[Multidisciplinary and systematic preoperatory-assessment in geriatric urologic oncology surgery: Feasibility and results]. / Évaluation pluridisciplinaire préopératoire systématique en chirurgie cancérologique urologique gériatrique : faisabilité et résultats.

INTRODUCTION: The incidence of cancer increases with age, especially for urological cancers. The frailty of the elderly persons may expose them to more postoperative complications resulting in prolonged hospitalization, increased morbidity or even increased mortality, and delayed or impossible return to normal life. In such cases, the benefit of surgery and therefore its realization can be questioned. PATIENTS AND METHOD: This article reports the experience of a pre-operative risk assessment in a population of elderly patients treated for urologic cancer. This retrospective study aims to report the feasibility and the main results of this systematic preoperative multi-professional evaluation. RESULTS: Between April 2016 and February 2017, 31 elderly patients were evaluated. The evaluation revealed: moderate to severe malnutrition in 59 % of cases, a patient judged from a geriatric point of view fit, intermediate or fragile in respectively 25 %, 35 % and 40 % of cases. This evaluation led to propose a modification of an element of care for 66 % of patients and to propose therapeutic abstention for only 3 patients. CONCLUSION: An evaluation whose purpose is to adapt to the physiological age of patients and their overall state of health, surgical treatment and postoperative management is feasible and seems to help unmask elements of fragility usually not detected. LEVEL OF EVIDENCE: 4.

Determinants of the interindividual variability in serum cytidine deaminase activity of patients with solid tumours.

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 < 0.1-candidate variables were analysed through a multivariate analysis. The association between CDA activity and toxicity was assessed for the 56 gemcitabine-treated patients. Intraindividual variability in CDA activity was explored in six pancreatic cancer patients treated with gemcitabine. RESULTS: Median CDA activity was 3.97 U mg-1 (range 1.53-15.49 U mg-1 ). A univariate analysis showed that CDA activity was statistically associated with Eastern Cooperative Oncology Group performance status, mild or severe malnutrition, inflammatory syndrome, leucocyte count, neutrophil count, albumin, C-reactive protein and -c.-33_-31delC single nucleotide polymorphism. A multivariate analysis identified that only neutrophil count (P < 0.0001) and severe malnutrition (P = 0.0278) were independently associated with CDA activity. Low CDA activity (<2 U mg-1 ) was not statistically associated with severe gemcitabine-related toxicities (P = 0.16). A decrease in CDA activity was observed during the longitudinal follow-up of six pancreatic cancer patients treated with gemcitabine (P = 0.03). CONCLUSIONS: These results suggest that neutrophil count and malnutrition should be considered for the interpretation of pretherapeutic CDA activity.

[Biomarkers predictive of PD1/PD-L1 immunotherapy in non-small cell lung cancer]. / Biomarqueurs prédictifs de l'immunothérapie anti-PD1/PD-L1 dans le cancer broncho-pulmonaire non à petites cellules.

Immune checkpoint inhibitors (ICI), targeting the PD1/PD-L1 axis has shown their efficacy in lung cancer but only in a restricted population of patients, thus it is mandatory to identify biomarkers predicting the clinical benefit. In this article we will describe and analyzed biomarkers already published, from protein, to RNA and at last DNA markers, discussing each markers feasibility and interest. In the future, combined analysis of several markers will probably be proposed, particularly with the increasing complexity of therapy schema with molecules association.

[IHC, FISH, CISH, NGS in non-small cell lung cancer: What changes in the biomarker era?] / IHC, FISH, CISH, NGS dans les cancers bronchiques non à petites cellules : quelles évolutions dans l'ère des biomarqueurs ?

Lung cancer is the leading cause of cancer deaths in France, with about 30,000 deaths per year. The overwhelming majority (90 %) are tobacco-related. The prognosis is dark but great therapeutic advances have been made with the development of targeted therapies first and then immunotherapy afterwards. These medications are conditioned to the expression of biomarkers that require specific tools in routine to measure them. We will detail in this chapter several techniques of anatomopathology, cytogenetics and molecular biology necessary for the detection of biomarkers in lung cancers, and their applications in thoracic oncology in 2018.

Estimation of glomerular filtration rate in cancer patients with abnormal body composition and relation with carboplatin toxicity.

PURPOSE: Carboplatin clearance is correlated with glomerular filtration rate (GFR) and usually estimated with creatinine clearance using Cockcroft-Gault (CG) formula. Because plasma creatinine level is highly correlated with muscle mass, we hypothesized that an abnormal body composition with a low lean body mass (LBM) percentage [(LBM/weight) × 100] may result in inadequate carboplatin dosing. Serum cystatin C is an alternative marker of GFR, not affected by muscle mass. We aimed to investigate the influence of total LBM and LBM percentage on GFR calculation, using creatinine (CrCl) or cystatin C (GFRcysC-creat) in cancer patients. METHODS: Pretreatment serum creatinine and cystatin C were prospectively measured in consecutive patients. CrCl (CG formula), GFRcysC-creat (CKD-EPI creatinine-cystatin equation), and LBM (CT scan) were calculated. Severe thrombocytopenia post-carboplatin were analyzed. RESULTS: In 131 patients without renal insufficiency, LBM was correlated with creatinine (r = 0.30, p < 0.005) but not with cystatin C (r = -0.07, p = 0.43). In patients with the lowest LBM percentage, the CrCl was significantly higher than GFRcysC-creat indicating an overestimation of GFR with creatinine (p = 0.0004). In 24 patients treated with carboplatin AUC 5 (mg/ml min) ± paclitaxel, the risk of severe thrombocytopenia was associated with lower LBM percentage (p = 0.0002) and higher CrCl/GFRcysC-creat ratio (p = 0.006). By ROC analysis, the CrCl/GFRcysC-creat ratio threshold predicting severe thrombocytopenia was 1.23. CONCLUSIONS: A low LBM percentage increases the risk of inadequate GFR calculation by CG formula, and carboplatin overdosage with severe thrombocytopenia. High CrCl/GFRcysC-creat ratio allows the identification of these patients.

Relation between plasma trough concentration of abiraterone and prostate-specific antigen response in metastatic castration-resistant prostate cancer patients.

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 Cmin) 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 Cmin 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 Cmin 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 Cmin was 8.4 ng/mL. Progression-free survival (PFS) was significantly higher in patients with ABI Cmin 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.

Use of chemotherapy near the end of life: what factors matter?

Background: Use of chemotherapy near the end of life in patients with metastatic cancer is often ineffective and toxic. Data about the factors associated with its use remain scarce, especially in Europe. Methods: Nationwide, register-based study including all hospitalized patients aged ≥20 years who died from metastatic solid tumors in France between 2010 and 2013. Results: A total of 279 846 hospitalized patients who died from metastatic cancer were included. During the last month before death, 19.5% received chemotherapy (including 11.3% during the last 2 weeks). Female sex (OR= 0.96, 95% CI= 0.93-0.98), older age (OR= 0.70, 95% CI= 0.69-0.71 for each 10-year increase) and higher number of chronic comorbidities (OR= 0.83, 95% CI= 0.82-0.84) were independently associated with lower rates of chemotherapy. Although patients with chemosensitive tumors were statistically more likely to receive chemotherapy during the last month before death (OR= 1.21, 1.18-1.25), this association was mostly fueled by testis and ovary tumors and we found no obvious pattern between the expected chemosensitivity of different cancers and the rates of chemotherapy use close to death. Compared with university hospitals, patients who died in for-profit clinics/hospital (OR= 1.40, 95% CI= 1.34-1.45), or comprehensive cancer centers (OR= 1.43, 95% CI= 1.36-1.50) were more likely to receive chemotherapy. Finally, high-volume centers and hospitals without palliative care units reported greater-than-average rates of chemotherapy near the end of life. Conclusion: among hospitalized patients with cancer, young individuals, treated in comprehensive cancer centers or in high-volume centers without palliative care units were the most likely to receive chemotherapy near the end of life. We found no evident pattern between the expected chemosensitivity of different cancers and the probability for patients to receive chemotherapy close to death.

[Red blood transfusion in palliative care situation]. / Transfusion de globules rouges en situation oncologique palliative.

Anemia is frequent in oncology. We debate the decision-making process of erythrocyte transfusion in palliative care situation from a case report. A patient with a prostatic metastatic cancer was in palliative situation with asthenia and coronary symptom. We analyze, in this particular case that does not describe reality of normal practice, the decision-making process of erythrocyte transfusion. These transfusions were based, in this case, on the evaluation of oncology prognosis, the short-term vital threats, life project and clinical safety of the transfusion. The patient has received 5 erythrocyte transfusions in 4 months until a multidisciplinary meeting decided to stop transfusion because of poor prognostic situation and bad tolerance of the act. This patient could be a collegial model used to measure the reasonable nature of prescription depending on the purpose and the goal of the patient but does not allow generalization. Although there is low risk of erythrocyte shortage, it seems important to train doctors to reduce abusive transfusion and define transfusion thresholds. Different levels of erythrocyte transfusion security would raise the issue of management of several stocks. Erythrocyte transfusion in palliative care can be considered subject to prognostic information and the palliative aim of the transfusions, multidisciplinary decision-making, during short hospitalizations and with evaluation of the act and consequences for the patient.

[Advance directives in dermato-oncology: The current situation and future prospects]. / Directives anticipées en dermato-oncologie : situation actuelle et perspectives.

INTRODUCTION: Patient information and advance directives (AD) are described in the French laws of 4 March 2002 and 22 April 2005, which concern the decisions of subjects regarding end-of-life treatment. At present, practitioners rarely seek the opinion of patients on this matter. The Claeys-Leonetti law requires doctors to identify any advance directives by patients, which are binding upon medical staff. The present study sought to analyse the extent of application of the laws of 2002 and 2005 and to collect the observations of clinicians in dermato-oncology regarding the new legislation. METHODS: We contacted members of the French dermato-oncology group by email and asked them to assess their practices with regard to information provision, patient surrogates and advance directives. RESULTS: To 111 requests we received 34 replies from hospital dermatologists, i.e. a response rate of 31 %. In all, 85 % of clinicians informed patients with metastasis that their disease was incurable, and 94 % stated that they have procedures in place concerning the appointment of a patient surrogate. One third of respondents reported having a procedure in place for provision of information or collection of advance directives. According to 91 % of clinicians, the binding nature of advance directives did not constitute any loss of chance for the patient in question; 59 % felt that the new law would affect their practices, but of these, paradoxically, 60 % felt that this would have no impact on their therapeutic decision-making. In all, 26 clinicians (76.5 %) did not intend to modify their decision-making process. CONCLUSION: The law of 2002 is generally better known than that of 2005. Dermato-oncologists are not aware of the practical consequences of the new binding nature of advance directives with regard to the doctor-patient relationship and the actual decision-making process.

Vemurafenib pharmacokinetics and its correlation with efficacy and safety in outpatients with advanced BRAF-mutated melanoma.

Vemurafenib is a BRAF kinase inhibitor approved for first-line treatment of metastatic BRAF (V600) -mutant melanoma. However, data on the pharmacokinetic/pharmacodynamic (PK/PD) relationship are lacking. The aim of this prospective, multicenter study was to explore the PK/PD relationship for vemurafenib in outpatients with advanced BRAF-mutated melanoma. Fifty-nine patients treated with single-agent vemurafenib were prospectively analyzed. Vemurafenib plasma concentration (n = 159) was measured at days 15, 30, 60, and 90 after treatment initiation. Clinical and biological determinants (including plasma vemurafenib concentration) for efficacy and safety were assessed using Cox's model and multivariate stepwise logistic regression. Median progression-free survival (PFS) and overall survival were 5.0 (95 % confidence interval [95 % CI] 2.0-6.0) and 11.0 (95% CI 7.0-16.0) months, respectively. Twenty-nine patients (49 %) experienced any grade ≥3 toxicity and the most frequent grade ≥2 toxicity was skin rash (37 %). Severe toxicities led to definitive discontinuation in seven patients (12 %). Grade ≥2 skin rash was not statistically associated with better objective response at day 60 (p = 0.06) and longer PFS (hazard ratio 0.47; 95 % CI 0.21-1.08; p = 0.075). Grade ≥2 skin rash was statistically increased in patients with ECOG ≥ 1 (odds ratio 4.67; 95 % CI 1.39-15.70; p = 0.012). Vemurafenib concentration below 40.4 mg/L at day 15 was significantly associated with a shorter PFS (1.5 [0.5-5.5] vs. 4.5 [2-undetermined] months, p = 0.029). Finally, vemurafenib concentration was significantly greater in patients developing grade ≥2 rash (61.7 ± 25.0 vs. 36.3 ± 17.9 mg/L, p < 0.0001). These results suggest that early plasma drug monitoring may help identify outpatients at high risk of non-response or grade ≥ 2 skin rash.

Role of the lean body mass and of pharmacogenetic variants on the pharmacokinetics and pharmacodynamics of sunitinib in cancer patients.

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 < 0.0001) and a polymorphism in the ABCG2 transporter (421C>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.

A phase I schedule dependency study of the aurora kinase inhibitor MSC1992371A in combination with gemcitabine in patients with solid tumors.

INTRODUCTION: MSC1992371A is an aurora kinase inhibitor with potential antitumor activity. METHODS: This trial established the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of oral MSC1992371A given before or after gemcitabine (1,000 mg/m(2)) in a 21-day cycle in patients with advanced malignancies. In schedule 1 (n = 31), gemcitabine was administered on days 1 and 8 followed by escalating doses of MSC1992371A on days 2 and 9. In schedule 2 (n = 35), MSC1992371A was given on days 1 and 8 followed by gemcitabine on days 2 and 9. Patients had a range of solid tumors, the most frequent of which was colorectal (n = 19). RESULTS: In both schedules, the 37 mg/m(2) dose level was defined as the MTD. The main DLT was grade 4 neutropenia. Adverse events consisted of neutropenia, thrombocytopenia, asthenia, fatigue, nausea, vomiting, anorexia, and diarrhea. Administration of MSC1992371A prior to gemcitabine had no effect on the metabolism or elimination of gemcitabine. Time to reach maximum plasma concentration and area under the plasma concentration-time curve for MSC1992371A increased proportionally with dose. Exploration of drug-target-related and tumor biomarkers did not identify predictors of biologic activity or response. Two patients (1 with lung carcinoma and 1 with hepatocellular carcinoma) had durable partial responses in schedule 2, and 5 patients had stable disease (SD) lasting 6 - 14 months. CONCLUSION: Oral MSC1992371A can be administered at a MTD of 37 mg/m(2) in combination with the standard 1,000 mg/m(2) dose of gemcitabine, but hematologic toxicity requires careful monitoring. Preliminary signs of efficacy were indicated by durable responses and SD.

[Endometriosis-associated ovarian cancers: pathogenesis and consequences on daily practice]. / Les cancers de l'ovaire associés à l'endométriose : physiopathologie et conséquences sur la pratique clinique.

Endometriosis is considered as a tumor-like lesion under the World Health Organization (WHO) classification of ovarian tumors. Data from large cohort and case-control studies indicate that patients with a history of endometriosis have an increased risk of ovarian cancer. Recent findings suggest an association between endometriosis and the entire type 1 ovarian tumors group including clear-cell, endometrioid and low-grade serous carcinomas. However, current evidence is lacking to draw definitive conclusion whether this association represents causality or the sharing of common risk factors. Nevertheless, assumption that endometriosis could be a precursor of malignancy raises many issues about serial screening, surgical management and surveillance of endometriosis. Beyond these concerns, endometriosis-associated ovarian cancers seem to be a genuine clinical entity as regards clinicopathological features. In view of the high incidence of endometriosis (10 % of women of childbearing age), the low incidence of endometriosis-associated ovarian cancers and the psychological consequences for those women, systematic screening and surgical exploration seem very questionable in this context.

Sarcopenia and body mass index predict sunitinib-induced early dose-limiting toxicities in renal cancer 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)<25 kg m(-2). Eighteen patients (29.5%) experienced a DLT during the first cycle. Sarcopenic patients with a BMI<25 kg m(-2) experienced more DLTs (P=0.01; odds ratio=4.1; 95% CI: (1.3-13.3)), more cumulative grade 2 or 3 toxicities (P=0.008), more grade 3 toxicities (P=0.04) and more acute vascular toxicities (P=0.009). CONCLUSION: Patients with sarcopenia and a BMI<25 kg m(-2) experienced significantly more DLTs during the first cycle of treatment.