Anatole Cessot

Histologic subtypes, immunohistochemistry, FISH or molecular screening for the accurate diagnosis of ALK-rearrangement in lung cancer: A comprehensive study of Caucasian non-smokers

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.

Effect of glucuronidation on transport and tissue accumulation of tyrosine kinase inhibitors: consequences for the clinical management of sorafenib and regorafenib

Introduction: 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. Areas covered: 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. Expert opinion: 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.

Drug safety evaluation of sorafenib for treatment of solid tumors: consequences for the risk assessment and management of cancer patients

Introduction: 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. Areas covered: 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. Expert opinion: 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.

Defining the clinical condition of cancer patients: it is time to switch from performance status to nutritional status.

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<0.0001) in men with performance status 1, 6.4 in men with performance status 2 (p<0.0001) and 2.0 (p<0.0001) in women with performance status 1 and 5, 2 in women with PS2 (p<0.0001). Malnutrition is strongly associated with performance status and is likely to be the determining factor of its deterioration. Of note, one third of PS1 patients have malnutrition, underlying the limitations of PS assessment. As a consequence, screening of malnutrition in all cancer patients prior to initiating cancer treatment is strongly recommended. Moreover, evaluation of the nutritional status appears as potentially more accurate than performance status to identify patients at risk for anticancer chemotherapy acute toxicity [1, 3]. The effects of early nutritional intervention in malnourished A. Cessot (*) :R. Coriat : J.-P. Durand :O. Mir :C. Mateus : W. Cacheux : F. Goldwasser Department of Medical Oncology, Cochin Teaching Hospital, AP-HP, Paris Descartes University, 27, rue du faubourg Saint Jacques, 75014, Paris, France e-mail: anatolecessot@gmail.com

Investigational therapies up to Phase II which target PDGF receptors: potential anti-cancer therapeutics

Introduction: 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. Areas covered: 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. Expert opinion: 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.

Drug monitoring of sunitinib in patients with advanced solid tumors: a monocentric observational French study

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.

Nutritional Status Is Superior to the ECOG Performance Status in Predicting the Dose-Intensity of the GEMOX Chemotherapy Regimen in Patients with Advanced Cancer

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/m2, body weight loss >10% over 3 mo, or albuminemia <35 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 (P > 0.05). Median relative dose-intensity was 0.90 (0.17–1.04). GEMOX dose-intensity correlated negatively with loss of baseline weight (r = −0.24, P < 0.02). In patients who did not complete more than 2 cycles of chemotherapy, median PS (P < 0.01), mean C-reactive protein (CRP; P < 0.01), and mean albuminemia (P < 0.05) 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.

A Real-Life Experience of Bevacizumab in Elderly Women With Advanced Ovarian Carcinoma.

Objective This 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. Methods Consecutive 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. Results Among 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 &khgr;2 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. Conclusions Bevacizumab is feasible in patients older than 70 years with advanced ovarian carcinoma. More attention must be paid to elderly patients with baseline HTN.

Inhibiteurs de tyrosine kinase ciblant l’angiogenèse et sujets âgés : tolérance, évaluation pré-thérapeutique et gestion des effets indésirables

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.

SynthèseInhibiteurs de tyrosine kinase ciblant l’angiogenèse et sujets âgés : tolérance, évaluation pré-thérapeutique et gestion des effets indésirablesTyrosine kinase inhibiting the VEGF pathway and elderly people: Tolerance, pre-treatment assessment and side effects management

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.