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International audience; Progress leads to increase life duration at the metastatic stage but metastatic disease is most often lethal. Decision-making is necessary for an increasing period of care, beyond evidence-based medicine, dealing with complexity and uncertain benefit/risk ratio. This requires to inform the patient realistically, to discuss prognostication, to develop anticipated written preferences. These changes mean to pass from a medicine based on informed consent to medicine based on respect of the patient wishes even if it can be complex to determine. A new multidisciplinarity is needed, centered on the meaning of the care, the proportionality of the care, the anticipated patient trajectory. The ASCO has published recommendations on early palliative care. The timing and the quality of the discussion between palliative care specialists and oncologists is crucial. We propose 10 steps to organize a multidisciplinary onco-palliative meeting, as it appears the key for the organization of care in non-curable disease.; Le progrès conduit à allonger la durée de vie de la maladie cancéreuse métastatique, qui demeure le plus souvent une maladie évolutive et mortelle. Les soins se réalisent pendant une durée croissante au-delà des preuves fournies par les études cliniques, donc dans la complexité et l’incertitude sur les rapports bénéfice/risque. Respecter le cadre éthique, renforcé par la loi Claeys-Leonetti de février 2016, pour une maladie évolutive potentiellement mortelle, conduit à informer le patient de manière réaliste, évoquer le pronostic, développer les discussions anticipées, recueillir et respecter ses préférences. Ces évolutions conduisent à passer d’une médecine du consentement éclairé à une médecine du respect de la volonté, avec toute la complexité que suppose la détermination de cette dernière. Tandis que s’est structurée la pluridisciplinarité au diagnostic par l’association des expertises diagnostiques et thérapeutiques vis-à-vis de la maladie tumorale, émerge ainsi un besoin de structuration d’une autre pluridisciplinarité, interrogeant le sens pour la personne, la proportionnalité du soin, la trajectoire personnelle et la sécurisation du parcours de soins. Pour atteindre cet objectif, la précocité de l’alliance des expertises complémentaires est décisive. Ceci a conduit à des recommandations de la Société américaine d’oncologie clinique (ASCO). L’introduction de l’équipe de soins palliatifs est un temps essentiel et la qualité de la concertation onco-palliative est déterminante. Nous décrivons notre préconisation pour mettre en pratique une réunion de concertation (RCP) onco-palliative, véritable pivot d’un changement d’organisation du soin en situation d’incurabilité.

Background Abiraterone (ABI) is a major oral agent for the treatment of metastatic castration-resistant prostate cancer (mCRPC) patients but its systemic exposure is subject to a large inter-individual variability. We aimed to explore the relationship between ABI trough plasma concentration and prostate-specific antigen (PSA) response in mCRPC patients and to identify the critical determinants for its activity. Patients and methods This is a monocentric prospective observational study in mCRPC patients treated with ABI. The plasmatic concentration of ABI at steady state was measured using liquid chromatography with fluorescence detection. The primary objective was to study the relationship between mean ABI plasma exposure (ABI C min ) and 3-month PSA response. Results From 2012 to 2016, 61 mCRPC patients were eligible for pharmacokinetic/pharmacodynamic assessment. Thirty-eight patients experienced PSA response (62%, [confidence interval {CI} 95% 50–78]). In univariate analysis, ABI C min was 1.5-fold higher in responders: 12.0 ng/mL (CI 95% 9.4–15.6) versus 8.0 ng/mL (CI 95% 5.8–11.6; P = 0.0015). In multivariate analysis, only ABI C min was independently associated with PSA response (odds ratio = 1.12 [CI 95% 1.01–1.25], P = 0.004). By receiver operating characteristic analysis, the optimal threshold for ABI C min was 8.4 ng/mL. Progression-free survival (PFS) was significantly higher in patients with ABI C min above 8.4 ng/mL (hazard ratio 0.55, [CI 95% 0.31–0.99], 12.2 [CI 95% 9.2–19.5] versus 7.4 [CI 95% 5.5–14.7] months otherwise, P = 0.044). Conclusions We showed that ABI trough concentration correlates with PSA response and PFS. Moreover, we could determine a cut-off value of plasmatic concentration for PSA response. Altogether, ABI concentration monitoring appears as a new approach to improve clinical outcome in mCPRC patients.

BACKGROUND Systemic hypertension is a frequent side effect of antiangiogenic drugs (AADs) and may represent a marker of efficacy on cancer. We hypothesized that large artery properties are affected by AADs, and contribute to the rise of blood pressure and may be better related to cancer progression and mortality than hypertension. METHODS AND RESULTS Participants were studied before AADs (V0), 10 days later (V1) and then every 2 weeks for 6 weeks (V1-V4). We included 57 consecutive patients in whom treatment with sorafenib (400 mg twice daily) or sunitinib (37.5-50 mg once daily) was indicated. The target dose could be adjusted according to tolerance and response. Aortic and carotid stiffness, brachial and central blood pressure and augmentation index were measured noninvasively at each visit. Data regarding cancer progression and mortality were collected at 6 months. Twenty-eight patients (49%) developed hypertension. Brachial SBP significantly increased during follow-up (V0-V1: +9.6 ± 15.2 mmHg, P

Therapeutic drug monitoring (TDM) could be helpful in oral targeted therapies. Data are sparse to evaluate its impact on treatment management. This study aimed to determine a threshold value of plasma drug exposure associated with the occurrence of grade 3-4 toxicity, then the potential impact of TDM on clinical decision. Consecutive outpatients treated with sunitinib were prospectively monitored between days 21 and 28 of the first cycle, then monthly until disease progression. At each consultation, the composite AUCƬ,ss (sunitinib + active metabolite SU12662) was assayed. The decisions taken during each consultation were matched with AUCƬ,ss and compared to the decisional algorithm based on TDM. A total of 105 cancer patients and 288 consultations were matched with the closest AUCƬ,ss measurement. The majority (60%) of the patients had metastatic renal clear-cell carcinoma (mRCC). Fifty-five (52%) patients experienced grade 3-4 toxicity. Multivariate analysis identified composite AUCƬ,ss as a parameter independently associated with grade 3-4 toxicity (P < 0.0001). Using the ROC curve, the threshold value of composite AUCƬ,ss predicting grade ≥3 toxicity was 2150 ng/mL/h (CI 95%, 0.6-0.79%; P < 0.0001). At disease progression in patients with mRCC, AUCƬ,ss tended to be lower than the one assayed during the first cycle (1678 vs. 2004 ng/mL/h, respectively, P = 0.072). TDM could have changed the medical decision for sunitinib dosing in 30% of patients at the first cycle of treatment, and in 46% of the patients over the whole treatment course. TDM is routinely feasible and may both contribute to improve toxicity management and to identify sunitinib underexposure at the time of disease progression.

Arterial pulse wave velocity (PWV) depends on blood pressure (BP). Correction of PWV for BP is commonly performed using a statistical approach, requiring a patient cohort. We recently developed a mechanistic, model-predictive approach to assess BP-independent changes in carotid PWV (cPWV) at the level of the individual. The goal of the present study is to compare our novel technique to conventional statistical correction, in the context of anti-cancer therapy using anti-angiogenic drugs (AADs). AADs frequently lead to a PWV increase, but also to hypertension, underlining the need for BP correction of PWV measurements. We obtained carotid artery systolic and diastolic cross-sectional areas (echotracking) and corresponding BPs (tonometry) in 48 patients before starting AAD treatment (sorafenib/sunitinib), and at four follow-up visits spaced 2 weeks apart. For each patient, we derived cPWV and a baseline single-exponential BP cross-sectional area curve. Based on these baseline curves and follow-up BPs, we predicted cPWV at follow-up due to BP. By comparing predicted and measured cPWVs at follow-up, we assessed the BP-independent cPWV increase. In the same way, we assessed whether diastolic cross-sectional area (A(d)) changed beyond the BP-induced amount. The AAD-induced BP-independent increase in cPWV was 0.43(0.09,0.77) ms(-1) (mean (95% CI), P=0.014, mechanistic approach) and 0.48(0.14,0.82) ms(-1) (P=0.006, statistical approach). Ad increased with 1.92(0.93,2.92) mm(2) (P

Breast cancer is the second cause for brain metastases. Their incidence is rising, partly due to the therapeutic improvements which alter the natural history of breast cancer. Predictive factors for brain metastases have been identified: HER2 oncogene overexpression, lack of expression of hormone receptors, young age and triple negative status. Brain metastases prognosis remains poor with a median survival shorter than 1 year, except for solitary lesions treated by surgery or radiosurgery. We have analysed two series of data from Institut Curie (Paris and Saint-Cloud). In women younger than 65 years, with HER2 negative breast carcinoma, median survival was 7.1 months. In women older than 65 years, median survival was 4 months.

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.

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.

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 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.

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)

Previous reports suggested that selective serotonin reuptake inhibitors (SSRI) could decrease the activity of 5-hydroxytryptamine type 3 (5-HT3) antagonists against acute chemotherapy-induced nausea and vomiting (CINV), possibly through serotonin accumulation for 5-HT3 receptors.Chemonaive cancer patients receiving SSRI and antiemetic agents, including the 5-HT3 antagonist ondansetron and the neurokinin 1 (NK1) antagonist aprepitant for highly emetogenic chemotherapy (etoposide-platinum), were matched to control patients for the following variables: age, gender, primary tumor, past history of gestational emesis, chronic intake of benzodiazepines and/or corticosteroids, chronic alcohol intake, and aprepitant use. The primary evaluation criterion was the occurrence of acute vomiting during the first two cycles of treatment.Forty-four patients were eligible for this analysis. The proportion of patients, who experienced at least one episode of grade ≥ 1 acute vomiting in patients receiving SSRI, compared to patients who did not, was significantly higher (59.1 vs. 22.7%, respectively, p = 0.03, odds ratio 4.72, 95% confidence interval 1.13-22.88). Grade ≥ 2 acute vomiting was also significantly more frequent in patients receiving SSRI, even after the implementation of aprepitant to antiemetic prophylaxis (41.2 vs. 5.9%, p = 0.04).Our findings reinforce the hypothesis that SSRI decrease the antiemetic activity of the 5-HT3 serotonin antagonist ondansetron, resulting in higher rates of acute vomiting in cancer patients despite adequate antiemetic prophylaxis. Adding the NK1 antagonist aprepitant do not counterbalance the deleterious effect of SSRI, probably due to the synergistic effects of SSRI and NK1 antagonists on serotonin transmission.

Background Oxaliplatin has less haematological toxicity than cisplatin and carboplatin. The combination of pemetrexed, oxaliplatin and bevacizumab appeared well tolerated and active as second- or third-line treatment in a previous phase II study. Its role as first-line therapy remains to define. Patients and methods From August 2008 to May 2011, consecutive chemo-naive patients with stage IV non-squamous non-small cell lung cancer (NSCLC) received pemetrexed 500mg/m 2 , oxaliplatin 100mg/m 2 and bevacizumab 7.5mg/kg every 3 weeks for 6 cycles, in the outpatient setting. Maintenance therapy including pemetrexed and bevacizumab was given to patients with non-progressive disease. The primary evaluation criterion was safety. Secondary evaluation criteria were response rate, progression-free survival (PFS) and overall survival (OS). Results Thirty-eight patients (50% males, median age: 55 years, range 38–76) received a total of 199 cycles (median per patient: 6, range 2–6), plus 98 cycles of maintenance therapy. Twenty patients (52.6%) had a PS of 2, and 6 (15.8%) had brain metastases. The most frequent toxicities were hypertension (all grades: 42.1%) and peripheral neuropathy (grade 2–3: 21.1%). Haematological toxicities included grade 4 neutropenia, grade 3 anaemia and thrombopenia (5.3% each). Neither febrile neutropenia nor arterial thrombo-embolic event occurred. The objective response rate was 55.3% (95%CI: 39.5–71.1). The median PFS and OS were 6.2 (95%CI: 5.4–9.0) and 14.6 (95%CI: 9.8–19.5) months, respectively. Conclusions In this single centre experience, the combination of pemetrexed, oxaliplatin and bevacizumab was well tolerated and had promising activity as first-line therapy in unselected patients with stage IV non-squamous NSCLC.

5041 Background: Abiraterone (ABI) is a standard treatment in metastatic castration-resistant prostate cancer (mCRPC). However, the large interindividual variability in ABI pharmacokinetics could c...

2572 Background: Sorafenib is approved in various advanced cancers, including hepatocellular carcinoma (HCC), differentiated iodo-resistant thyroid cancer (DTC), and renal cell carcinoma (RCC). We ...

170 Background: Older age is a cause of disparity in cancer treatment decision and treatment guidelines for patients with comorbidities, polypharmacy, denutrition or psycho-social frailty are needed. A pre-therapeutic multidimensional assessment might improve the complex patient management. We developed an experimental program of integrated medicine called ARIANE. We report 18 months activity of this outpatient setting evaluation, its feasibility and impact on treatment decision-making. Methods: Complex patients with predefined cancer treatment strategy entered into the program. A one-day evaluation combined consultations of cardiologist, geriatrician, diabetologist, anesthetist, pharmacist, pain specialist, dietician, psychologist and social worker. Evaluation of performance status, EKG, ejection fraction, ASA score, diabetes, social vulnerability and malnutrition was performed including a geriatric assessment, which focused on items like comorbidity (CIRS-G), dependance (ADL, IADL), fails (Up and Go Test), cognitive impairment (MMSE, Clock Drawing Test) and depression (GDS scale). A pharmacist assessed the risk of drug-drug interactions. Results: Eighty-seven pts, median age 81 years (range 25-94), 76% male, 51% PS 0-1, 77% grade 3 or 4 comorbidity were included. Genito-urinary, lung cancers and sarcoma represented 77% of pts. Eighty-two percent of pts were assessed by at least ≥ 7 participants. Identified factors of vulnerability were polypharmacy (n=65; 75%; >3 drugs), social distress or severe malnutrition (both n=21; 24%), depression (n=17; 19.5%) and cognitive impairment (n=13; 15%). We identified drug interaction in 18 pts (27%). The risk assessment resulted in anticancer treatment changes in 47/87 patients (54%): protocol adaptation (n=19/87; 22%), less aggressive treatment (n=15/87; 17.2%), or more intensive therapy (n=13/87; 15%). Conclusions: A one-day multidisciplinary risk assessment is an answer to the complexity of unfit cancer patients and improves the safety of anticancer treatments.

e20523 Background: Elderly people represent a growing population susceptible to be treated with sunitinib (SU). The aim of this retrospective study was to explore the relationship between SU exposu...

e13589 Background: Targeting angiogenesis with anti-VEGF receptors is a new approach for cancer treatment. The most common side effect is arterial hypertension. We hypothesize that pre-existing large artery remodeling with increased arterial stiffness is a determinant of blood pressure (BP) increase under antiangiogenic (AAD) and that AAD may alter mechanical properties of large arteries independently of BP increase. Methods: 49 patients (mean age=57[15] years, mean bSBP=128[22] mmHg and mean DBP=75[11] mmHg; treated for a cancer with an indication to start AAD (Sorafenib, Sunitinib or Bevacizumab) were included in this longitudinal study. Arterial evaluation was assessed at baseline (BL) before the introduction of AAD and every two weeks for 2 months (V1 to V4) with aortic stiffness (PWV) and central BP measurements by aplanation tonometry (SphygmoCor), carotid distensibility with high resolution echotracking system (ArtLab). Results: 43% of the patients developed hypertension between BL and V1. Using linear mixed model analysis with random effects, PWV significantly increased between BL and V1 (BL-V1, adjusted slope 0.89 m/s, F value=6.8, p=0.04) after adjustment to age and mean BP, carotid distensibility decreased significantly during follow-up (BL-V1, adjusted slope= -4.4, p=0.04; BL-V2, adjusted slope= -5.23, p=0.001) after adjustment to age and mean BP. The determinants of BP increase were studied between BL and V1 since anti-hypertensive drugs were introduced after V1. Using multivariate analysis, BL PWV was an independent determinant of the delta brachial SBP (β= -1.36 [-2.61; 0.11], p=0.034) with age (β=0.25 [0.04; 0.47], p=0.02). Conclusions: AAD induce functional alterations of large arteries, increasing arterial stiffness, independently of BP increase. In addition, pre-AAD administration arterial properties influence the hypertensive response to AAD.

9620 Background: Alterations of performance status (PS) and of nutritional status are predictors of acute toxicity following anticancer treatment. Resting energy expenditure (REE) is often increase...