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Venlafaxine is an antidepressant which acts through the inhibition of the reuptake of norepinephrine and serotonin. Venlafaxine is active against neuropathic and chronic pain. We report the case of a 69-year-old woman who presented a paclitaxel-induced neuropathy. She presented paresthesias, pin pricks in both hands with functional impairment. Venlafaxine hydrochloride was introduced at 37.5 mg twice daily. The patient noticed a dramatic recovery of her symptoms within 2 days, with both reduction of the paresthesias and functional improvement. This is the first report of efficacious use of venlafaxine for the treatment of paclitaxel cumulative neurosensory toxicity.

Combination of chemotherapy and surgical resection of metastases is the most promising strategy to improve the fraction of long-term survivors and cured patients in metastatic colorectal cancer. We reproducibly observed evidence of exacerbation of the oxaliplatin-induced neurosensory toxicity following surgery. Total, protein-bound and intra-erythrocytic concentrations of oxaliplatin were measured, whenever possible, immediately prior to surgery and 4, 24 and 48 h following surgical resection. Among 12 patients, seven (58%) patients reported immediate post-operative aggravation of the pre-existing neurotoxicity. At the time of surgery, we detected high intra-erythrocytic platinum concentrations in all patients (median: 1365 µg/l, range: 820–2968 µg/l). While ultrafilterable oxaliplatin was not detectable prior to surgery, it could be detected immediately after surgery and during 48 h. These results suggest that patients heavily pretreated with oxaliplatin may experience aggravation of neurotoxicity after surgery, probably through a redistribution of the pool of intra-erythrocytic oxaliplatin biotransformation products into the plasma. This clinical observation might be the consequence of peroperative hemolysis.

Following the articles by Verheijen and colleagues and Mir and colleagues reporting individualized pazopanib dosing strategy ([1, 2][1]), we wish to share our experience on pazopanib dose monitoring. From January 2014 to June 2017, we monitored trough pazopanib concentration ( C min) in plasma from

Introduction Le methotrexate haute-dose (HD-MTX ≥ 1 g/m2) est utilise pour traiter certaines hemopathies malignes et osteosarcomes. La survenue d’une insuffisance renale aigue (IRA) est une complication classique qui favorise le retard d’elimination du MTX et ses diverses toxicites. Au-dela des mesures therapeutiques classiques (hyperhydratation alcaline, acide folinique, epuration extrarenale), une enzymotherapie specifique onereuse est disponible (glucarpidase), mais son impact clinique est mal evalue. Patients et methodes Nous avons analyse les prescriptions d’HD-MTX dans 11 centres au cours des 15 dernieres annees, afin d’identifier et decrire les patients adultes ayant developpe une IRA (classification KDIGO). Nous avons reference un eventuel usage de glucarpidase (ATU officielle : methotrexatemie ≥ 10 μmol/L apres H48, ou ≥ 3 μmol/L apres H48 avec IRA). Resultats Dans une cohorte preliminaire de 126 patients adultes traites par HD-MTX, l’incidence d’IRA etait de 20 cas (18 % des patients en oncologie et 15 % en hematologie). Au total 76 cas d’IRA ont ete etudies. En moyenne, le pic de creatinine etait de 206 μmol/L (+227 %), observe apres 5,6 jours ; il y avait 19 IRA stade 1 (25,0 %), 29 IRA stade 2 (38,2 %) et 27 IRA stade 3 (35,5 %). L’anurie (1 cas) et le recours a la dialyse (4 cas) etaient rares, la surcharge hydrosodee frequente (29 % des patients). A 3 mois, 13 patients etaient decedes (17,3 %) et dix (15,4 %) presentaient des sequelles renales. Lors de l’episode d’IRA, 61 % des patients ont recu de la glucarpidase. Malgre un effet spectaculaire sur la methotrexatemie, la glucarpidase (comparativement a un traitement conservateur) ne modifiait ni le profil evolutif de l’IRA (severite, delai de recuperation, recours a l’epuration extrarenale) ni l’incidence des toxicites extrarenales. L’absence de benefice persistait apres stratification pour les taux residuels de MTX, le delai d’utilisation ou encore le respect ou non du libelle d’ATU. Discussion La glucarpidase a probablement peu d’effet sur le MTX deja present au niveau de la lumiere tubulaire ou dans la cellule tubulaire renale, ce qui pourrait expliquer l’absence d’effet nephroprotecteur observe. Conclusion La glucarpidase ne modifie pas le profil evolutif de l’IRA post-HD-MTX.

Little is known on factors predicting toxicity of anti-PD1 checkpoint inhibitors. Sarcopenic obesity is associated with increased acute toxicity of cytotoxic agents and targeted therapies. We explored whether body composition also influenced the occurrence of early acute limiting toxicity (ALT) of anti-PD1 in melanoma patients. This is a monocentric, retrospective study analyzing toxicity outcome in consecutive melanoma patients treated with nivolumab or pembrolizumab. Various parameters linked to the patient or the disease status have been analysed. Body mass index (BMI; kg/m2) and muscle mass using CT were measured prior to treatment initiation. Chi-squared test and Mann-Whitney’s tests were used for the comparison of categorical and continuous variables respectively. Among 68 melanoma patients treated with anti-PD1 (47 pembrolizumab, 21 nivolumab), 38 (56%) patients had a BMI ≥ 25 kg/m2 and 11 (16%) a BMI ≥ 30, while 13 (19%) had both sarcopenia and a BMI ≥ 25 kg/m2. For the 11 (16%) patients who experienced early ALT, the mean BMI was higher (27.9 versus 24.7 kg/m2; p = 0.04). Among the 32 female patients, sarcopenic overweight patients had a 6.5-fold increased risk of ALT (50 versus 7.7%; p = 0.01). Sarcopenic overweight is associated with more early ALT of anti-PD1 in melanoma patients.

e16022 Background: Sarcopenia, the condition of low muscle mass, is a prognostic factor across many cancer types including bladder cancer. Moreover, sarcopenia was shown to predict severe toxicity induced by many anticancer agents. Conversely, NAC may increase the prevalence of sarcopenia before surgery. This retrospective study aimed to investigate the association of sarcopenia with pathologic response and toxicity in localized bladder cancer patients treated by NAC and RC. Methods: Among the 52 patients who underwent RC after NAC between Jan 2010 and Dec 2016, the preoperative sarcopenia status could be determined for 39 patients. Skeletal muscle cross-sectional area at the third lumbar vertebra was measured on CT scan images, and sarcopenia was defined as skeletal muscle index of < 43 cm2/m2 for men with body mass index (BMI) < 25 kg/m2, SMI < 53 cm2/m2 for men with BMI > 25 kg/m2, and SMI < 41 cm2/m2 for women. The criteria for efficacy was pathologic response defined by pathological down-staging to ≤ pT1N0. Patients were compared using χ2 or Fischer’s exact test when appropriate. Results: 48% of patients were sarcopenic before RC. A significant higher rate of pathological response was found in non-sarcopenic patients compared to sarcopenic patients (13/20 vs 5/19, P = 0.01). More severe chemotherapy related toxicity was found in sarcopenic patients compared to non-sarcopenic patients for neutropenia (P = 0.06), thrombopenia (P = 0.15), and neuropathy (P = 0.23). Among the 21 patients for whom sarcopenia status before chemotherapy was available, 3 patients became sarcopenic and 4 patients initially sarcopenic gained muscle mass on post-chemotherapy CT scan. Conclusions: Sarcopenia is frequent in localized bladder cancer patients. Muscle mass correlates with pathological response to NAC.

e18266 Background: Nivolumab, a human antibody targeting programmed death 1 receptor, is part of the armamentarium of lung cancer. Serious treatment-related adverse effects have been reported, including pneumonitis, whose mechanism is unclear. The aim of this study was to evaluate the occurrence of subclinical or patent pulmonary hypertension in patients receiving Nivolumab for advanced lung carcinoma. Methods: Clinical and morphometric data of patients receiving Nivolumab for treatment of advanced lung carcinoma are prospectively collected in our Institution and reviewed monthly by a multidisciplinary panel. For the purposes of the study, a blinded analysis of computed tomography (CT)-scans was performed, by two radiologists, to measure pulmonary artery (PA) and ascending aorta (Ao) diameters at the level of the bifurcation. Pre- and post-treatment PA/Ao ratios were calculated. Results: There were 62 patients with mean age and body mass index of 62.3 years and 24.3 kg/m2, all current or former smokers. Main histological type of carcinomas (stage IV in all cases) was adenocarcinoma (58.1%). Mean PA (+SD) diameters (before and after 4 cycles of Nivolumab [3mg/Kg]) were 26.3 (+/-2.8) mm and 28.0 (+3.0) mm, respectively (p = 4.9*10-7). Mean Pre- and post-treatment by Nivolumab PA/Ao ratios were 0.82 (+0.09) and 0.87 (+0.11), respectively (p < 0.001). There was no significant change in CT-scan aspect of lung parenchyma. Two patients experienced acute respiratory failure at day 52 and 58 after starting of Nivolumab therapy. CT-scan ruled out pulmonary embolism, but we observed PA/Ao ratio > 1 suggesting acute pulmonary hypertension, confirmed by echocardiography. They both died despite intensive care. Even excluding these 2 patients from comparative analysis, PA diameters and PA/Ao ratios remain significantly higher after Nivolumab treatment (both p < 0.001). Conclusions: Nivolumabcan induce subclinical or symptomatic acute pulmonary hypertensionpossibly leading to fatal adverse events.

3055 Background: Nivolumab is the first checkpoint immunotherapeutic agent approved for NSCLC. By enabling host immune-mediated cytotoxic activity against tumor cells, nivolumab induces a tumor response in 15% of patients (pts). However, host-related parameters to predict nivolumab activity are still missing. We evaluated the predictive and prognostic value of the presence of a systemic inflammatory response. Methods: From July 2015 to December 2016, we measured at nivolumab initiation the Glasgow Prognostic Score (GPS), a cumulative prognostic score based on C-reactive protein and albumin, the neutrophil-lymphocyte ratio (NLR), the Nutrition Risk Index (NRI) and the Prognostic Nutritional Index (PNI). Univariate and multivariate analyses tested the association between initial patient characteristics and clinical outcome. Results: The characteristics of the 57 consecutive pts analyzed are: median age of 66 years (range 41-78), 65% non-squamous cell lung cancer, 61.4% males and 52.6% Performance Status (PS) 0-1. GPS was 0 in 27 (47.4%), 1 in 21 (36.8%) and 2 in 9 (15.8%) pts. In multivariate analysis, parameters associated with disease progression (per RECIST 1.1) were GPS (1-2 vs 0; HR 1.45 [1.11-1.90], p= 0.009) and number of metastatic sites (>2 vs ≤ 2; HR: 0.75 [0.57-0.98], p = 0.04). Overall survival was significantly worse for pts with PS 2-3 vs PS 0-1 (p=0.01) and for pts with GPS 2 vs GPS 0-1 (p=0.01). The GPS was an independent predictive marker of progression and was superior to other inflammation-based prognostic scores in our cohort (Table). Conclusions: The Glasgow Prognostic Score (GPS) allows identifying patients with disease progression and long survivors among metastatic NSCLC patients treated with nivolumab. [Table: see text]

3015 Background: Use of antibiotics (ATB) alters the gut microbiota composition and decreases bacterial diversity. Pre-clinical evidences demonstrated the impact of the microbiota in the efficacy of immune checkpoint blockades (ICB) in cancer. Interaction between ATB and ICB has not been extensively investigated in cancer patients (pts). Our study evaluated the effect of ATB in cancer pts treated with PD-1/PD-L1 inhibitors. Methods: We conducted a retrospective analysis of pts treated with PD-1/PD-L1 inhibitors for advanced Renal Cell Carcinoma (RCC), Urothelial Cancer (UC) and Non-Small Cell Lung Cancer (NSCLC) and data on ATB use were collected. ATB(+)/(-) groups were defined as pts treated or not with ATB before (2 months period) or within the first month of ICB. PFS and OS were compared between both groups among all pts and then according to tumor site. Statistical analyses were performed using the Kaplan-Meier method. Cox regression analyses were performed separately for each cancer type adjusting for its specific risk factors. Results: Among 175 pts included, 51 (29%) received ATB (mostly beta-lactamases and fluoroquinolones). ATB(+) group had shorter PFS and OS when compared to ATB(-) group: 3.4 vs. 5.2 months, p < 0.013, and 12.2 vs. 20.8 months, p < 0.001, respectively. According to tumor type, ATB(+) group translated into decrease OS (7.0 vs. 13.8 months, p < 0.038) in NSCLC. In RCC and UC pts, ATB (+) group had shorter PFS when compared to ATB(-) group (4.3 vs. 7.4 months, p < 0.013 and 1.8 vs. 4.3 months, p = 0.048, respectively). The negative impact of ATB was maintained after multivariate analyses adjusting for risk factors in each tumor type. Conclusions: ATB prescription preceding or concomitant to the first injection of PD-1/PD-L1 inhibitors impaired the outcome in patients with advanced cancers. This reduction in efficacy seems to be independent of classical prognostic factors in RCC, UC and NSCLC. These data should be validated in larger cohort. In addition, the role of gut composition to explain this interaction is ongoing, as well as novel diagnosis tools based on microbiota to predict response/resistance to ICB.

e17594 Background: In the phase III DECISION trial comparing SOR with placebo, pts with advanced RAI-R DTC treated with SOR experienced higher rates of adverse events (AEs) than pts with renal cell carcinoma and hepatocellular carcinoma treated with SOR (Brose et al. Lancet 2014). We hypothesized that long-term thyroxine suppressive therapy might result in a high prevalence of sarcopenia, which is known to be associated with increased toxicity of SOR (Antoun et al. Ann Oncol 2010), and we investigated whether sarcopenia at baseline correlated with DLT. Methods: In DECISION, pts with an analyzable baseline lumbar CT scan were eligible. Skeletal muscle cross-sectional area at the third lumbar vertebra was measured, and the median value for each sex defined the cut-off points for sarcopenia. DLT was defined as any AE leading to dose modification; early toxicities occurred ≤30 days after treatment initiation. Results: Of 365 eligible pts, 199 (55%) were sarcopenic (SOR n = 100, placebo n = 99) with large geographic differences: 65/91 Asians (71%), 29/62 North Americans (47%), and 105/212 Europeans (50%). Sarcopenia was 3-fold more frequent than non-sarcopenia in pts ≥75 years of age (19% vs 6%) and was associated with lower body weight (mean [standard deviation]: 71.3 [16.8] vs 80.8 [19.5]; P < 0.0001). Among SOR pts, 76/180 (42%) experienced early DLT of which 44/76 (58%) occurred in sarcopenic pts (P = 0.6497). Among the 90 males, 61 (68%) were sarcopenic and of the 35 males with early DLT, 27 (77%) were sarcopenic. Median time to DLT in sarcopenic vs non-sarcopenic pts who received SOR was 63 vs 95 days, respectively (log-rank P = 0.5328). Conclusions: In this exploratory analysis from DECISION, approximately half of the pts were sarcopenic. In the overall population, no association between sarcopenia and early DLT or DLT were found. Clinical trial information: NCT00984282.

11544 Background: Erlotinib (E) and gefitinib (G) are indicated as first-line therapy of EGFR-mutated NSCLC patients (pts). Many studies highlighted TKI pharmacokinetic (PK) impact on toxicities. However, data about the relationship between PK and efficacy are sparse. Recently, ctDNA has been shown to be a strong prognostic factor for metastatic NSCLC pts undergoing specific treatment. Thus, we underwent an observational study to determine plasma drug concentration and ctDNA impact on outcomes in NSCLC pts treated with E or G. Then, we explored the correlation between PK and ctDNA in order to improve management of pts treated with EGFR-TKI. Methods: We analyzed consecutive pts with EGFR-mutated NSCLC treated with TKI in Cochin and European Georges Pompidou hospitals (APHP, Paris) from April 2010 to March 2016. Plasma samples were collected 2 to 6 weeks after TKI initiation. Steady state trough concentration (Cssmin) was assessed by high performance chromatography. CtDNA was analyzed using Next-Generation Sequencing (Ampliseq ColonLungV2 panel, BPER method). Therapeutic ranges obtained from previous studies were between 1200 to 2000 ng/mL and > 200 ng/mL for E and G, respectively. Results: Out of 77 pts, 56 had Cssmin analysis, 40 ctDNA analysis and 31 both. Median age was 70 years (range: 31-90), 49 were treated with E, 24 with G. Median follow-up was 19 months. Whatever EGFR TKI, pts with Cssmin into therapeutic ranges had longer PFS than pts over or under-exposed (median: 17.5 vs 7.5 months, p = 0.002). Those with early indetectable ctDNA had significantly better PFS (median 13 vs 5.8 months, p = 0.01) and OS (median: 21.4 vs 14.3 months, p = 0.02). No correlation was found between ctDNA and Cssmin. Occurrence of toxicity > grade 2 in pts treated with E was associated with higher plasma concentration (mean 1991 vs 1184 ng/mL, p < 0.01). Conclusions: Early Cssmin and ctDNA assessment appear as markers to predict outcomes. Our observational study is the proof of concept that pts undergoing EGFR-TKI therapy could be monitored with Cssmin and ctDNA to define optimal personalized treatment strategies. A prospective study is planned to evaluate dose adaptation of TKI based on those 2 tools.

Francois Goldwasser poursuit la reflexion amorcee dans Laennec en avril 20161. Avec le progres medical, de plus en plus de patients atteints de cancer evoluent vers la maladie chronique. Il faut, pour eux, repenser les terminologies – projet curatif, phase curative, phase palliative, cancer curable, cancer en phase chronique ou incurable – et redefinir une offre de soins appropriee, faisant toute leur place aux soins palliatifs.

This prospective interventional study aims to show the feasibility and impact of information procedure on surrogate and advance directives (AD), for patients with incurable lung or gastrointestinal cancer. The intervention consisted of two semi-structured interviews. The first included: collection of preferences for prognostic information and involvement in decision-making, initial assessment of knowledge, information and surrogate and DA. The second assessed the impact of the first interview on knowledge, surrogate designation and DA writing, the assessment procedure by the patient and assessment of anxiety generated. Among 77 eligible patients, 23 (30 %) were included, 6/29 (21 %) refused to participate, 20/23 (87 %) completed both interviews. Patients not included had a higher 4-month death rate than included ones (39 % vs. 4 %, P=0.002). Patients included had high expectations of information and appreciated it be delivered early, by someone not involved in their care. The study shows the feasibility of the procedure and its impact on the use of surrogate and DA by patients, however, revealing the complexity of approaching end-of-life wills and the importance of a process of anticipated discussion.

AIM: To investigate the efficacy and safety of gemcitabine and platinum salt, with or without trastuzumab, in patients with locally advanced or metastatic urothelial carcinoma overexpressing Her2. METHODS: The main eligibility criterion was Her2 overexpression on immunohistochemistry (IHC 2+ or 3+) of primary tumour tissue confirmed by fluorescence in situ hybridisation (FISH). Patients were randomised to Arm A: gemcitabine 1000mg/m(2) (days 1 and 8) plus either cisplatin (70mg/m(2)) or carboplatin (AUC=5) (day 1 every 3 weeks) or Arm B: added trastuzumab (8mg/kg loading dose, then 6 mg/kg every 21 days until progression). The primary end-point was progression-free survival (PFS). RESULTS: Among 563 screened patients, 75 (13.3%) were Her2 positive (IHC 2+/3+ and FISH+) and 61 met all eligibility criteria (median age, 64 years; 54/61 males; 50/61 baseline ECOG-PS 0-1; 11 locally advanced and 50 metastatic). There was no significant difference between Arms A and B in median PFS (10.2 versus 8.2 months, respectively, p=0.689), objective response rate (65.5% versus 53.2%, p=0.39), and median overall survival (15.7 versus 14.1 months, respectively, p=0.684). In an exploratory analysis, trastuzumab-treated patients receiving cisplatin rather than carboplatin-based chemotherapy fared better (PFS: 10.6 versus 8.0; OS: 33.1 versus 9.5 months). Myelosuppression was the main grade 3/4 toxicity. A case of grade 3 cardiotoxicity and one death from febrile neutropenia occurred in arm B. CONCLUSION: The unexpectedly low incidence of Her2 overexpression precluded the detection of a significant difference in efficacy on addition of trastuzumab to platinum-based chemotherapy with gemcitabine. However, the satisfactory tolerance of the combination warrants further studies, especially of the cisplatin-based combination, in well-defined patient subsets.

Introduction Sunitinib is a multikinase inhibitor active in various cancers types including renal cancers and endocrine tumors. The study analyzed the influence of the lean body mass (LBM) and of pharmacogenetic variants on the exposure to sunitinib and its active metabolite, SU12662, and on sunitinib toxicity and clinical activity. Materials and Methods Exposure to sunitinib and SU12662 was assessed on days 10 and 21 during the first treatment cycle. Acute toxicity was graded using the NCI 4.0 CTCAE ver. 4.0. The LBM and 14 common single nucleotide polymorphisms in the CYP3A4/3A5, NR1I2, NR1I3, ABCB1, and ABCG2 genes were analyzed according to the drug exposure at day 10. Determinants (including sunitinib exposure and pharmacogenetic variants) for toxicities were assessed, as well as the relationship between drug exposure and survival in renal cancer patients. Results Ninety-two patients (60 % with renal cancer) were assessable for pharmacokinetics, toxicity and survival, and 66 for genetic analysis. The LBM (p A) (p = 0.014) were two independent parameters accounting for the variability of composite (sunitinib + SU12662) exposure. Advanced age (OR = 1.47 [1.01–2.15], p = 0.048) and high sunitinib exposure (OR = 1.16 [1.05–1.28], p = 0.005) were independently associated with any grade ≥ 3 acute toxicity, and high SU12662 exposure was associated with grade ≥ 2 thrombocytopenia (OR = 1.27 [1.03–1.57], p = 0.028). A high composite area under the curve (AUC) >1,973 ng/mL∙h at day 21 was associated with a doubled survival (35.2 vs 16.7 months; log-rank p = 0.0051) in renal cancer patients. Conclusions This study indicates that LBM and drug monitoring may be helpful in the management of sunitinib-treated patients.

Sorafenib is a multi-tyrosine kinase inhibitor (TKI). Considerable clinical experience has been accumulated since its first Phase III clinical trial in metastatic renal cancer patients in 2007. The management of its early acute toxicity in fit patients is well known. The management of prolonged treatment becomes the new challenge.Using sorafenib as a key word for PubMed search, we review preclinical and clinical data and discuss the pharmacokinetics and pharmacodynamics of sorafenib, its acute and cumulative toxicities and their consequences for patient management.The systematic multi-disciplinary risk assessment of cancer patients prior to TKI initiation reduces the risks of acute and late toxicity, especially drug-drug interactions and arterial risks. Sarcopenia is now identified as a major risk of severe toxicity. The very diverse clinical pictures of cumulative toxicity must be known. The monitoring of sorafenib systemic exposure is helpful especially in elderly patients. Moreover, at disease progression, it allows distinguishing between underexposure to sorafenib and truly acquired resistance to the drug. The optimal use of sorafenib should allow improving the reported results of flat-dose. Finally, most of this knowledge could be used for the development and optimal use of the other TKIs.

ObjectiveHypertension is a frequent side effect of antiangiogenic drugs (AAD). Targeting VEGF pathway may also affect large and small artery properties, along with or independently of blood pressure changes. We hypothesized that large and small artery property changes in response to AAD reflect their effect on the microcirculation at the site of the tumor, and thus may be related to cancer progression and mortality.Design and methodWe included 60 patients [age 58 (15) years, mean SBP 127(21)mmHg] in whom treatment with AAD was indicated for various metastatic solid tumors. Noninvasive arterial investigation was performed before AAD (V0), 1 week later (V1) and then every two weeks for two months (V1 to V4): carotid-femoral pulse wave velocity (cfPWV), central SBP and augmentation index (cAIx) by applanation tonometry (SphygmoCor®), and carotid stiffness (CStiff) and internal diameter (CiD) by high resolution echotracking (Artlab®). Cancer progression and mortality were assessed at 6 months.Results and conclusion28(47%) patients developed hypertension during follow-up. bSBP significantly increased during follow-up (V0-V1: +9.3± 15.2mmHg, P

The treatment of metastatic colorectal cancer has been transformed during the last decade with biotherapies, two of them were marketed in 2013. Four agents are monoclonal antibodies, while the fifth agent is a tyrosine kinase inhibitor. Two agents are inhibitors of the EGF-receptor pathway, cetuximab and panitumumab, and have as class-toxicity, cutaneous toxicity. The other three agents are bevacizumab, aflibercept and regorafenib, and interact with angiogenesis, they are associated with a risk of vascular toxicity, mainly hypertension. These agents participate to an improvement of disease control at the metastatic stage, and in some cases, favour the curative surgical resection of metastases. Their use is discussed in multidisciplinary meetings dedicated to gastrointestinal cancers, in the presence of liver surgeons.

Background. The majority of patients receiving the platinum-based chemotherapy drug oxaliplatin develop peripheral neurotoxicity. Because this neurotoxicity involves ROS production, we investigated the efficacy of mangafodipir, a molecule that has antioxidant properties and is approved for use as an MRI contrast enhancer. Methods. The effects of mangafodipir were examined in mice following treatment with oxaliplatin. Neurotoxicity, axon myelination, and advanced oxidized protein products (AOPPs) were monitored. In addition, we enrolled 23 cancer patients with grade ≥2 oxaliplatin-induced neuropathy in a phase II study, with 22 patients receiving i.v. mangafodipir following oxaliplatin. Neuropathic effects were monitored for up to 8 cycles of oxaliplatin and mangafodipir. Results. Mangafodipir prevented motor and sensory dysfunction and demyelinating lesion formation. In mice, serum AOPPs decreased after 4 weeks of mangafodipir treatment. In 77% of patients treated with oxaliplatin and mangafodipir, neuropathy improved or stabilized after 4 cycles. After 8 cycles, neurotoxicity was downgraded to grade ≥2 in 6 of 7 patients. Prior to enrollment, patients received an average of 880 ± 239 mg/m 2 oxaliplatin. Patients treated with mangafodipir tolerated an additional dose of 458 ± 207 mg/m 2 oxaliplatin despite preexisting neuropathy. Mangafodipir responders managed a cumulative dose of 1,426 ± 204 mg/m 2 oxaliplatin. Serum AOPPs were lower in responders compared with those in nonresponders. Conclusion. Our study suggests that mangafodipir can prevent and/or relieve oxaliplatin-induced neuropathy in cancer patients. Trial registration. Clinicaltrials.gov NCT00727922.

Introduction Le taux de reponse objective aux anti-PD1 est de 40 % dans le melanome. Les facteurs predictifs de reponse sont encore mal connus. Nous avons etudie l’association entre la rapidite d’evolution de la maladie et le type de dissemination (lymphatique ou hematogene) et la reponse aux anti-PD1. Materiel et methodes Les dossiers des patients de dermatologie de l’hopital Cochin ayant recu des anti-PD1 pour un melanome metastatique ont ete revus retrospectivement. Etaient etudies : l’âge, le sexe, le type de melanome primitif, le statut BRAF, les traitements anterieurs, la reponse objective (RO) (reponse complete ou partielle selon les criteres RECIST 1.1), le type de dissemination (lymphatique defini comme l’existence de metastases ganglionnaires exclusives ou la survenue d’une metastase ganglionnaire avant celle d’une metastase viscerale et hematogene le reste). Les patients avec un stade N2c (metastases en transit isolees) ont ete exclus. Nous avons egalement etudie le temps de passage ganglionnaire defini comme le delai entre 1 e metastase ganglionnaire et 1 e metastase viscerale et le delai de traitement defini comme le temps entre le diagnostic du melanome et l’initiation des anti-PD1. Les patients n’ayant recu qu’une perfusion d’anti-PD1 ont ete exclus. Resultats Sur les 79 patients traites par anti-PD1 entre aout 2014 et fevrier 2016, 65 ont ete inclus (31 femmes, âge median 65 ans [21–90 ans]). Le traitement etait toujours introduit pour progression de la maladie. Soixante treize pour cent des patients ont recu du pembrolizumab (2 mg/kg/3 semaines), 27 % du nivolumab (3 mg/kg/2 semaines). Trente-six pour cent des patients etaient naifs de traitement. Quarante-trois pour cent des melanomes etaient des SSM. Vingt-huit pour cent des melanomes etaient porteurs d’une mutation BRAF V600. Vingt-cinq pour cent des patients avaient des metastases cerebrales. Le taux de RO dans la cohorte etait de 42 %. La dissemination etait lymphatique chez 23 patients (37 %), hematogene chez 39 (63 %) et 3 stades N2c exclus. Il n’y avait pas d’association significative entre le type de dissemination et la reponse. Le temps de passage ganglionnaire moyen etait de 26 mois (2 a 132 mois). Un temps de passage ganglionnaire superieur a 4 ans etait associe a une meilleure reponse au traitement (0 % chez les non-repondeurs et 33 % chez les repondeurs, p = 0,03). Le delai de traitement moyen etait de 71 mois (2 a 409 mois) et etait statistiquement associe a la reponse : delai moyen de 99 mois chez les repondeurs et de 53 mois chez les non-repondeurs ( p = 0,01). Discussion L’evolutivite des melanomes est difficile a prendre en compte dans les essais et seule la LDH de debut de traitement est utilisee. Les valeurs elevees sont predictives de mauvaise reponse aux anti-PD1. Nous proposons avec le temps de passage ganglionnaire et le delai entre le diagnostic initial du melanome et l’introduction des anti-PD1 des mesures indirectes de l’evolutivite des melanomes. Conclusion Les melanomes d’evolution lente repondent mieux aux anti-PD1.

Introduction Les anti-PD1 ont un taux de reponse de pres de 40 % dans le melanome et permettent une augmentation de la survie globale de 24 mois. En France, l’esperance de vie des hommes de 85 ans est de 5 ans. Le but de notre etude etait de determiner la tolerance de ce medicament sur l’autonomie des patients de plus de 85 ans. Materiel et methodes Les dossiers des patients (pts) de plus de 85 ans traites par anti-PD1 pour un melanome dans le service de dermatologie de l’hopital Cochin etaient revus retrospectivement. L’âge, le sexe, le stade au traitement, les scores « Activities of Daily Living » (ADL) et « Instrumental Activities of Daily Living » (IADL) avant et apres 2 cures, les effets secondaires et le taux de reponse etaient releves, ainsi que la realisation ou non d’une evaluation par un geriatre avant ou au cours du traitement. Resultats Sept patients ont ete inclus : 5 femmes et 2 hommes, âge median 89 ans [87–93]. Aucun n’avait d’antecedent de troubles cognitifs. Trois ont eu une evaluation geriatrique. Tous les patients ont ete traites par pembrolizumab (Pe) (3 mg/kg/3 semaines). La mediane des ADL avant traitement etait de 6/6 [5–6] et celle des IADL de 5 [3–6] (sur 5 pour les hommes et sur 7 pour les femmes). Un patient a ete traite au stade III et 6 au stade IV (M1a : 1 pt ; M1b : 2 pts ; M1c : 3 pts). Mutation BRAF en V600 : 0. Une patiente avait ete traitee au prealable par DTIC. Quatre (57 %) pts ont eu des effets secondaires de grades III ou IV relatifs au Pe ou au dispositif d’administration : 2 pseudopolyarthrites rhizomeliques (PPR), une polymyosite severe (4 mois d’hospitalisation), 1 infection articulaire sur PAC. Une patiente est decedee une semaine apres la deuxieme perfusion (cause indeterminee). Les 3 patients ayant eu un effet auto-immun avaient, avant traitement, un taux d’AAN faible mais positif. Le nombre de cures median etait de 2 [1–8]. Quatre patients (57 %) ont eu une reponse partielle dont un patient une reponse quasi complete apres une seule cure, un patient a eu une stabilisation et 2 patients une progression. Apres 2 cures, les ADL etaient abaisses a 4 en mediane et les IADL a 2,5 ( p = 0,03 dans les 2 cas). Discussion L’utilisation des anti-PD1 est a l’etude dans differents cancers touchant particulierement le sujet âge (carcinome de Merkel). La necessite de conserver l’autonomie chez les patients de plus de 85 ans doit etre au cœur de l’acte therapeutique. Dans notre cohorte, il y a une diminution de l’autonomie apres deux cures d’anti-PD1. Il ne peut etre exclu que cette perte d’autonomie soit liee a l’evolution de la maladie. Par ailleurs, 4 patients ont eu des effets secondaires importants dont des PPR non decrites dans les etudes princeps et une patiente est decedee sans que l’on puisse exclure une cause toxique. Conclusion Les anti-PD1 ont probablement un impact sur l’autonomie des personnes de plus de 85 ans. Leur utilisation doit etre discutee au cas par cas apres une evaluation complete du patient et seulement en cas de melanome avec des localisations menacantes.

Reactivation of tuberculosis is rare in patients receiving chemotherapy for solid tumours, and poorly documented in patients receiving molecular targeted therapy. We report on a patient with metastatic renal-cell carcinoma treated with temsirolimus, who developed respiratory symptoms and mild fever after 6 weeks of treatment. CT-scan and laboratory tests were consistent with reactivation of tuberculosis. The patient received anti-tuberculosis therapy including rifampicin, a potent CYP3A4/5 inducer. After introduction of rifampicin-based treatment, the patient experienced tumour progression, leaving questionable the potential pharmacokinetic interaction between rifampicin and temsirolimus, a substrate for CYP3A4.

Hepatocellular carcinoma (HCC) is one of the most frequent cancers. The only curative treatment is liver transplantation or complete surgical resection; however, most patients have inoperable disease at diagnosis. To date, no cytotoxic agent has demonstrated a clinical impact on time-related parameters, especially survival. The development of new treatments of inoperable HCC patients is highly desirable. Among the new cytotoxic agents, DNA topoisomerase I poisons are those with the widest spectrum of antitumor activity. However, few data are available in HCC patients. One of the main obstacles to the use of irinotecan in HCC is the frequent alterations of liver function at diagnosis. A 48-year-old patient with a HCC that had developed within a normal liver but of very poor prognosis because of a multifocal primary tumor with a large nodule measuring 10 cm of diameter, associated with a portal thrombosis, could tolerate very intensive treatment with irinotecan using doses up to 700 mg/m2 every 2 weeks and was responsive to treatment as measured by alpha-fetoprotein levels. Despite initial criteria of inoperability, the absence of disease progression under therapy with a follow-up of 1 year invited us to propose a liver transplant. The patient is still in post-surgical complete remission and has consolidation chemotherapy with irinotecan. This result invites us to consider the evaluation of the efficacy of topoisomerase I poisons in HCC patients and to escalate the dose of irinotecan in patients with less than grade 4 neutropenia.

Hemolytic uremic syndrome (HUS) is a rare clinical and biological entity. HUS has been reported after several anticancer chemotherapies and most often after mitomycin C-based chemotherapy regimens. Little information is available concerning the occurrence and outcome of this syndrome after administration of more recent chemotherapeutic agents. We present a case of HUS in an advanced ovarian cancer patient treated with carboplatin and gemcitabine, and described its favorable outcome after chemotherapy interruption and supportive care with a 1 year follow-up.

The clinical development of combinations of cisplatin or carboplatin with DNA topoisomerase I (Topo I) inhibitors is based on their overlapping spectrum of antitumor activity and their in vitro synergy, but is limited by significant hematotoxicity. We studied the cellular interactions between oxaliplatin and topotecan in the IGROV-1 human ovarian cancer cell line prior to evaluating the combination in the clinic. Growth inhibition was studied after a 96 h exposure to oxaliplatin and topotecan. The analysis of the cytotoxicity by the isobolograms method revealed supra-additivity with maximal cytotoxicity obtained by giving oxaliplatin prior to topotecan. In the presence of topotecan, the formation of oxaliplatin-induced DNA interstrand crosslinks was not modified in cells, but their reversion was slower, as measured by alkaline elution. Successive topotecan exposures did not affect the level of Topo I-mediated DNA single-strand breaks (SSBs). Pre-exposure to oxaliplatin transiently increased Topo I-mediated SSBs, suggesting that DNA platination might stimulate Topo I DNA cleavage activity. Hence, the cellular pharmacology of oxaliplatin combined with topotecan appeared highly dependent on the schedule. Therefore, this study suggests that the combination of topotecan with oxaliplatin might exhibit sequence-dependent pharmacodynamic interactions in the clinic.

Cervico-isthmic pregnancy is a rare form of ectopic pregnancy with a poor obstetrical prognosis, whose mechanism remains unclear. Preclinical data indicate that HER-2 plays a major role in embryo implantation. We report a case of cervico-isthmic pregnancy occurring during treatment with trastuzumab (Herceptin™, a monoclonal antibody to HER-2). A 43-year-old woman presented with abnormal vaginal bleeding, while she was receiving trastuzumab for the last 14 months as an adjuvant therapy for a node-positive, HER-2 positive breast cancer. The diagnosis of evolutive cervico-isthmic pregnancy was confirmed by iterative ultrasonographic examinations. Given the poor obstetrical prognosis, the patient underwent voluntary abortion. The use of trastuzumab during pregnancy is still poorly documented, and its safety is not yet established. Given the importance of HER-2 in embryo implantation and fetal development, its putative role in this abnormal embryo implantation should be discussed.

Introduction Le vemurafenib (VMF) inhibiteur du gene BRAF est un des traitements de premiere ligne des melanomes inoperables porteurs de la mutation V600. Nous rapportons 4 cas de sarcoidose sous VMF. Observations Deux hommes et 2 femmes, âges de 38 a 43 ans, etaient traites par VMF pour un melanome de stade IV avec mutation BRAF, prescrit en premiere ligne pour 3 patients et en septieme ligne (apres, entre autres, interferon et ipilimumab) pour une patiente. Des lesions d’hypodermite ou des papules erythemateuses lupoides a la vitropression apparaissaient entre 2 et 9 mois apres le debut du vemurafenib. La biopsie de ces lesions trouvait des granulomes epithelioides et giganto-cellulaires sans necrose, compatibles avec une sarcoidose. La decouverte de sarcoidose etait fortuite chez 1 patient devant la presence de granulomes epithelioides intra-dermiques sur la piece de l’exerese d’un naevus atypique. L’enzyme de conversion de l’angiotensine etait elevee chez 2 patients. Une localisation extra-cutanee de sarcoidose etait trouvee chez 2 patients : adenopathies hilaires bilaterales chez une patiente (contemporaines des lesions cutanees), uveite anterieure et intermediaire bilaterale chez une autre (1 an apres les lesions cutanees). Les lesions cutanees regressaient rapidement sous dermocorticoides malgre la poursuite du VMF. La survie moyenne sous VMF etait de 18 mois (4,5–32+), avec 3 reponses completes et 1 reponse partielle. La prevalence des sarcoidoses sous VMF etait de 5,7 % dans notre service (70 patients traites). Discussion Une prevalence de 0,58 % des sarcoidoses a ete rapportee dans une serie de 1199 patients atteints de melanome. Des sarcoidoses apparues sous traitement par interferon et ipilimumab ont ete decrites. Dans nos observations, l’imputabilite du VMF est plausible devant l’absence de signes evocateurs de sarcoidose avant le debut du traitement et le developpement rapide des symptomes (a M2 dans 2 cas). L’explication pourrait etre une activation paradoxale de la proliferation lymphocytaire Th1 dans les cellules sans mutation BRAF. La sarcoidose semble associee a une meilleure reponse aux inhibiteurs de BRAF. Par ailleurs, les uveites sont un des effets indesirables connus de ces traitements, et celle de notre patiente en presentait les caracteristiques cliniques. Notre observation suggere toutefois de rechercher des localisations viscerales de sarcoidose en cas d’uveite. Conclusion Le VMF, qui a aussi une action immunomudulante, doit etre ajoute, comme les interferons alpha et l’ipilimumab, a la liste des traitements inducteurs de sarcoidose.

Introduction et but de l’etude 27–40 % des patients > 70 ans atteints de cancer sont denutris. Leur etat nutritionnel repose souvent sur l’evaluation du medecin seul, du fait de troubles cognitifs frequents (10–15 % des sujets âges atteints de cancer). Mais on ne connait pas la perception que les patients âges ont de leur etat et prise en charge nutritionnels. L’objectif de l’etude etait de comparer la perception de la denutrition du medecin a celle des patients > 70 ans, a la realite de l’etat nutritionnel. Materiel et methodes Etude « un jour donne » realisee dans 30 centres francais, incluant les patients adultes atteints d’un cancer, presents dans l’un de ces centres le jour de l’etude et consentant a participer. Les donnees recueillies sous forme de questionnaires specifiques comprenaient notamment la localisation et le stade de la maladie, la prise en charge nutritionnelle, l’anthropometrie, l’albuminemie, la prise alimentaire, la capacite fonctionnelle. Seules les donnees portant sur les patients > 70 ans sont presentees ci-apres. La denutrition etait definie par une perte de poids ≥ 5 % en 1 mois ou ≥ 10 % en 6 mois, et/ ou un IMC ≤ 21 et/ou albuminemie Resultats et Analyse statistique Sur 2197 patients, 578 etaient ≥ 70 ans (26 %), dont 154 ≥ 80 ans (7 %). Les localisations tumorales les plus frequentes etaient : digestives (41 %) et hematologiques (10 %). Le PS score etait plus altere chez les ≥ 70 ans (PS2+ 53% vs.38 %; P 70 ans. Les medecins surestimaient la prise alimentaire chez les ≥ 70 ans qui declaraient plus souvent l’existence d’une prise en charge nutritionnelle que les Conclusion Pres de la moitie des patients âges atteints de cancer sont denutris. Ils sous-estiment leur etat de denutrition et l’efficacite d’une prise en charge nutritionnelle alors meme qu’ils recoivent plus de conseils dietetiques et de CNO. Ces patients devraient etre mieux informes de l’importance du suivi nutritionnel au cours de la maladie.

The increasing number of unfit patients calls for better risk assessment prior to initiating anti-tumor treatment. This is a major concern in the prevention and reduction of treatment-related complications. The aim of our study was to evaluate the nutritional status for the risk assessment of patients qualifying to receive the gemcitabine and oxaliplatin (GEMOX) regimen. This single-center, retrospective study examined baseline clinical and biological characteristics in a cohort of 165 unselected, consecutive cancer patients receiving GEMOX. Malnutrition was defined as either body mass index (BMI)18.5 kg/m(2), body weight loss10% over 3 mo, or albuminemia35 g/L. A total of 165 patients (median age 61 yr, PS 0-1: 71%) were studied. Malnutrition was seen in 43% of PS 0-1 patients, vs. 60% of PS 2 and 66% of PS 3 patients (P0.05). Median relative dose-intensity was 0.90 (0.17-1.04). GEMOX dose-intensity correlated negatively with loss of baseline weight (r = -0.24, P0.02). In patients who did not complete more than 2 cycles of chemotherapy, median PS (P0.01), mean C-reactive protein (CRP; P0.01), and mean albuminemia (P0.05) were, respectively, significantly higher, higher, and lower. Malnutrition is associated with a high risk of early discontinuance of treatment. Systematic basal evaluation of the nutritional status, including albuminemia and BMI, is recommended.

Sorafenib, a multi-kinase inhibitor that targets the VEGF, PDGF and BRAF pathways, has demonstrated significant clinical activity in metastatic differentiated thyroid cancer. However, all patients eventually experience disease progression with a median progression-free survival close to 10 months. Since sorafenib exposure is known to decrease over time, we hypothesized that dose adjustments aiming to restore adequate exposure could lead to further clinical activity. We report, as a proof of concept on a patient with radio-iodine resistant metastatic thyroid cancer, who experienced disease progression after an initial response to sorafenib (400 mg twice daily). Whereas the thyroglobulin-progression-free survival at standard doses was 6 months, iterative dose optimization led to a prolonged progression-free survival up to 41 months. Sorafenib doses were increased up to 1600 mg bid, in order to maintain clinical activity, and to restore active plasma concentration, since sorafenib exposure had decreased over the time. Toxicity was mild and manageable for more than 2 years. However, the patient eventually experienced grade 3 proteinuria leading to treatment discontinuation. This observation opens up new horizons for daily management of radioactive iodine-refractory differentiated thyroid cancer patients progressing under standard doses of sorafenib, and stress the need to monitor its plasma concentration.

The objective was to quantify the risk dynamics for the sorafenib-induced hand-foot syndrome (HFS) and to explore by simulations the dose-toxicity relationships according to different dosing regimens.Eighty-nine patients treated with sorafenib were considered: Treatment duration and regimen, and number and frequency of HFS observations were highly variable. A nonlinear mixed-effect model was built to link sorafenib administrations to the risk of each HFS score, through a latent variable model. Model evaluation was driven by goodness-of-fit and simulation-based diagnostics. Impact of sorafenib regimen on HFS dynamics was evaluated by simulations. A surrogate measure of benefit-to-risk ratio was calculated by using the concept of utility function, accounting for efficacy on tumor growth inhibition and severe HFS risk.An original pharmacokinetic-pharmacodynamic model for sorafenib-induced HFS, including the kinetics of a latent variable model, relating sorafenib administrations, per se its exposure, to HFS dynamics is proposed. From the model simulations, it appears that the more the daily dose is fractioned, the more the patients are at risk of HFS. Interestingly, the number of daily occasions was found more influential than the dose itself. Taking into account tumor growth inhibition in the utility function, the twice-daily administration schedule is favored for daily doses600 mg. This approach illustrates how understanding the dynamic relationship between drug administrations and a limiting adverse event may help to control toxicity and adequately adjust treatment modalities.

Background: Although the efficiency of oxaliplatin in patients with advanced ovarian cancer has been demonstrated, it is not commonly used. In cells, oxaliplatin is metabolized by the enzymes belonging to the glutathione-S-transferase (GST) family. Case: A 55-year-old woman with advanced ovarian cancer received 6 cycles of paclitaxel and carboplatin after debulking surgery. Six months later, she experienced a clinical recurrence. A second-line chemotherapy combining 500 mg/m2 cyclophosphamide with 100 mg/m2 oxaliplatin was initiated and maintained for 10 cycles. The patient thus experienced a second complete remission that lasted for 6 years. We found that she had deficient GSTM1 enzyme activity with homozygous deletion and normal GSTP1 and GSTT1 activities. Conclusion: The association of a homozygous deletion of GSTM1 with hypersensitivity to oxaliplatin and cyclophosphamide combination chemotherapy has not been described to date in ovarian cancer. Further study of its potential interest to personalized second-line therapy in these patients is called for.

The Glasgow Prognostic Score (GPS), combination of C-reactive protein and albumin, has proven its prognostic value in metastatic colorectal cancer (mCRC) patients receiving conventional cytotoxic therapy. More recently, anti-EGFR therapies have been validated in mCRC and roll forward the patients’ overall survival (OS). We aimed to evaluate the prognostic accuracy of the GPS in patients receiving anti-EGFR therapy in addition to conventional chemotherapy. From January 2007 to February 2012, consecutive mCRC patients who received 5-fluorouracil-based chemotherapy plus cetuximab were included in the present analysis. Patients were eligible for the study if they met the following criteria: advanced pathologically proven MCRC, age >18 years, adequate renal function (creatinine clearance >40 ml/min), C-reactive protein and albumin and performance status evaluation before treatment initiation. A total of 49 patients received cetuximab plus 5-fluorouracil-based chemotherapy (colon, n = 34; rectum, n = 15) and were treated with a median follow-up of 35 months (16.5–74.7). Median age was 48 years old. In addition to cetuximab, patients received oxaliplatin- (n = 34, 60 %) or irinotecan (n = 15, 30 %)-based chemotherapy. At time of diagnosis, 55, 29 and 16 % of patients had a GPS of 0 (n = 27), 1 (n = 14) and 2 (n = 8), respectively. Fifty-five, 29 and 14 % of patients add one, two or ≥3 metastatic sites, respectively. Considering two groups (GPS = 0 and GPS ≥1), median progression-free survivals were significantly different (p = 0.0084). Median OS in the GPS 0, 1 and 2 groups were 38.2, 14 and 12.1 months, respectively (p = 0.0093). The results of the present study confirm that the GPS is still a simple and effective prognostic factor in the era of cetuximab therapy in mCRC patients.

Background: Little is known on factors predicting sunitinib toxicity. Recently, the condition of low muscle mass, named sarcopenia, was identified as a significant predictor of toxicity in metastatic renal cell cancer (mRCC) patients treated with sorafenib. We investigated whether sarcopenia could predict early dose-limiting toxicities (DLTs) occurrence in mRCC patients treated with sunitinib. Methods: Consecutive mRCC patients treated with sunitinib were retrospectively reviewed. A DLT was defined as any toxicity leading to dose reduction or treatment discontinuation. Body composition was evaluated using CT scan obtained within 1 month before treatment initiation. Results: Among 61 patients eligible for analysis, 52.5% were sarcopenic and 32.8% had both sarcopenia and a body mass index (BMI)