[Needs assessment for the establishment of an Oral Therapy Unit].

Introduction: Oncological at home-treatment improves patient quality of life and autonomy but requires close watchfulness of adverse events and compliance to treatment. For nearly ten years, pharmaceutical consultations for home-based anticancer oral therapies patients are proposed on medical request in Avignon-Provence Cancer Institute (ICAP). Organizational changes led us to modify this management by integrating dedicated nurses to create an Oral Therapy Unit (OTU).

Inaugural bone metastases in non-small cell lung cancer: a specific prognostic entity?

Background: In non-small cell lung cancer patients (NSCLC), median survival from the time patients develop bone metastasis is classically described being inferior to 6 months. We investigated the subcategory of patients having an inaugural skeletal-related-event revealing NSCLC. The purpose of this study was to assess the impact of bone involvement on overall survival and to determine biological and tumoral prognosis factors on OS and PFS.

Critical role of sorafenib exposure over time for its antitumor activity in thyroid cancer.

Sorafenib, a multi-kinase inhibitor that targets the VEGF, PDGF and BRAF pathways, has demonstrated significant clinical activity in metastatic differentiated thyroid cancer. However, all patients eventually experience disease progression with a median progression-free survival close to 10 months. Since sorafenib exposure is known to decrease over time, we hypothesized that dose adjustments aiming to restore adequate exposure could lead to further clinical activity.

Phase I dose-escalation study of intravenous aflibercept administered in combination with irinotecan, 5-fluorouracil and leucovorin in patients with advanced solid tumours.

Background: To determine dose-limiting toxicities (DLTs), recommended phase II trial dose (RPTD), safety, preliminary antitumour activity and pharmacokinetics of intravenous aflibercept with irinotecan, 5-fluorouracil and leucovorin (LV5FU2).

Patients And Methods: In this open-label study, 38 patients with advanced solid tumours received aflibercept 2, 4, 5, or 6 mg/kg on day 1, then irinotecan and LV5FU2 on days 1 and 2 every 2 weeks.

Results: Two grade 3/4 aflibercept-associated DLTs occurred with 4 mg/kg: proteinuria lasting >2 weeks and acute nephrotic syndrome with thrombotic microangiopathy.

Sorafenib in advanced melanoma: a critical role for pharmacokinetics?

Background: Inter-patient pharmacokinetic variability can lead to suboptimal drug exposure, and therefore might impact the efficacy of sorafenib. This study reports long-term pharmacokinetic monitoring of patients treated with sorafenib and a retrospective pharmacodynamic/pharmacokinetic analysis in melanoma patients.

Patients And Methods: Heavily pretreated patients with stage IV melanoma were started on sorafenib 400 mg twice daily (bid).

Variability of sorafenib toxicity and exposure over time: a pharmacokinetic/pharmacodynamic analysis.

Background: Sorafenib displays major interpatient pharmacokinetic variability. It is unknown whether the pharmacokinetics of sorafenib influence its toxicity.

Methods: We analyzed the severity and kinetics of sorafenib-induced toxicities in unselected consecutive patients with cancer, as well as their relationship with biological, clinical, and pharmacokinetic parameters.

Saturable absorption of sorafenib in patients with solid tumors: a population model.

Sorafenib is an oral tyrosine kinase inhibitor approved for the treatment of advanced renal cell carcinoma and hepatocellular carcinoma. By using a population approach, this study aimed to characterise its pharmacokinetics. Plasma concentration-time data (n = 372) from 71 patients under sorafenib were analysed using nonlinear mixed-effect modelling to estimate population pharmacokinetic parameters, as well as relationships between these parameters and different covariates (demographic, biological).

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.

Transcription factor E3 and transcription factor EB renal cell carcinomas: clinical features, biological behavior and prognostic factors.

Purpose: Translocation renal cell carcinomas represent a distinct clinicopathological entity. Studying the natural history, biological behavior and potential prognostic factors are crucially warranted.

Materials And Methods: We selected 54 patients with renal cell carcinoma with positive nuclear transcription factor E3 and transcription factor EB expression from the Juvenile RCC Network.

Treatment of bevacizumab-induced hypertension by amlodipine.

Background: Hypertension is a common toxicity of anti-VEGF agents, but its optimal treatment remains to define. This study aimed to describe the efficacy and tolerability of amlodipine, a calcium channel blocker, in patients with metastatic malignancies treated with bevacizumab, a humanized monoclonal antibody to VEGF.

Patients And Methods: One hundred and eighty-seven patients with advanced or metastatic NSCLC, colorectal or ovarian cancer receiving bevacizumab (5 mg/kg every 2 weeks or 7.

Pharmacokinetic interaction involving sorafenib and the calcium-channel blocker felodipine in a patient with hepatocellular carcinoma.

Sorafenib, an orally active multi-kinase inhibitor approved for the treatment of hepatocellular carcinoma (HCC), is primarily metabolized both via cytochrome P450 3A4 isoform (CYP3A4) and UGT1A9. Due to the contribution of these two biotransformation pathways, sorafenib is considered to be less susceptible than other agents to CYP3A4 drug-drug interactions. This report discusses a clinically relevant pharmacokinetic CYP3A4 drug-drug interaction between sorafenib and felodipine in an 80-year-old Caucasian patient with HCC.

Reactivation of tuberculosis during temsirolimus therapy.

Reactivation of tuberculosis is rare in patients receiving chemotherapy for solid tumours, and poorly documented in patients receiving molecular targeted therapy. We report on a patient with metastatic renal-cell carcinoma treated with temsirolimus, who developed respiratory symptoms and mild fever after 6 weeks of treatment. CT-scan and laboratory tests were consistent with reactivation of tuberculosis.

Systemic mastocytosis and bone involvement in a cohort of 75 patients.

Objectives: To investigate bone involvement in a large cohort of systemic mastocytosis (SM) patients, and evaluate the efficacy of bisphosphonate therapy.

Patients And Methods: From 2000 to 2004, 75 patients with SM according to WHO criteria underwent skeletal x-rays and bone mineral density (BMD) assessment. Sequential BMD assessments were performed in nine patients treated with bisphosphonate (mean follow-up 65 months).

Pneumatosis intestinalis associated with treatment of cancer patients with the vascular growth factor receptor tyrosine kinase inhibitors sorafenib and sunitinib.

Recently, pneumatosis intestinalis has been described in patients receiving bevacizumab, a monoclonal antibody to VEGF-A. Pneumatosis intestinalis is a condition characterized by subserosal and submucosal gas-filled cysts in the gastrointestinal tract. We report on pneumatosis intestinalis in patients receiving oral anti-VEGF agents.

[New therapeutics strategies in renal cell carcinoma].

New medical strategies have emerged over the past decade for the treatment of advanced renal cell carcinoma based on the discovery of specific molecular abnormalities. However, molecular targeted therapeutics including anti-angiogenics have demonstrated significant limits (limited impact on overall survival, development of potential severe toxicities). We review the future directions for drug development based on specific interaction with cellular and extra-cellular pathways.

Targeted agents in metastatic Xp11 translocation/TFE3 gene fusion renal cell carcinoma (RCC): a report from the Juvenile RCC Network.

Background: Xp11 translocation renal cell carcinoma (RCC) is an RCC subtype affecting 15% of RCC patients <45 years. We analyzed the benefit of targeted therapy [vascular endothelial growth factor receptor (VEGFR)-targeted agents and/or mammalian target of rapamycin (mTOR) inhibitors] in these patients.

Patients And Methods: Patients with Xp11 translocation/TFE3 fusion gene metastatic RCC who had received targeted therapy were identified.

Toxicity of sorafenib: clinical and molecular aspects.

Importance Of The Field: Sorafenib is a novel oral bis-aryl urea compound originally developed as an inhibitor of RAF kinase for its anti-proliferative property. Sorafenib also inhibits receptor tyrosine kinases of multiple pro-angiogenic factors such as VEGFR-1/2/3, Flt-3 and PDGFR-beta. The combination of both its anti-proliferative and anti-angiogenic properties makes sorafenib an attractive agent in cancer treatment.

Ambulatory administration of 5-day infusion ifosfamide+mesna: a pilot study in sarcoma patients.

Purpose: Ifosfamide is a cornerstone of chemotherapy in bone and soft-tissue sarcoma. Results of pharmacokinetic studies indicate that the optimal schedule of ifosfamide should be repeated doses over several days. With the development of 5-day infusion devices, we developed and evaluated a 5-day infusion regimen of ifosfamide in sarcoma patients in the outpatient setting.

Renal toxicity of targeted therapies.

The use of molecular targeted therapies for the treatment of cancer has increased over the last decade. The benefits of these compounds in terms of efficacy are often relatively modest and counter balanced by the occurrence of significant toxicities. Many of these newer agents used in clinical practice lack specificity and selectivity and have a propensity to inhibit multiple targets.

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.

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.

[Angiogenesis: a new therapeutic target of thoracic and laryngopharyngeal carcinoma].

Angiogenesis or new blood vessel formation is a complex and fundamental event in the process of tumor growth and metastatic dissemination. Actually, most of antiangiogenic agents target the VEGF considered like the most potent proangiogenic factor. These molecules directly inhibit VEGF or the kinase activity of its receptor (VEGFR) and represent a significant therapeutic progress in several solid tumors types.