Stanislas Ropert

Sarcopenia Predicts Early Dose-Limiting Toxicities and Pharmacokinetics of Sorafenib in Patients with Hepatocellular Carcinoma

Background Sorafenib induces frequent dose limiting toxicities (DLT) in patients with advanced hepatocellular carcinoma (HCC). Sarcopenia has been associated with poor performance status and shortened survival in cancer patients. Patients and Methods The characteristics of Child Pugh A cirrhotic patients with HCC receiving sorafenib in our institution were retrospectively analyzed. Sorafenib plasma concentrations were determined at each visit. Toxicities were recorded during the first month of treatment, and sarcopenia was determined from baseline CT-scans. Results Forty patients (30 males) were included. Eleven (27.5%) were sarcopenic. Eighteen patients (45%) experienced a DLT during the first month of treatment. Sarcopenic patients experienced significantly more DLTs than non-sarcopenic patients did (82% versus 31%, p = 0.005). Grade 3 diarrhea was significantly more frequent in sarcopenic patients than in non-sarcopenic patients (45.5% versus 6.9%, p = 0.01), but not grade 3 hand foot syndrome reaction (9% versus 17.2%, p = 1). On day 28, median sorafenib AUC (n = 17) was significantly higher in sarcopenic patients (102.4 mg/l.h versus 53.7 mg/l.h, p = 0.013). Conclusions Among cirrhotic Child Pugh A patients with advanced HCC, sarcopenia predicts sorafenib exposure and the occurrence of DLT within the first month of treatment.

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.

Use of platinum derivatives during pregnancy.

The incidence of cancer during pregnancy is increasing given the trend for women to postpone childbearing. Knowledge of the potential toxicity and teratogenicity of chemotherapy agents is crucial for patient counseling. Platinum derivatives are active against various malignancies that occur more frequently during pregnancy: melanoma, cervical and ovarian cancers, and lung cancer. The authors of this article performed a systematic review of reports documenting the use of platinum derivatives during pregnancy in the English literature from 1977 through January 2008. Forty‐three pregnancies were described: 36 patients received cisplatin, 6 patients received carboplatin, and 1 patient received both drugs. Two fetal malformations occurred after in utero exposure to cisplatin, but the causative link between cisplatin administration and these malformations remains speculative. However, either detectable cisplatin levels or platinum‐DNA adducts were observed in neonates who were exposed to platinum derivatives during the third trimester, providing evidence for a late‐onset transplacental transfer of these drugs. The administration of platinum derivatives, although feasible during the second and third trimesters of pregnancy, raises concern regarding the transplacental transfer of these drugs in late pregnancy and has unknown short‐ and long‐term effects. Cancer 2008.

Validation of an HPLC-UV method for sorafenib determination in human plasma and application to cancer patients in routine clinical practice.

Sorafenib, a new oral multikinase inhibitor with antiangiogenic properties, has demonstrated preclinical and clinical activity against several tumor types. The aims of this study were to validate a method for the measurement of sorafenib in plasma from cancer patients, then to test this method in clinical practice. Following liquid-liquid extraction, the compounds were separated with gradient elution (on a C18 ultrasphere ODS column using a mobile phase of acetonitrile/20 mM ammonium acetate), then detected at 255 nm. The calibration was linear in the range 0.5-20 mg/L. Intra- and inter-assay precision was lower than 7 and 10%, respectively, at 0.5, 3 and 20 mg/L. Plasma sorafenib concentrations were measured in 22 cancer patients (99 samples). The mean trough sorafenib concentration (C(min)) and concentration at peak were 4.3+/-2.5 mg/L (n=68, CV=57.5%) and 6.2+/-3.0 mg/L (n=31, CV=47.5%), respectively. Mean sorafenib C(min) in eight patients who experienced grade 3 drug-related adverse events was approximately 1.5-fold greater than that observed in the remaining patients (7.7+/-3.6 mg/L vs. 4.4+/-2.4 mg/L, P=0.0083). In conclusion, the method was successfully used in routine practice to monitor plasma concentrations of sorafenib in cancer patients. Finally, large interindividual variability and higher exposure in patients experiencing severe toxicity support the need for therapeutic drug monitoring to ensure an optimal exposure to sorafenib.

Posterior reversible encephalopathy syndrome induced by anti-VEGF agents

Posterior reversible encephalopathy syndrome (PRES) is a clinico-radiological entity that may occur in patients receiving anti-vascular endothelial growth factor (VEGF) agents such as bevacizumab and tyrosine kinase inhibitors. Little is known about the characteristics of patients at risk for PRES under anti-VEGF agents. We carried out a comprehensive review of reports documenting the occurrence of PRES in patients receiving anti-VEGF agents. Twenty-six patients are described with a majority of females (73.1%). Almost a third of patients had a past history of hypertension. The most common symptoms included headache, visual disturbance and seizure. A vast majority of patients had hypertension at the diagnosis of PRES, and proteinuria was detectable each time it was investigated. Neurological outcome was favorable in all cases with a symptomatic treatment including blood pressure control. The risk of PRES is increased when blood pressure is poorly controlled and when proteinuria is detectable. The clinical course appears favorable with a symptomatic treatment. PRES is a potentially severe but manageable toxicity of anti-VEGF agents.

Sorafenib-Induced Hepatocellular Carcinoma Cell Death Depends on Reactive Oxygen Species Production In Vitro and In Vivo

Sorafenib is presently the only effective therapy in advanced hepatocellular carcinoma (HCC). Because most anticancer drugs act, at least in part, through the generation of reactive oxygen species, we investigated whether sorafenib can induce an oxidative stress. The effects of sorafenib on intracellular ROS production and cell death were assessed in vitro in human (HepG2) and murine (Hepa 1.6) HCC cell lines and human endothelial cells (HUVEC) as controls. In addition, 26 sera from HCC patients treated by sorafenib were analyzed for serum levels of advanced oxidation protein products (AOPP). Sorafenib significantly and dose-dependently enhanced in vitro ROS production by HCC cells. The SOD mimic MnTBAP decreased sorafenib-induced lysis of HepG2 cells by 20% and of Hepa 1.6 cells by 75% compared with HCC cells treated with 5 mg/L sorafenib alone. MnTBAP significantly enhanced by 25% tumor growth in mice treated by sorafenib. On the other hand, serum levels of AOPP were higher in HCC patients treated by sorafenib than in sera collected before treatment (P < 0.001). An increase in serum AOPP concentration ≥0.2 μmol/L chloramine T equivalent after 15 days of treatment is a predictive factor for sorafenib response with higher progression free survival (P < 0.05) and overall survival rates (P < 0.05). As a conclusion, sorafenib dose-dependently induces the generation of ROS in tumor cells in vitro and in vivo. The sera of Sorafenib-treated HCC patients contain increased AOPP levels that are correlated with the clinical effectiveness of sorafenib and can be used as a marker of effectiveness of the drug. Mol Cancer Ther; 11(10); 2284–93. ©2012 AACR.

High-dose intrathecal trastuzumab for leptomeningeal metastases secondary to HER-2 overexpressing breast cancer

We are facing an increasing incidence of brain and leptomeningeal metastases (LM) during the history of patients with HER-2-overexpressing breast cancer. This clinical issue is due to the neurotropism of HER-2-overexpressing breast cancer cells, combined with the high antitumoral activity of systemic administrations of trastuzumab but without preventive effect in the brain and leptomeninges. Indeed, trastuzumab is a monoclonal IgG1 antibody to HER-2, which poorly reaches the cerebrospinal fluid (CSF) when given i.v. [1]. Intrathecal (IT) administration of trastuzumab has been scarcely tested [2–5] in patients with LM occurring after a systemic complete remission induced by i.v. trastuzumab (Table 1). Therefore, we eagerly need to accumulate experience on the use of IT trastuzumab in this setting. We report here the case of a patient with HER-2-overexpressing breast cancer who developed LM. We obtained a long-lasting control of the disease progression using high doses of IT trastuzumab. In April 2001, a 55-year-old patient was diagnosed with a breast cancer (T1N0M0, ER+). She was initially treated by surgery, radiotherapy and tamoxifen. Eighteen months later, she developed multiple liver metastases. The breast cancer was tested for HER-2 and was found positive (3+ by immunohistochemistry). She received docetaxel plus epirubicin, then paclitaxel plus trastuzumab and achieved a complete remission. One year later, headaches and ataxia revealed massive involvement of the brain by multiple metastases. A whole-brain irradiation allowed achieving a complete remission of the brain metastases. However, while under i.v. trastuzumab, 15 months after the liver remission and 9 months after the brain remission, she developed midback pain, cerebellar ataxia and headaches, leading to a clinical diagnosis of LM. Cerebral and spinal MRI scans revealed pericerebellar and cervical leptomeningeal foci, consistent with carcinomatous involvement. Initial CSF examination was normal, except for proteins of 0.68 g/l. Computed tomography scans confirmed that she had no recurrence of liver and brain metastases. The patient underwent daily oral corticosteroids and was informed of the poor prognosis for this condition. She refused a conventional treatment by IT high-dose methotrexate as described by Fizazi et al. [6]. Hence, after she gave her informed consent, she was administered weekly IT trastuzumab 20 mg (20 mg being the highest IT dose experienced in humans [2–5]) by lumbar puncture. The first administration was well tolerated and thereafter we carried out a dose escalation every week: 40 mg, then 100 mg weekly, for a total of six cycles of IT trastuzumab over 6 weeks (20 mg · 1, 40 mg · 1, 100 mg · 4). The patient experienced striking clinical neurological improvement, with complete disappearance of headaches and ataxia after 2 weeks of treatment. The changes in CSF are summarized in Table 2. It is noteworthy that the CSF proteins increased with repeated administrations. The cerebral magnetic resonance imaging (MRI) at 6 weeks showed a stable disease. However, 2 months later, the patient’s status worsened due to progression of brain metastases in previously irradiated areas, without evidence of meningeal disease progression. Despite high doses of i.v. corticosteroids, she finally developed intracranial hypertension and died of brain metastases 5 months later, 7 months from the diagnosis of LM. The use of IT IgG1 mAbs is supported by the knowledge that they poorly cross the blood–brain barrier when given i.v. [1, 7], making the CNS a sanctuary for cancer cells. To our knowledge, this case is the first report of a safe administration of IT trastuzumab at high doses (100 mg weekly). The major clinical improvement observed in our patient was not reflected by changes in CSF proteins, whereas MRI scans showed a stable disease. We assume that the discrepancy between clinical improvement and CSF proteins could be due to the accumulation of high doses of trastuzumab in the CSF. However, monitoring of trastuzumab CSF levels as described letters to the editor Annals of Oncology

An Observational Study of Bevacizumab-Induced Hypertension as a Clinical Biomarker of Antitumor Activity

BACKGROUND Hypertension is a common toxicity of bevacizumab, but the frequency of assessment of blood pressure and standardized grading remain to be defined. This study aimed to describe the incidence of bevacizumab-induced hypertension and factors associated with its development, then to retrospectively assess its relation with activity. PATIENTS AND METHODS One hundred nineteen patients with advanced or metastatic non-small cell lung cancer, colorectal cancer, or ovarian cancer receiving bevacizumab (2.5 mg/kg per week) and chemotherapy were eligible for this analysis. Blood pressure was measured at home twice daily according to international guidelines, and graded according to the National Cancer Institute Common Toxicity Criteria (NCI-CTC), version 3.0, and the European Society of Hypertension (ESH) criteria. RESULTS Home-based measurements detected significantly more cases of hypertension than in-clinic measurements did, according to the ESH criteria (54.6% versus 24.4%; p < .001) or the NCI-CTC (42.9% versus 22.7%; p = .0015). Very early hypertension (within 42 days, according to the ESH criteria) but not hypertension (occurring at any time during treatment period) was predictive of response (p = .0011 and p = .26, respectively). CONCLUSIONS Our preliminary results indicate that home-based measurement and grading according to the ESH criteria represents a reliable method to detect bevacizumab-induced hypertension. Whether hypertension is a biomarker of bevacizumab activity remains to be determined in a prospective study.

Development and validation of an HPLC-UV-visible method for sunitinib quantification in human plasma.

BACKGROUND Sunitinib malate is a novel oral multitargeted tyrosine kinase inhibitor with antitumor and antiangiogenic activities. Only mass spectrometry detection is currently available to determine sunitinib in human plasma. The purpose of this study was to develop a simple and sensitive high-performance liquid chromatographic method with UV-Visible detection for quantification of sunitinib concentrations in human plasma. METHODS After a liquid-liquid extraction with ethyl acetate, sunitinib and ranitidine (internal standard) are separated on cyanopropyl column using a simple binary mobile phase of ammonium acetate buffer (20 mM; pH 6.8):acetonitrile (55:45,v/v). Samples were eluted isocratically at a flow rate of 1 mL/min throughout the 10 min run. Dual wavelength mode was used, with ranitidine monitored at 255 nm, and sunitinib at 431 nm. RESULTS The calibration was linear in the range 20-200 ng/mL. Inter- and intra-day coefficients of variation were less than 7%. This method is sensitive, accurate and selective. It has been successfully implemented to monitor trough sunitinib concentrations in plasma samples (n = 39) from 14 unselected cancer patients treated with the recommended once daily dose of 50 mg or less. CONCLUSION This method can be used in routine clinical practice to monitor plasma sunitinib concentrations in cancer patients treated with once daily administration.

A simple HPLC-UV method for the simultaneous quantification of gefitinib and erlotinib in human plasma

Gefitinib and erlotinib are two oral tyrosine kinase inhibitors (TKI) approved for the treatment of advanced non-small cell lung cancer (NSCLC). Published methods for simultaneous analysis of erlotinib and gefitinib in plasma are exclusively based on mass spectrometry. The purpose of this study was to develop a simple and sensitive HPLC-UV method to simultaneously quantify these two TKI in plasma. Following liquid-liquid extraction, gefitinib, erlotinib and sorafenib (internal standard), were separated with gradient elution (on a C8+ Satisfaction(®) using a mobile phase of acetonitrile/20mM ammonium acetate pH 4.5). Samples were eluted at a flow rate of 0.4 ml/min throughout the 15-min run. Dual UV wavelength mode was used, with gefitinib and erlotinib monitored at 331 nm, and sorafenib at 249 nm. The calibration was linear in the range 20-1000 ng/ml and 80-4000 ng/ml for gefitinib and erlotinib, respectively. Inter- and intra-day imprecision were less than 7.2% and 7.6% for gefitinib and erlotinib, respectively. This analytical method was successfully applied to assess the steady state plasma exposure to these TKI in NSCLC patients. This simple, sensitive, accurate and cost-effective method can be used in routine clinical practice to monitor gefitinib or erlotinib concentrations in plasma from NSCLC patients.