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AIMS Cytidine deaminase (CDA) activity in cancer patients' serum has been proposed as a predictive biomarker for efficacy and toxicity of nucleoside analogues. However, discrepant results about its predictive value have been reported due to the high interindividual variability in CDA activity. This study aimed at identifying determinants of this interindividual variability. METHODS From December 2014 to November 2015, 183 patients were prospectively included. Serum CDA activity, biological and clinical characteristics as well as five common single nucleotide polymorphisms (SNPs) in the CDA gene (c.-451C > T, c.-92A > G, c.-33_-31delC, c.79A > C, c.435 T > C) were analysed. Associations between clinical characteristics, pharmacogenetic variants and CDA activity were univariately tested. P

International audience; BACKGROUND: The management of older cancer patients has been highly challenging for clinicians in a health-care system operating at maximum capacity during the COVID-19 pandemic. PATIENTS AND METHODS: We analyzed data from 9 different institutions. The primary endpoint was to assess the prevalence of adapted patient care during the pandemic for elderly cancer patients. The secondary endpoint was to assess the incidence of hospitalization and mortality due to COVID-19. All patients were older than 65years of age. RESULTS: We analyzed data from 332 outpatients’ case files between 9th of March and 30th of April 2020. The median age was 75years (range: 65-101) and 53% were male. Because of the COVID-19 pandemic, more than half of the outpatients received modified patient care, defined as postponement or cancellation of surgery, irradiation scheme adapted, systemic treatment or the use of telemedicine. Among patients with localized cancer, 60% had a change in management strategy due to the pandemic. Changes in management strategy were made for 53% of patients at the metastatic stage. GCSF was used , in 83% of patients, increasing considerably in the context of the pandemic. Sixty-nine percent of physicians used telemedicine. In the final analysis, only one patient was hospitalized for COVID-19 infection. No deaths due to COVID-19 were reported in elderly cancer patients during this time period. CONCLUSION: Our study is the first to assess modification of patient care in elderly cancer outpatients during an epidemic. With this unprecedented crisis, our objective is to protect our patients from infection via protective barrier measures and social distancing, but also to guarantee the continuity of cancer care without overexposing this fragile population. Physicians were able to adapt their practice and used new forms of management, like telemedicine.

Background Cancer patients are thought to have an increased risk of developing severe Coronavirus Disease 2019 (COVID-19) infection and of dying from the disease. In this work, predictive factors for COVID-19 severity and mortality in cancer patients were investigated. Patients and Methods In this large nationwide retro-prospective cohort study, we collected data on patients with solid tumours and COVID-19 diagnosed between March 1 and June 11, 2020. The primary endpoint was all-cause mortality and COVID-19 severity, defined as admission to an intensive care unit (ICU) and/or mechanical ventilation and/or death, was one of the secondary endpoints. Results From April 4 to June 11, 2020, 1289 patients were analysed. The most frequent cancers were digestive and thoracic. Altogether, 424 (33%) patients had a severe form of COVID-19 and 370 (29%) patients died. In multivariate analysis, independent factors associated with death were male sex (odds ratio 1.73, 95%CI: 1.18-2.52), ECOG PS ≥ 2 (OR 3.23, 95%CI: 2.27-4.61), updated Charlson comorbidity index (OR 1.08, 95%CI: 1.01-1.16) and admission to ICU (OR 3.62, 95%CI 2.14-6.11). The same factors, age along with corticosteroids before COVID-19 diagnosis, and thoracic primary tumour site were independently associated with COVID-19 severity. None of the anticancer treatments administered within the previous 3 months had any effect on mortality or COVID-19 severity, except cytotoxic chemotherapy in the subgroup of patients with detectable SARS-CoV-2 by RT-PCR, which was associated with a slight increase of the risk of death (OR 1.53; 95%CI: 1.00-2.34; p = 0.05). A total of 431 (39%) patients had their systemic anticancer treatment interrupted or stopped following diagnosis of COVID-19. Conclusions Mortality and COVID-19 severity in cancer patients are high and are associated with general characteristics of patients. We found no deleterious effects of recent anticancer treatments, except for cytotoxic chemotherapy in the RT-PCR-confirmed subgroup of patients. In almost 40% of patients, the systemic anticancer therapy was interrupted or stopped after COVID-19 diagnosis., Highlights • A total of 1289 patients with solid tumours and COVID-19 were analysed. • Mortality and COVID-19 severity were mainly driven by patient general characteristics. • Overall, we found no deleterious effects of recent anticancer treatments on mortality. . • Systemic anticancer treatment was interrupted or stopped in 39% of patients.

Background: The cancer population seems to be more susceptible to COVID-19 infection and have worse outcomes Front of this pandemic, we had to adapt our patient care to protect our patients without compromising their prognosis related to their cancer The national PRATICOVID study aims to describe the modification of the medical and surgical patient care for this population, according to the recommendations in this context of pandemic, within our hospitals which are strongly mobilized Methods: We analyzed data from 9 different institutions, 3 Military Hospitals, 4 Academics Hospital, 2 Private Hospital, from oncologists, surgeons, radiotherapists The primary endpoint was to assess the prevalence of adapted patient care during pandemic The secondary endpoints were to describe the point of view of clinicians and patients during and after the pandemic Results: We analyzed 435 medical care between 9th of March and 30th of April The median age was 69 years (range, 24-99), 54% was male 167 patients (38 4%) were newly diagnosed and only 4% were included in a clinical trial Because of COVID-19 pandemic, 47 6% of the outpatients had modified patient care The main primary tumor site was breast cancer (22 7%) at a metastatic stage 24 6% have postponed surgery, or not receive perioperative chemotherapy, 18 4% received hypofractioned schedule and 57% had an adaptive systemic protocol (stopped, oral protocol, spacing between cures) 70% of physicians are used telemedicine During this period, 67% of the physicians were relaxed to taking care of their patients 57% of the patients have seen to be relaxed or low worried about the pandemic However, 71% are worried after the lockdown, because of future patient care, stage at diagnosis, access to clinical trial, our abilities to receive in the same time all the patients Conclusions: PRATICOVID study is the first to assess modification of patients cares during an epidemic in cancer outpatients Faces with this unprecedented crisis, physicians were able to adapt their practice in order to protect their patients against the virus and while ensuring the course of patient care But physicians are worried after de lockdown because of the care pathway’s issues Clinical trial identification: CNIL;reference number: 2217722v0 Legal entity responsible for the study: The authors Funding: Has not received any funding Disclosure: All authors have declared no conflicts of interest

The cancer population seems to be more susceptible to COVID‐19 infection and have worse outcomes. We had to adapt our medical practice to protect our patients without compromising their cancer prognosis. The national PRATICOVID study aims to describe the adaptation of cancer patient care for this population. We analyzed data from nine different institutions. The primary endpoint was to assess the prevalence of adapted patient care during the pandemic. The secondary endpoints were to describe the point of view of clinicians and patients during and after the pandemic. We analyzed 435 medical procedures between 9th of March and 30th of April. Because of the COVID‐19 pandemic, 47.6% of the outpatients received modified patient care. Twenty‐four percent of scheduled surgeries were postponed, or were performed without perioperative chemotherapy, 18.4% followed a hypofractioned schedule, and 57% had an adaptive systemic protocol (stopped, oral protocol, and spacing between treatments). Seventy percent of physicians used telemedicine. During this period, 67% of the physicians did not feel distressed taking care of their patients. However, 70% of physicians are worried about the aftermath of the lockdown, as regards future patient care. The PRATICOVID study is the first to assess modification of patient care in cancer outpatients during an epidemic. With this unprecedented crisis, physicians were able to adapt their practice in order to protect their patients against the virus while ensuring continuity of patient care. But physicians are worried about the aftereffects of the lockdown specifically in regard to care pathway issues., The PRATICOVID study is the first to assess modification of patient care in cancer outpatients during an epidemic. With this unprecedented crisis, physicians were able to adapt their practice in order to protect their patients against the virus while ensuring continuity of patient care.

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.

Objectifs Depuis decembre 2019, nous devons faire face a la pandemie mondiale du COVID-19. Cela a entraine une adaptation des soins, notamment pour les patients atteints d’un cancer urologique. L’etude PRATICOVID vise a decrire la modification de la prise en charge medicale et chirurgicale des patients pour cette population, selon les recommandations dans ce contexte de pandemie, au sein de nos hopitaux fortement mobilises. Methodes Nous avons analyse les donnees de 9 institutions differentes : 3 hopitaux militaires, 4 hopitaux universitaires, 2 hopitaux prives. Nous avons considere les patients suivis par les oncologues, chirurgiens et radiotherapeutes. Au total, 435 patients ont ete inclus entre le 9 mars et le 30 avril 2020 dans l’etude PRATICOVID. Parmi eux 178 patients presentaient un cancer urologique. Le critere d’evaluation principal etait d’evaluer la prevalence des soins adaptes aux patients pendant la pandemie. Les criteres d’evaluation secondaires etaient de decrire le point de vue des cliniciens et des patients pendant et apres la pandemie. Resultats Cent quarante-cinq patients avec un cancer urologique ont ete retenus pour l’analyse finale. L’âge median etait de 71 ans (24–97), dont 90,3 % etaient des hommes. Parmi les patients, 62 (42,8 %) etaient nouvellement diagnostiques et seuls 10 etaient inclus dans un essai clinique. En raison de la pandemie de COVID19, 46,2 % des patients ambulatoires avaient modifie les soins aux patients. Le cancer de la prostate representait 50,7 % des cancers urologiques avec une modification de prise en charge. La chirurgie ne concernait que 11 % des patients inclus contre 56,6 % pour les traitements systemiques. Parmi les patients, 31,7 % ont beneficies exclusivement d’une teleconsultation. Parmi les medecins, 67 % etaient detendus et 57 % des patients se sont dits detendus ou peu inquiets par rapport a la pandemie. Parmi les patients, 71 % sont inquiets pour l’evolution de leur maladie. Conclusion L’etude PRATICOVID est la premiere a evaluer la modification des soins lors d’une epidemie des patients cancereux. Le suivi a long terme de ces patients est necessaire pour mesurer l’impact en termes de survie globale, specifique et sans progression.

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.

Resume Contexte Depuis la loi du 4 mars 2002 le medecin doit a son patient une information claire, loyale et appropriee. En cancerologie, face a l’annonce d’un mauvais pronostic, le devoir d’information loyale au patient pour faire valoir et respecter son autonomie peut entrer en contradiction avec le principe de non-malfaisance. Objectif Cette etude visait a identifier et comprendre les attentes d’information pronostique des patients atteints de cancer metastatique incurable ainsi que l’impact et le sens de ces informations. Patients et methodes Cette etude qualitative prospective se basait sur neuf entretiens semi-directifs conduits chez les patients atteints de cancer incurable suivis a l’hopital Cochin et qui avaient recu une mauvaise nouvelle liee au pronostic par leur medecin referent dans le mois precedent et il y a plus de 6 jours. Le guide d’entretien suivi visait a identifier le sens des informations recues ou manquantes selon qu’elles etaient desirees ou non. Resultats L’analyse des themes et sous-themes a permis de mettre en evidence sept themes qui se declinent differemment selon que le patient esperait la guerison et rejetait les autres possibilites, esperait la guerison mais envisageait qu’elle ne soit pas possible, ou avait fait le deuil de la guerison. Le caractere utile et acceptable de l’information pronostique ne dependait pas de criteres precis mais d’un faisceau d’arguments correspondant a des axes : la nature des objectifs qui passaient de la guerison a la qualite de vie, la demande de verite et de reassurance qui devenait de moins en moins pregnante, le rapport a l’incertitude qui d’angoissante devenait source d’espoir, l’espoir centre sur la guerison se centrait ensuite sur la qualite de vie, les manifestations d’angoisse qui s’estompaient au cours du cheminement, la temporalite qui se reduisait et le rapport a la mort qui entrait dans le champs des possibles. Conclusion L’identification de ces axes est un prealable a l’amelioration des pratiques d’annonce pronostique en cancerologie mais des etudes complementaires sont necessaires afin de determiner une facon adaptee de les utiliser en pratique clinique.

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.

Background Older non-small cell lung cancer (NSCLC) patients under erlotinib are reported to experience more acute toxicity. We hypothesized that modifications in erlotinib pharmacokinetics might explain this observation. Methods A monocentric prospective clinico-pharmacological study included stage IIIb/IV NSCLC consecutive pts. treated with erlotinib. The plasma concentration of erlotinib (Ce) was measured at steady state on day 15. We studied the relationship between age > 75 years, and Ce, using the Mann-Whitney U test and with the occurrence of acute toxicity, using a Fisher’s test. Results A total of 53 pts. were analyzed. Median age was 68 years (31–83), 56 % were female. All pts. > 75 years experienced toxicity: all grade acute adverse events were 1.6 fold more frequent (100 % vs 61 %; OR 95 % CI [1.9-INF]; p = 0.003). At day 15, Ce increased with age. Over 75 years old, the mean Ce was 1.5 fold higher: 2091 ng/mL (95 % CI [1476; 2706]) vs 1359 (95 % CI [1029; 1689]; p = 0.024). In pts. over 80 years old, the mean Ce was doubled: 2729 (95 % CI [1961; 3497]) vs 1358 ng/mL (95 % CI [1070; 1646]; p = 0.0019). Reduced lean body mass over 75 years (median 36.6 kg versus 49.1 kg) might account for these differences. Finally, the risk of early erlotinib discontinuation was increased by 11 in older pts. (33 % vs 3 % OR 17.2; 95 % CI [1.7; 892.5] p = .005). Conclusion The risk of overexposure to erlotinib increases with age. Reduced lean body mass may explain erlotinib pharmacokinetics and excessive acute toxicity in the elderly.

ObjectiveThis study aimed to assess the tolerance of bevacizumab (BEVA) among older ovarian cancer patients in daily clinical practice and identify a subpopulation of patients with a high risk of severe adverse effects.MethodsConsecutive patients with a pathologically proven high-grade serous ovarian, tubal, or peritoneal carcinoma who received BEVA between January 2006 and June 2014 were included in a retrospective analysis.ResultsAmong 86 BEVA-treated patients, 42 (48.8%) received concomitant chemotherapy, 26 (30%) had baseline arterial hypertension (HTN), and 33 (38.4%) were considered elderly (>70 years). Incidence of arterial, venous thromboembolism, hemorrhage, and bowel perforation were 2%, 8%, 12%, and 0%, respectively, and was not related to age. Incidence of severe (NCI-CTC v4 G3–4) HTN was significantly higher in elderly patients than in younger ones (39%; 95% confidence interval [CI], 22%–56% vs 17%; 95% CI, 7%–27%) (P = 0.017 by χ2 test) and in patients with baseline HTN (P < 0.05). Twenty-three percent of younger patients had baseline HTN compared with 42% of older ones (P = 0.052). Among patients without baseline HTN, older age was not associated with increased risk of severe HTN. However, incidence of severe HTN reached 71% (95% CI, 47%–95%) in older patients with baseline HTN. Exploratory analysis indicates that progression-free survival was similar in younger and older patients.ConclusionsBevacizumab is feasible in patients older than 70 years with advanced ovarian carcinoma. More attention must be paid to elderly patients with baseline HTN.

EML4 - ALK adenocarcinomas constitute a new molecular subgroup of lung tumours that respond very well to crizotinib, an ALK inhibitor. However, the diagnosis of ALK rearrangement in lung cancer is challenging. The aim of this study was to compare the diagnostic accuracy of five different methods in a series of 20 EGFR wt/wt lung adenocarcinomas from non- or light- smokers. Multiplex RT-PCR was considered as gold standard and identified four ALK -rearranged tumours among the 20 tested tumours. qRT-PCR got an interpretability rate of 100% and accurately typed all 20 tumours. qRT-PCR from corresponding formalin-fixed paraffin-embedded (FFPE) specimens got an interpretability rate of 65%. Out of the four previously identified ALK -rearranged cases, three were interpretable and two were retrieved using FFPE qRT-PCR. ALK break-apart FISH got an interpretability rate of 60% and accurately typed all of the twelve remaining cases. Anti-ALK immunohistochemistry (IHC) accurately typed all twenty tumours using a cut-off value of strong staining of 100% tumour cells. The 16 non ALK -rearranged tumours got no/light staining in 13 cases, and a moderate staining of 80–100% tumour cells in 3 cases. We then analysed four solid signet-ring lung adenocarcinomas. FFPE qRT-PCR, FISH and immunohistochemistry were concordant in three cases, with positive and negative results in respectively one and two cases. The fourth case, which was positive by FISH and immunohistochemistry but negative by RT-PCR, was shown to have a non- EML4 - ALK ALK -rearrangement. As various factors such as RNA quality, fixation quality and type of ALK rearrangement may impede ALK screening, we propose a combined FISH/molecular biology diagnostic algorithm in which anti-ALK immunohistochemistry is used as a pre-screening step.

Some patients with advanced hepatocellular carcinoma (HCC) progressing under sorafenib remain eligible for further systemic therapy. Little is known on the feasibility of systemic treatment beyond sorafenib in this setting. Consecutive HCC patients pre-treated with sorafenib received gemcitabine 1,000 mg/m² and oxaliplatin 100 mg/m² every 14 days. Exclusion criteria included Child C cirrhosis, PS≥3, creatinine clearance20 ml/min, albumin25 g/L and bilirubin54 μmol/L. Pre-treatment body composition was evaluated by CT scan to detect muscle wasting (sarcopenia). The primary evaluation criterion was safety. Secondary evaluation criteria were response rate, and progression-free (PFS) and overall survival (OS). Eighteen patients (median age: 64 years, range 25-77) received a total of 90 cycles (median per patient: 4, range 1-16). Eight patients (44.4 %) had a PS of 2, 5 (27.8%) had Child-Pugh B cirrhosis and 13 (72.2%) had a CLIP score3. The most frequent toxicities were thrombocytopenia (grade 2-4: n=7, 38.9%) and peripheral neuropathy (grade 2-3: n=7, 38.9%). The overall response rate was 18.8% (95% CI: 0-37.9), and another 18.8 % of patients had stable disease. The median PFS and OS were 3.2 (95% CI: 2.3-3.9) and 4.7 (95% CI: 3.8-8.1) months, respectively. Overall survival was significantly longer in patients without sarcopenia [10.0 months (95% CI: 7.0-13.8) vs. 3.0 months (95 % CI: 2.5-3.9), p0.001] and in patients with an ECOG PS2 [8.1 months (95% CI: 7.0-13.8) vs. 3.8 months (95% CI: 2.5-3.9), p=0.017]. In our experience, gemcitabine-oxaliplatin was feasible and had detectable clinical activity in HCC patients pre-treated with sorafenib. Further studies are needed to confirm these findings.

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.

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.

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.

Pegylated liposomal doxorubicin (PLD) is widely used in relapsing ovarian carcinoma. Its original formulation is metabolized by the monocyte–macrophage system. One of its main toxicities is the palmoplantar erythrodysesthesia (PPE) syndrome. To date, no predictive factors of PPE have been identified. Data of patients (pts) treated with PLD between 2005 and 2014 were retrospectively collected. A case–control study was performed, comparing main baseline clinical and biological characteristics of pts experiencing PPE and those who did not, after at least three cycles of PLD. A pilot analysis of blood monocyte subpopulations (classical, intermediate and non-classical) was performed by FACS in selected pts. Among 88 pts treated with PLD, 28 experienced PPE of any grade (31, 95 % CI 21–41). The first occurrence of PPE was at first cycle in only 11 % of pts, peaked at cycle 2 (32 %) and represented 57 % of cases after cycle 3. Baseline characteristics of pts with PPE were compared to 27 control pts who received at least 3 cycles. Older pts represented 61 % of pts with PPE and 15 % of pts without PPE (p = 0.04 by Chi-square test). Monocyte count and inflammatory parameters were not associated with PPE. However, the analysis of monocyte subpopulations revealed a large inter-patient variability. Contrary to most acute toxicities, PPE occurred more frequently after several cycles, suggesting a PLD body accumulation through repeated cycles. PPE was more frequent in pts older than 70 years. Monocyte subpopulations may have different roles on PLD metabolism and warrant further studies.

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.

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.

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.

e14096Background: Cytidine deaminase (CDA) catabolizes gemcitabine and cytosine arabinoside and its serum activity (CDA-A) has been associated with efficacy and toxicity of both treatment. CDA is a...

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 neurosensory toxicity is dose limiting and may present as acute symptoms and/or cumulative peripheral neuropathy. Patients and methods From October 2005 to May 2008, patients with oxaliplatin-induced acute neurotoxicity were randomized into a double-blind study, to receive either venlafaxine 50 mg 1 h prior oxaliplatin infusion and venlafaxine extended release 37.5 mg b.i.d. from day 2 to day 11 or placebo. Neurotoxicity was evaluated using numeric rating scale (NRS) for pain intensity and experienced relief under treatment, the Neuropathic Pain Symptom Inventory and the oxaliplatin-specific neurotoxicity scale. The primary end point was the percentage of patients with a 100% relief under treatment. Results Forty-eight patients were included (27 males, median age: 67.6 years). Most patients had colorectal cancer (72.9%). Median number of cycles administered at inclusion was 4.5 (mean cumulative oxaliplatin dose: 684.6 mg). Twenty out of 24 patients in arm A (venlafaxine) and 22 out of 24 patients in arm B (placebo) were assessable for neurotoxicity. Based on the NRS, full relief was more frequent in the venlafaxine arm: 31.3% versus 5.3% (P = 0.03). Venlafaxine side-effects included grade 1–2 nausea (43.1%) and asthenia (39.2%) without grade 3–4 events. Conclusions Venlafaxine has clinical activity against oxaliplatin-induced acute neurosensory toxicity.

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...

e13569 Background: Pegylated liposomal doxorubicin (PLD) is widely used in relapsing ovarian carcinoma (ROC). Its original formulation is metabolized by the monocyte-macrophage system. One of its m...

9537 Background: Given the median age of 70 years in patients (pts) presenting NSCLC, the impact of age on outcomes including efficacy and toxicity of erlotinib remains unclear. In the BR21 study, ...

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 ...

Performance status (PS) is universally used in oncology to evaluate the clinical condition of the patients. The performance status has been shown to correlate with survival, as well as with acute toxicity following anticancer chemotherapy [1–5]. To test whether altered performance status is associated with malnutrition, we retrospectively examined data from a 1-day malnutrition prevalence survey, carried out in 154 oncology wards of private or public hospitals in 24 cities in France [6]. Height and present and usual body weights were assessed in outpatients and inpatients who were present that day. The European Society for Clinical Nutrition and Metabolism and the Cachexia Society recently considered pre-cachectic a patient who involuntarily lost 5% of body weight during the previous 12 months [7, 8]. Malnutrition was defined as a body mass index 10% from diagnosis in our study. The prevalence of malnutrition was studied in the overall population and stratified for the performance status. Amongst 2,068 patients (1,189 men and 879 women) aged 60±13 years, nutritional status was available in 1,903 patients. The performance status was 0 in 338 (19%), 1 in 560 (32%), 2 in 451 (25%), 3 in 249 (14%), and 4 in 129 (7%) patients. Overall, 723 (38%) of the patients were malnourished. The prevalences of malnutrition were 14.4%, 31.4%, 52.3%, 53.6%, and 65.3% in patients with a performance status ranging from 0 to 4, respectively (Fig. 1). In comparison to patients with performance status 0, the relative risk of malnutrition was 2.5 (p

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.

Aim: The WHO Performance Status (PS) of cancer patients (pts) correlates with survival and with anticancer treatments tolerability. However, PS is subject to inter-observer variability and is not sensitive to detect pts with high-risk of treatment toxicity. We studied the relationship between Rest Metabolic Rate (RMR) and PS. Methods: A prospective observational, monocentric study was conducted. Before treatment initiation, RMR was measured using indirect calorimetry (Fitmate®, Cosmed srl) and compared to estimated RMR obtained by the modified Harris and Benedict equation. Hypermetabolics (Hm) pts were defined as having measured RMR ≥110% of calculated RMR and Not Hypermetabolics (NoHm) pts Results: A total of 161 consecutive pts were analyzed : 58% males, median age : 64 years (20-94). Primary tumor: genito-urinary (23%) gastro-intestinal (20%), lung (17%); 10% were PS ≥3; median weight loss : 4.1% (-14.9–+18.5); mean energetic gap: +80 kcal/d; mean RMR : 1676 kcal/d; 60% of the pts were Hm with mean RMR= 1815 kcal/d vs 1433 kcal/d in NoHm pts (P 5% in 52% vs 32% of the pts (p = 0.03). Hm pts had more inflammation: a1-GP 1.5 vs 1.1 g/L (t=3.41, p Conclusions: Hypermetabolism may account for cancer-induced asthenia and development of cachexia. The measurement of RMR allows to detect pts at high-risk of malnutrition amongst pts with PS Disclosure: All authors have declared no conflicts of interest.

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...

e15592 Background: Su (su), a tyrosine kinase VEGFR inhibitor, is subject to large inter-individual variability in drug exposure (AUC) and toxicity. We investigated the variability factors influencing AUC as well as the relationship between acute severe toxicity, AUC and genetic polymorphisms in adult cancer patients under su. Methods: The plasma concentrations of su and SU12662 (active metabolite) were assessed on day 7 and 21 of the first cycle. For variability investigation, su, SU 12662 and composite AUC (su+SU12662) were estimated from a population approach, then normalized to 50mg daily dose of su. Genetic polymorphisms for CYP3A4, CYP3A5, CYP1A2, NR1I2, NR1I3, P-gP and BCRP1 were analyzed. Clinical acute toxicity was graded using the NCI 4.0 scale on days 7 and 21. Baseline clinical and biologic characteristics including the lean body mass (LBM), absolute AUC and pharmacogenetic variants were tested univariately for association with toxicities. LBM was simply estimated from gender, height and weight. Candidate variables with pA) were identified as major variability factors (p

Metastasis, a recognized multistep biological process, is the main cause of mortality in cancer patients. Although EGFR mutated lung cancers are of better prognosis, a group of patients develop metastasis and died of disease. We previously showed that EGFR mutations were associated with a copy number variation at a locus encompassing the TWIST1 gene on chromosome 7. TWIST1 is a highly conserved developmental gene involved in embryogenesis that turned out to be frequently reactived in cancers promoting both malignant conversion and cancer progression. The aim of this study was to investigate the role of TWIST1 on progression in EGFR mutated lung cancer. Using 6 human lung cell lines with or without EGFR mutations or TWIST1 reactivation, we demonstrated that epithelial-mesenchymal transition (EMT) and the associated mobility were dependent upon TWIST1 expression in cells with EGFR mutation. Indeed, EGF treatment only induced EMT and mobility in cells with TWIST reactivation. EGF treatment induced a translocation of TWIST1 to the nucleus, up-regulated mesenchymal markers and down-regulated epithelial markers at mRNA and protein levels. Moreover, inhibition of either the oncogenic EGF pathway stimulation or TWIST1 expression by small RNA technology reversed the phenomenon suggesting that both EGF pathway activation and TWIST1 reactivation are necessary for EMT in lung cancer with EGFR mutation. In a second step, we analyzed surgical lung cancer specimens from non-smokers with and without EGFR mutations and looked for TWIST1 and epithelial or mesenchymal markers expression. Hierarchical clustering combining TWIST1, epithelial (CDH1, JUP) and mesenchymal (VIM, CDH2) gene mRNA expression in tumors perfectly individualizes the EGFR mutated group as the group with TWIST1 reactivation. Immunohistochemical analysis of lung cancer samples revealed that TWIST1 protein expression was associated with EGFR mutation and low CDH1 expression supporting our in vitro observations. Collectively, our observations support that TWIST1 collaborates with EGF/EGFR mutated signaling pathway in promoting EMT in lung cancers and thereby drives the metastatic dissemination in this group of patients. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3418. doi:10.1158/1538-7445.AM2011-3418

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...