a probable class-effect of anti-VEGF agents.

Bladder cancer often occurs in patients with high risk of acute toxicity under chemotherapy. So-called unfit patients are a heterogenous population, sharing a contra-indication for cisplatin and presenting either chronic renal failure, and/or elderly, and/or altered performance status, and/or severe co-morbidities. Therefore, it is necessary to develop chemotherapy protocols feasible in renal insufficient patients, and well tolerated in frail patients. The medical evaluation prior to initiate chemotherapy is of major importance to screen for chronic disorders and to anticipate the potential acute complications following chemotherapy. Chemotherapy of elderly patients with severe comorbidities is a common situation in bladder cancer, and will concern all cancer patients. The evaluation of the benefit/risk ratio of the chemotherapy protocol is a typical expertise of medical oncologists, which requires to integrate the complex links between the patient, the antitumor agent, and toxicity. The physician must also have a honest dialogue to inform, advise, listen to the patients priorities. Medical oncologists have to have in mind this situation and to adapt their clinic and their vocabulary to this emerging reality.

3066Background: The occurrence of severe, acute limiting toxicity in patients receiving anti-PD-1 monoclonal antibodies, such as nivolumab, is largely unpredictable. Sarcopenia was found associated...

e22133Background: sarcoma are rare tumors, with an incidence < 1% of all neoplasms. Supportive care of pts with advanced sarcomas is an underestimated aspect in oncology practice. Methods: in our u...

e21066Background: The SCAN study is a French nationwide study which aimed to measure the prevalence of sarcopenia in real-life cancer patients (pts). A secondary objective was to study the relation...

Introduction Chez les sujets âges atteints de cancer, la depression est difficile a reperer du fait de l’heterogeneite de son expression clinique. L’echelle GDS (« Geriatric Depression Scale ») est une echelle de reperage. L’echelle GDS-4, comportant quatre items, est attractive de par sa courte duree de passation mais non validee chez les sujets âges atteints de cancer. L’objectif etait de tester les performances diagnostiques de l’echelle GDS-4 dans l’ensemble de la population et selon la localisation du cancer et le statut metastatique. Methodes Il s’agit d’une analyse transversale des donnees d’inclusion de la cohorte « ELderly Cancer Patient » (ELCAPA). Tous les patients âges de 70 ans ou plus, atteints de cancer et adresses au geriatre pour une evaluation geriatrique entre 2007 et 2012 dans deux centres, ont ete inclus. Le « gold standard » etait la presence d’un syndrome depressif selon l’entretien semi-structure du geriatre (base sur le DSM-IV). Les indices de performances diagnostiques de l’echelle GDS-4 (score de 0 a 4) ont ete calcules avec leur intervalle de confiance a 95 % : sensibilite, specificite, valeurs predictives positive et negative, rapports de vraisemblance positif et negatif. L’aire sous la courbe ROC a ete determinee. La meme strategie a ete menee selon la localisation du cancer (colorectal, sein, prostate et voies urinaires) et le statut metastatique. Resultats Sur 1092 patients, 965 avaient un questionnaire GDS-4 renseigne (âge moyen : 80,4 ± 5,6 ans, 48,6 % de femmes, 61,2 % etaient vus en ambulatoire, 91,5 % avaient un cancer solide dont 51,5 % au stade metastatique). La prevalence de la depression etait de 27,7 % (intervalle de confiance a 95 % : 24,9–30,6). Pour le seuil ≥ 1/4, la sensibilite etait de 91,0 % (86,9–94,2), la specificite de 88,0 % (85,3–90,3), la valeur predictive positive de 74,3 % (69,2–79,0) et la valeur predictive negative de 96,2 % (94,5–97,6), le rapport de vraisemblance positif de 7,56 (6,2–9,3) et le rapport de vraisemblance negatif de 0,10 (0,1–0,2). L’aire sous la courbe ROC etait de 92,6 % (90,6–94,6). En analyse en sous-groupes, la prevalence du syndrome depressif variait de 21,1 % pour les patients avec un cancer de la prostate a 29,0 % pour ceux avec un cancer du sein. Les sensibilites variaient de 84,8 % (68,1–94,9) pour les patients avec un cancer des voies urinaires a 96,2 % (86,8–99,5) pour ceux avec un cancer colorectal, les specificites entre 86,1 % (78,4–91,8) pour les patients avec un cancer du sein et 95,6 % (89,0–98,8) pour ceux avec un cancer de la prostate. Les aires sous la courbe ROC etaient comprises entre 88,5 % (81,5–95,4) pour les patients avec un cancer des voies urinaires et 95,8 % (92,7–99,0) pour ceux avec un cancer colorectal. La prevalence du syndrome depressif etait de 34,1 % (29,5–38,9) chez les patients avec metastases et de 20,3 % (16,4–24,7) chez les patients sans. Les sensibilites etaient respectivement de 91,4 % (85,4–95,5) et de 87,2 % (77,7–93,7), les specificites de 89,2 % (84,9–92,7) et de 88,2 % (84,1–91,6). Les aires sous la courbe ROC etaient de 93,1 % (90,4–95,8) et de 90,5 % (86,3–94,6). Conclusion La GDS-4, au seuil ≥ 1, semble etre un outil performant de reperage de la depression chez les sujets âges atteints de cancer quels que soient la localisation et le stade. Sa rapidite de realisation est un argument supplementaire en faveur de sa faisabilite et de son utilisation en pratique courante.

Background/Objective: Oxaliplatin-based chemotherapy induces sinusoidal obstruction syndrome (SOS) lesions in the nontumorous liver parenchyma, which may increase the risk of liver resection for colorectal liver metastases. The objective of this study was to evaluate the accuracy of aspartate aminotransferase to platelet ratio index (APRI) and FIB-4 scoring systems to predict chemotherapy-associated liver injury and to correlate the severity of sinusoidal injury with postoperative outcome. Methods: Between 1998 and 2007, 78 patients were operated for colorectal liver metastases after preoperative oxaliplatin-based chemotherapy. Grading of steatosis and SOS in the nontumorous liver parenchyma was obtained in these patients. Univariate analysis of 18 preoperative factors to predict SOS occurrence was performed as well as multivariate analysis. Relevance of preoperative platelet count level, transaminase levels, and fibrosis scoring systems were evaluated to predict high grade lesions of SOS using a receiving operative curve analysis. Ninety-day mortality and morbidity were studied according to SOS severity in 51 patients who underwent major liver resection. Results: Overall, pathologic examination showed high-grade lesions of SOS (SOS 2/3) in 46 (59%) patients. Univariate analysis showed that a low preoperative platelet count, elevated preoperative aspartate aminotransferase, short interval between chemotherapy and surgery were significant factors associated with high-grade lesions of SOS. Multivariate analysis showed that only the APRI score was an independent predictive factor for severe SOS. Receiving operative curve analysis revealed that the cut-off value predicting high-grade lesions of SOS with the best accuracy was an APRI score of 0.36 (area under the curve, 0.85; sensitivity, 87%; specificity, 69%). After major liver resection (n = 51), SOS 2/3 (n = 38) was associated with postoperative hepatic dysfunction (26/38 in SOS 2/3 vs. 3/13 in SOS 0/1; P = 0.004) and ascites (P = 0.03). Conclusion: A low preoperative platelet count and high APRI score seem to be the most reliable indicators to predict SOS severity.

Sorafenib is a novel oral bis-aryl urea compound originally developed as an inhibitor of RAF kinase for its anti-proliferative property. Sorafenib also inhibits receptor tyrosine kinases of multiple pro-angiogenic factors such as VEGFR-1/2/3, Flt-3 and PDGFR-beta. The combination of both its anti-proliferative and anti-angiogenic properties makes sorafenib an attractive agent in cancer treatment. Sorafenib has been approved for the treatment of metastatic renal cell carcinoma as well as hepatocellular cancer. Despite its inherent selectivity, sorafenib can cause unusual adverse events whose the management represents a challenge for oncologists.Relevant literature was identified using a Pubmed search of articles published up to June 2009. Search terms included 'sorafenib' and 'toxicity'. Original articles were reviewed and relevant citations from these articles were also considered.The clinical aspect of sorafenib-induced adverse events and the molecular basis behind this toxicity are discussed. Finally, recommendations for the management of these adverse events are proposed.Although not life-threatening, toxicity of sorafenib can severely impact the physical, psychological and social well-being of patients. The management of this unusual toxicity highlights the particular need of new pluridisciplinarities linking oncologist, cardiologist and dermatologist.

Proteinuria is a dose-related side-effect occurring after inhibition of vascular endothelial growth factor (VEGF) signalling and may reflect severe glomerular damage. The inhibition of the VEGF signalling axis induces downexpression or suppression of nephrin, an important protein for the maintenance of the glomerular slit diaphragm, sometimes leading to nephritic syndrome and/or glomerular thrombotic microangiopathy, the main-associated kidney disease. A MEDLINE search was carried out using the following criteria: (1) all MEDLINE listings as of 01-01-2000 with abstracts; (2) English language; and (3) Humans. The following phrases were used to query the database: (proteinuria) AND (anti-VEGF OR VEGF inhibition OR bevacizumab OR sunitinib OR sorafenib OR VEGF Trap OR axitinib OR pazopanib OR AZ 2171). The references of each article identified were carefully reviewed for additional reference. The incidence of mild and asymptomatic proteinuria ranges from 21% up to 63%, but heavy proteinuria has been reported in up to 6.5% of renal cell carcinoma patients. Although discontinuation of anti-VEGF agent induced significant reduction, persistence of proteinuria is common. Although angiotensinconverting-enzyme inhibitors and/or angiotensin receptor blockers seem to be preferred, no specific recommendation for an antiproteinuric agent can be made in this context because there are no controlled studies addressing the subject. Periodic monitoring of urinary protein should be carried out in anti-VEGF-treated patients and patients showing proteinuria need special referral to nephrologists.

Background Sunitinib malate is a novel oral multitargeted tyrosine kinase inhibitor with antitumor and antiangiogenic activities. Only mass spectrometry detection is currently available to determine sunitinib in human plasma. The purpose of this study was to develop a simple and sensitive high-performance liquid chromatographic method with UV-Visible detection for quantification of sunitinib concentrations in human plasma. Methods After a liquid–liquid extraction with ethyl acetate, sunitinib and ranitidine (internal standard) are separated on cyanopropyl column using a simple binary mobile phase of ammonium acetate buffer (20 mM; pH 6.8):acetonitrile (55:45,v/v). Samples were eluted isocratically at a flow rate of 1 mL/min throughout the 10 min run. Dual wavelength mode was used, with ranitidine monitored at 255 nm, and sunitinib at 431 nm. Results The calibration was linear in the range 20–200 ng/mL. Inter- and intra-day coefficients of variation were less than 7%. This method is sensitive, accurate and selective. It has been successfully implemented to monitor trough sunitinib concentrations in plasma samples (n = 39) from 14 unselected cancer patients treated with the recommended once daily dose of 50 mg or less. Conclusion This method can be used in routine clinical practice to monitor plasma sunitinib concentrations in cancer patients treated with once daily administration.

Background Hypertension (HTN) is one of the most frequent side-effects of systemic inhibition of vascular endothelial growth factor (VEGF) signaling. Its incidence and severity are dependent on the type of drugs, dose, and schedule used. The recognition of this side-effect is an important issue because poorly controlled HTN could lead to serious cardiovascular events. On another hand, HTN induced by anti-VEGF agents maybe a predictive factor of oncologic response. Knowledge of this clinical toxicity and/or therapeutic target or novel biomarker of drug activity can aid clinicians choosing the optimal and least toxic regimen suitable for an individual patient. Methods A Medline search was carried out using the following criteria: (i) all Medline listings as of 1 January 2000 with abstracts, (ii) English language, and (iii) Humans. The following phrases were used to query the database: (‘hypertension’, OR ‘blood pressure’) AND (‘anti-VEGF’ OR ‘VEGF inhibition’ OR ‘bevacizumab’ OR ‘sunitinib’ OR ‘sorafenib’ OR ‘VEGF Trap’). The references of each article identified were carefully reviewed for additional reference. Results Lifestyle modification should be encouraged. However, these nonpharmacologic strategies are not always suitable to patients with altered performance status related to metastatic cancer necessitating early drug intervention. Only one randomized study showed a beneficial effect of a calcium channel blocker use to prevent or minimize HTN secondary to antiangiogenic therapy. Nitrates looks as effective in controlling such side-effect. Conclusions No clear recommendation for an antihypertensive agent can be made in this context because there is a lack of controlled studies addressing the subject. Blood pressure-lowering drugs should be individualized to the patient's clinical circumstances and angiogenic inhibitors should be withheld only from patients who experienced hypertensive crisis.

Sorafenib, a new oral multikinase inhibitor with antiangiogenic properties, has demonstrated preclinical and clinical activity against several tumor types. The aims of this study were to validate a method for the measurement of sorafenib in plasma from cancer patients, then to test this method in clinical practice. Following liquid-liquid extraction, the compounds were separated with gradient elution (on a C18 ultrasphere ODS column using a mobile phase of acetonitrile/20 mM ammonium acetate), then detected at 255 nm. The calibration was linear in the range 0.5-20 mg/L. Intra- and inter-assay precision was lower than 7 and 10%, respectively, at 0.5, 3 and 20 mg/L. Plasma sorafenib concentrations were measured in 22 cancer patients (99 samples). The mean trough sorafenib concentration (C(min)) and concentration at peak were 4.3+/-2.5 mg/L (n=68, CV=57.5%) and 6.2+/-3.0 mg/L (n=31, CV=47.5%), respectively. Mean sorafenib C(min) in eight patients who experienced grade 3 drug-related adverse events was approximately 1.5-fold greater than that observed in the remaining patients (7.7+/-3.6 mg/L vs. 4.4+/-2.4 mg/L, P=0.0083). In conclusion, the method was successfully used in routine practice to monitor plasma concentrations of sorafenib in cancer patients. Finally, large interindividual variability and higher exposure in patients experiencing severe toxicity support the need for therapeutic drug monitoring to ensure an optimal exposure to sorafenib.

Background Glutathione-S-transferases (GST) regulate the cellular response to oxidative stress. We previously highlighted the importance of oxidative stress in taxane toxicity and therefore investigated the relationship between the GST isoforms M1, T1 and P1 gene polymorphisms and docetaxel (Taxotere)-induced peripheral neuropathy (DIPN). Patients and methods The GSTM1 (null), GSTT1 (null) and GSTP1 (Ile(105)Val and Ala(114)Val) polymorphisms were determined in a cohort of cancer patients treated with docetaxel and entered in a clinical trial database. The relationship between GST polymorphisms and grade > or = 2 DIPN as primary end point was studied. Results Fifty-eight patients (median age 61 years) received a total of 261 cycles of docetaxel given as single agent. Patients with GSTP1 (105)Ile/(105)Ile genotype had a higher risk of developing a grade > or = 2 DIPN than did those with other GSTP1 genotypes (8 of 27 versus 2 of 31, respectively, odds ratio 6.11; 95% confidence interval 1.17-31.94; P = 0.03). In multivariate analysis, grade > or = 2 DIPN was strongly correlated with GSTP1 (105)Ile/(105)Ile genotype (P = 0.01) and the number of cycles (P = 0.03). Conclusion We found a significant correlation between GSTP1 (105)Ile/(105)Ile genotype and the development of grade > or = 2 DIPN. This finding strongly suggests a role of oxidative stress in the pathophysiology of DIPN.

Background: Breast cancer is the commonest solid tumor observed during pregnancy. Anthracycline-based chemotherapy is feasible during the 2nd and 3rd trimesters of pregnancy, but few data are available on recent and highly active drugs taxanes, vinorelbine and anti-HER-2 agents in this setting. Patients and methods: We carried out a comprehensive review of reports documenting the use of taxanes, vinorelbine, trastuzumab and lapatinib during pregnancy in the English literature, in order to evaluate their safety profile in pregnant patients. Results: Twenty-four pregnancies are described, in which no grade 3–4 maternal toxicity nor malformation in the offspring was reported. Whereas only one report studied the pharmacokinetics of paclitaxel (Taxol) during pregnancy, several preclinical reports indicate that the placental P-glycoprotein could prevent the transplacental transfer of taxanes and vinorelbine. The use of trastuzumab was associated with the occurrence of anhydramnios in three of six cases. Conclusion: The administration of recent drugs taxanes and vinorelbine seems feasible during the 2nd and 3rd trimesters of pregnancy, with a favorable toxicity profile. In contrast, anti-HER-2 agents may obscure the normal development of the fetal kidney, and should be avoided during pregnancy.

Ifosfamide (IFOS) is a bifunctional alkylator with a wide spectrum of activity in solid tumors and has an autoinductive liver metabolism through P450 cytochromes. Autoinduction might permit a better therapeutic index for combination therapy. A phase I trial was investigated with interpatient dose escalation of a single dose of IFOS given every 2 weeks in advanced solid tumor patients. IFOS, its dechloroethylated and active 4-hydroxy metabolites, were measured at cycles 1 and 2 at the end of infusion, 2 and 5 h later, using gas chromatography. IFOS elimination was considered as following monocompartimental model kinetics. The results of 20 patients from January 2004 to June 2006 were included. The median of previous chemotherapies was 2 (0-5). The primary tumor was most often ovarian (5), peritoneal (3), sarcoma (2), melanoma (2) or miscellaneous (8). Ten patients received 2.5 g/m 2 and the other 10 patients received 3 g/m 2 . A total of 79 cycles were evaluable for toxicity. The median number of cycles was 4 (1-8). No grade 3-4 toxicity, no alopecia at first dose level and no toxicity-related fatal events were noted. One objective response was noted in a pancreatic cancer patient and one sustained CA125 decline in a heavily pretreated ovarian cancer patient. A slight (7-10%) but reproducible decrease of areas under the curve was detectable at cycle 2, at both dose levels, related to autoinductive metabolism. Intraindividual variations (large SD) were noticed for each pharmacokinetic parameter. A patient-dependent autoinduction of IFOS metabolism was detected rather than a slight nondose-dependent autoinduction. The toxicity profile allows the development of bi-weekly IFOS-based combination therapies.

Over the last decades, the development of new drugs has allowed cancer patients to experience several lines of chemotherapy, the objective of which is a long term stabilization of the tumour. The objectives of this work was to delineate a composite index of relative antitumoural efficacy (In-RATE) of a regimen over another, including response rate (RR), median time to progression (TTP) and progression rate (PR). When considering two treatments a and b, the In-RATE was defined as RRa/RRb × TTPa/TTPb × PRb/PRa. Values significantly superior or inferior to 1 reveal an advantage for treatment a or b, respectively. The applicability of the In-RATE to published randomized trials in four frequent tumour types (colorectal, non-small cell lung, advanced ovarian and metastatic breast cancers) was suggested to more precisely distinguish the effects of different drugs, and sometimes to detect a significant difference when the published data did not conclude to statistical difference.

We hypothesized that cancer-related inflammation might increase the risk of febrile neutropenia (FN) induced by docetaxel (DCX, Taxotere), by both affecting the exposure to DCX and the tissue sensitivity.Advanced cancer patients with normal liver function, performance status (PS)3, were included. Cytochrome P450 3A (CYP 3A) activity was estimated before the first cycle of DCX by a single determination of midazolam plasma concentration, 4 hours after 0.015 mg/kg i.v. bolus. Following the first cycle of 75-100 mg/m2 DCX, clearance and area under the concentration versus time curve (AUC) were estimated using a limited sampling strategy.Among 56 assessable patients, 7 FNs occurred after first cycle (13%). In univariate analysis, high midazolam concentration and free DCX AUC were associated with severe neutropenia and FN. In addition to DCX exposure-related parameters, the risk of FN was also correlated with poor PS, baseline lymphopenia and lung cancer, while high ferritin level, indicator of an inflammatory state, reached borderline significance (P=0.07). By multivariate analysis, total DCX AUC and baseline lymphopenia were associated with FN. High midazolam concentration was correlated with elevated ferritin level (r=0.32; P=0.02).Inflammatory status and lymphocyte count should be included in the evaluation of the benefice/risk ratio before the initiation of DCX.

In a study of the integration of oncology and palliative care, shared decision-making in patient care is addressed by the existing set of indicators. However, oncologists may have a variable level of participation in onco-palliative meetings, and further study is needed to support this novel intervention.

Vemurafenib is a BRAF kinase inhibitor approved for first-line treatment of metastatic BRAF V600 -mutant melanoma. However, data on the pharmacokinetic/pharmacodynamic (PK/PD) relationship are lacking. The aim of this prospective, multicenter study was to explore the PK/PD relationship for vemurafenib in outpatients with advanced BRAF-mutated melanoma. Fifty-nine patients treated with single-agent vemurafenib were prospectively analyzed. Vemurafenib plasma concentration (n = 159) was measured at days 15, 30, 60, and 90 after treatment initiation. Clinical and biological determinants (including plasma vemurafenib concentration) for efficacy and safety were assessed using Cox's model and multivariate stepwise logistic regression. Median progression-free survival (PFS) and overall survival were 5.0 (95 % confidence interval [95 % CI] 2.0–6.0) and 11.0 (95% CI 7.0–16.0) months, respectively. Twenty-nine patients (49 %) experienced any grade ≥3 toxicity and the most frequent grade ≥2 toxicity was skin rash (37 %). Severe toxicities led to definitive discontinuation in seven patients (12 %). Grade ≥2 skin rash was not statistically associated with better objective response at day 60 (p = 0.06) and longer PFS (hazard ratio 0.47; 95 % CI 0.21–1.08; p = 0.075). Grade ≥2 skin rash was statistically increased in patients with ECOG ≥ 1 (odds ratio 4.67; 95 % CI 1.39–15.70; p = 0.012). Vemurafenib concentration below 40.4 mg/L at day 15 was significantly associated with a shorter PFS (1.5 [0.5–5.5] vs. 4.5 [2–undetermined] months, p = 0.029). Finally, vemurafenib concentration was significantly greater in patients developing grade ≥2 rash (61.7 ± 25.0 vs. 36.3 ± 17.9 mg/L, p

Background: Vemurafenib, a BRAF inhibitor, is a first-line treatment for inoperable melanoma. Sarcoidosis has never been reported in patients on vemurafenib. Objectives: We describe 5 cases of sarcoidosis in patients treated with vemurafenib. Methods: Seventy patients receiving vemurafenib for a BRAF-mutated inoperable stage III or IV melanoma were treated in our centre. Results: Five patients (7.1%) developed sarcoidosis or a sarcoid-like reaction on vemurafenib; 4 patients had cutaneous signs and 3 had extracutaneous disorders (bilateral hilar lymph nodes, uveitis). Histological analysis of skin lesions revealed epithelioid granulomas without necrosis, consistent with sarcoidosis. Angiotensin-converting enzyme levels were high in 2 patients. Cutaneous and ophthalmological lesions rapidly disappeared on topical corticosteroid treatment without the cessation of vemurafenib treatment. Complete remission of melanoma was observed in 3 patients and partial remission was observed in another. Conclusion: BRAF inhibitors probably have immune system-enhancing effects and should therefore be recognized as potential inducers of sarcoidosis.

UDP-glucuronosyltransferases (UGTs) are a multigenic family of enzymes responsible for the glucuronidation reaction. Many therapeutic classes of drugs used in solid tumors are UGT substrates, including cancer therapies.This article describes the tyrosine kinase inhibitors (TKIs) undergoing hepatic glucuronidation; its effect on transport and tissue accumulation and the clinical consequences of this particular metabolism. A PubMed search concerning the pharmacokinetics of the TKIs was performed. All are extensively metabolized by CYP450. Two TKIs, sorafenib and regorafenib, also have a major UGT-mediated metabolism and were therefore studied.The prescription of the same dose of sorafenib and regorafenib for all patients may be inappropriate since at each enzymatic step of this multistep metabolism inter-individual fluctuations exist. Having a non-exclusive CYP-mediated route of metabolism may reduce the risk of variability in drug exposure when CYP3A4 substrates are concomitantly given. Several clinical consequences derive from this pharmacokinetic particularity of sorafenib and regorafenib. Since no clear difference distinguishes TKIs in efficacy in large randomized trials, the differences for the clinical management of their toxicity is a critical aspect.

Angiogenesis inhibition is a major antitumor strategy that has emerged during the last decade. Oral tyrosine kinase inhibitors (TKI) targeting the VEGF receptor, including sunitinib, sorafenib, axitinib, regorafenib, pazopanib, and vandetanib reduce tumor growth and metastasis. These agents are approved for the treatment of metastatic diseases in first or second-line. They display a narrow therapeutic index. However, data in the elderly and/or in patients with multiple illnesses remain scarce. This population is classically excluded from clinical trials. The aim of this review is to provide an overview of existing literature regarding antiangiogenic TKI tolerance in the elderly (70 years old). We also highlight key points of the pre-therapeutic evaluation and summarize the management of common toxicities.

The platelet-derived growth factor receptor (PDGFR) pathway has important functions in cell growth and, by overexpression or mutation, could also be a driver for tumor development. Moreover, PDGFR is expressed in a tumoral microenvironment and could promote tumorigenesis. With these biological considerations, the PDGFR pathway could be an interesting target for therapeutics. Currently, there are many molecules under development that target the PDGFR pathway in different types of cancer.In this review, the authors report the different molecules under development, as well as those approved albeit briefly, which inhibit the PDGFR pathway. Furthermore, the authors summarize their specificities, their toxicities, and their development.Currently, most PDGFR kinase inhibitors are multikinase inhibitors and therefore do not simply target the PDGFR pathway. The development of more specific PDGFR inhibitors could improve drug efficacy. Moreover, selecting tumors harboring mutations or amplifications of PDGFR could improve outcomes associated with the use of these molecules. The authors believe that new technologies, such as kinome arrays or pharmacologic assays, could be of benefit to understanding resistance mechanisms and develop more selective PDGFR inhibitors.

Background : Anticancer drugs act by increasing intracellular hydrogen peroxide levels. Mangafodipir, a superoxide dismutase (SOD) mimic with catalase and glutathione reductase activities, protects normal cells from apoptosis induced by H 2 O 2 . We investigated its and other oxidative stress modulators’ effects on anticancer drug activity in vitro and in vivo. Methods : Cell lysis and intracellular reactive oxygen species levels were assessed in vitro in human leukocytes from healthy subjects and in murine CT26 colon cancer cells. Cells were exposed to the chemotherapeutic agents paclitaxel, oxaliplatin, or 5-fl uorouracil, either in the presence or absence of mangafodipir and other oxidative stress modulators. Cell viability was evaluated by the methylthiazoletetrazolium assay. The effects of mangafodipir and other oxidative stress modulators on peripheral blood counts and on tumor growth were studied in BALB/c mice that were implanted with CT26 tumors and treated with 20 mg/kg paclitaxel. Survival of BALB/c mice infected with Staphylococcus aureus was also examined by treatment group. Statistical tests were two-sided. Results : In vitro lysis of leukocytes exposed to paclitaxel, oxaliplatin, or 5-fl uorouracil in combination with mangafodipir was decreased by 46% (95% confi dence interval [CI] = 44% to 48%), 30.5% (95% CI = 29% to 32%), and 15% (95% CI = 10% to 20%), compared with lysis of cells treated with anticancer agent alone. Mangafodipir also statistically signifi cantly enhanced in vitro anticancer drug cytotoxicity toward CT26 cancer cells. In vivo, mangafodipir protected mice against paclitaxel-induced leukopenia. Moreover, the survival rate of mice infected with S. aureus and treated with paclitaxel was higher when mangafodipir was also administered (survival: 3 of 17 versus 14 of 17, P

Background: To determine maximum tolerated dose (MTD), recommended dose, safety and pharmacokinetics of irofulven combined with cisplatin in advanced solid tumor patients. Patients and methods: Cisplatin and irofulven were given sequentially i.v. over 30 min on day 1 and 15 every 4 weeks. Four dose levels (DL) were explored: irofulven (mg/kg)/cisplatin (mg/m2): DL1: 0.3/30; DL2: 0.4/30; DL3: 0.4/40; DL4: 0.5/40. Dose-limiting toxicity (DLT) included dosing omission and delay >1 week. MTD was the DL with DLT in 2/2 or ≤2/6 patients during cycle 1–2. Results: Between March 2002 and April 2003, 33 patients were treated. DLT occurred in 1/6 patients in DL1 (hypomagnesemia, hypocalcemia); 1/6 in DL2 (thrombocytopenia); 2 heavily pretreated patients out of 6 patients in DL3 (neutropenic infection, thrombocytopenia, stomatitis); 2/3 in DL4 (asthenia, blurred vision). Three DLT occurred in 12 additional patients treated at DL2. No toxic deaths occurred; grade 4 toxicity and grade 3 non-hematological toxicity were infrequent. Six patients reported grade 1–2 visual events. Antitumor activity was observed over a broad spectrum of tumor types in all DLs: 1 partial response in bulky sarcoma (DL1); 1 clinical response in endometrial carcinoma (DL1); 2 partial responses not confirmed due to discontinuation (ovarian DL2, renal DL4); 8 stabilizations >3 months; PSA response: 3/9 prostate cancer patients. Irofulven showed rapid elimination and high interpatient variability. Platinum and irofulven pharmacokinetics did not suggest drug-drug interactions. Conclusion: Irofulven with cisplatin was adequately tolerated and substantial evidence of antitumor activity was observed. The recommended dose is irofulven 0.4 mg/kg and cisplatin 30 mg/m2.

Intracellular events following paclitaxel binding to microtubules that lead to cell death remain poorly understood. Because reactive oxygen species (ROS) are involved in the cytotoxicity of anticancer agents acting through independent molecular targets, we explored the role of ROS in paclitaxel cytotoxicity. Within 15 min after in vitro exposure of A549 human lung cancer cells to paclitaxel, a concentration-dependent intracellular increase in O(o)(2)(-) and H(2)O(2) levels was detected by spectrofluorometry. Addition of N-acetylcysteine (NAC) or glutathione, two H(2)O(2) scavenger, induced a 4-fold increase in paclitaxel IC(50). Delaying NAC co-incubation by 4 hr, resulted in a 3-fold reduction in cell protection. The glutathione synthesis inhibitor, buthionine sulfoximine significantly increased paclitaxel cytotoxicity and H(2)O(2) accumulation, but did not modify O(o)(2)(-) levels. Co-incubation with diphenylene iodonium suggested that paclitaxel induced-O(o)(2)(-) production was in part associated with increased activity of cytoplasmic NADPH oxidase. Concomitant treatment with inhibitors of caspases 3 and 8 increased cell survival but did not prevent the early accumulation of H(2)O(2.) To evaluate the role of ROS in paclitaxel antitumoral activity, mice were injected with LLC1 lung cancer cells and treated with paclitaxel i.p. and/or NAC. The antitumoral activity of paclitaxel in mice was abolished by NAC. In conclusion, the accumulation of H(2)O(2) is an early and crucial step for paclitaxel-induced cancer cell death before the commitment of the cells into apoptosis. These results suggest that ROS participate in vitro and in vivo to paclitaxel cytotoxicity.

Clinical trials in urothelial cancer exclude a large population of patients. An observational study evaluated the behavior of frail patients not eligible for cisplatin- or carboplatin-based regimens. Urothelial cancer patients requiring chemotherapy with either chronic renal failure (creatinine clearance60 ml/min), and/or performance status (PS)or =2 and/or cardiac dysfunction were prospectively observed. The treatment associated gemcitabine 1200 mg/m and oxaliplatin 85 mg/m, bimonthly (GO). Over 2 years, 31 of 45 (69%) patients with urothelial cancer requiring chemotherapy were not eligible for cisplatin- or carboplatin-based chemotherapy. Sixteen (52%) had a PSor =2, 23 (74%) had creatinine clearance60 ml/min, and 20 (65%) had an underlying cardiopathy. A total of 178 cycles of GO were administered (median 6 per patient, range 2-12). No aggravation of renal or cardiac status was noted. Acute grade 3 and 4 neutropenia and thrombocytopenia were observed in 16 and 13% of patients, respectively, with one febrile neutropenia. The median progression-free and overall survival values were 4.2 and 9.5 months, respectively. The majority of urothelial cancer patients have severe renal or cardiac comorbidities, and we conclude that in this subset of patients the combination of gemcitabine and oxaliplatin is well tolerated, and its clinical activity warrants further evaluation.

Monoclonal antibodies such as bevacizumab are widely used in medical oncology, either alone or in combination with chemotherapy. No specific recommendations on the management of monoclonal antibodies extravasation exist. Incidence rates vary considerably. Estimates of 0.5-6% have been reported in the literature. Also, patient-associated and procedure-associated risk factors of extravasation are multiple, such as bolus injections or poorly implanted central venous access. We report on an 86-year-old woman with colon cancer with liver metastasis who was treated with 5-fluorouracil, folinic acid, and bevacizumab. Extravasation occurred during chemotherapy infusion because of a catheter migration of the port outside of the superior vena cava, causing cervical pain without skin modifications. Diagnosis was confirmed with the appearance of clinical right cervical tumefaction and cervicothoracic computed tomography scan indicated a perijugular hypodense collection, corresponding to the extravasation. Conservative management was proposed. The patient recovered within 3 weeks from all symptoms. Physicians should be aware that in cases of bevacizumab extravasation, a nonsurgical approach might be effective.

Background: The toxicity outcome of cancer patients receiving chemotherapy is difficult to predict. In this study the influence of malnutrition and inflammation on acute haematological toxicity was investigated. Patients and methods: Between January 1999 and January 2000, 48 consecutive cancer patients experienced severe haematological toxicity (SHT), either neutropenic fever or severe thrombocytopenia, following various chemotherapy regimens. Their baseline characteristics were compared with those of 59 control patients. Previous chemotherapy regimens, type of chemotherapy, performance status (PS), calculated creatinine clearance, bilirubin, C-reactive protein (1), alpha-1 acid glycoprotein (2), albumin (3), pre-albumin (4) and the nutritional and inflammatory status (NIS) ratio [NIS = (1 × 2)/(3 x 4)] were studied. Statistical analysis was carried out using either a t-test or a chi-square test. A receiver operating characteristic (ROC) curve determined the cut-off value for NIS. Results: Patients experiencing SHT had a higher PS (P

Combinations of topoisomerase I (topo I) poisons and platinum derivatives have synergistic antitumoral effects. However, their clinical development is limited by supra-additive haematological toxicity. The aim of this study was to determine whether sustained doses of topotecan and oxaliplatin could be achieved using a synergistic sequence. 34 advanced cancer patients and 186 cycles were evaluable for toxicity over five dosing levels. Oxaliplatin at 85-110 mg/m(2) was given on day 1, followed by topotecan 0.5-1.25 mg/m(2)/day x 5 from day 1 to 5, every 3 weeks. Plasma pharmacokinetics (PK) of total and ultrafiltrable platinum, total and lactone forms of topotecan were determined in the first cycle. The dose-limiting toxicity (DT) was identified as grade 4 thrombocytopenia. The occurrence of grade 4 thrombocytopenia did not correlate with topotecan PK, but it did with the patient's characteristics. Severe thrombocytopenia was seen in 1/8 of patients without clinical or biological evidence of malnutrition, with a creatinine clearance higher than 1 ml/s, and no more than two previous chemotherapy regimens, while it was seen in 8/10 patients with one of these characteristics (P