Interleukin-2 chronotherapy for metastatic renal cell carcinoma: Results of a phase I-II study.

BACKGROUND: Interleukin-2 (IL-2) was the cornerstone treatment for metastatic renal cell carcinoma (RCC) until the advent of tyrosine kinase inhibitors, but it still has therapeutic value. As a single bolus of IL-2 causes toxicity, there is interest in administration regimens with better tolerability and efficacy. Chronotherapy is the administration of therapy according to the circadian rhythm's influence on the immune and hormonal systems. This phase I-II trial evaluated the safety of IL-2 chronotherapy in metastatic RCC patients and determined the maximum tolerated dose. The secondary objective was to identify prognostic factors for survival. METHODS: Three chronomodulation schedules (5:00-13:00, 13:00-21:00, and 21:00-5:00) were tested. Each schedule was an 8-h IL-2 infusion, with a Gaussian distribution of drug concentration peaking at 4 h. To identify the maximum tolerated dose, the dose for different patients was escalated from 2 MIU/m2 (level I) to 18.6 MIU/m2 (level VI). RESULTS: Thirty patients were enrolled and completed treatment. Two patients were treated at 5:00-13:00, 15 at 13:00-21:00, and 13 at 21:00-5:00. Nine cases of grade 3 toxicity occurred in 7 patients at the highest dose (18.6 MIU/m2); no grade 4 toxicity occurred. The maximum tolerated dose was 14.0 MUI/m2. Patients were followed for a median of 16 months (range, 2-107). One patient was lost to follow-up, 3 patients were alive at last contact, and 26 patients died. Six patients achieved long-term survival (≥48 months). There was one complete response, four partial responses, 11 cases of stable disease and 14 of progressive disease. The response rate was 16% (5/30) and disease-control rate was 53% (16/30). Median progression-free survival was 4.5 months, and median overall survival was 14.5 months. Kaplan-Meier analyses revealed significant associations between overall survival and ECOG performance score (0 vs. 1-2), MSKCC score (0-2 vs. ≥ 3), IMDC risk score (0-2 vs. ≥ 3), IL-2 dose level (IV-VI vs. I-III), and prolactin (increase vs. no increase), and but not for chronotherapy schedule. CONCLUSION: IL-2 chronotherapy appears to be safe, moderately toxic and active in metastatic RCC. It may represent a new modality of IL-2 administration for these patients.

Nanocarriers in cancer clinical practice: a pharmacokinetic issue.

The advent of nanocarriers for drug delivery has given rise to new intriguing scenarios in the cancer field. Nanocarriers indeed partly overcome the limits of traditional cytotoxic drugs principally changing the pharmacokinetic behavior of the parental drug. The peculiar characteristics of these systems strongly minimize the adverse reactions and ensure a more precise release of the compound to the tumor site. Several nanocarriers have been developed for the delivery of cytotoxic drugs such as paclitaxel and doxorubicin in order to improve both the outcome and the patients' quality of life. The aims of this review are to describe in detail the pharmacokinetics of nanocarriers, already marketed or in advanced clinical phases, for paclitaxel and doxorubicin, to highlight the main differences with the parental drugs, and to underline, in a critical manner, benefits and disadvantages related to the use of these new drug delivery systems.

Safety Profiles and Pharmacovigilance Considerations for Recently Patented Anticancer Drugs: Lung Cancer.

BACKGROUND: Lung cancer is the most frequent cause of cancer-related death. In the last decades, the introduction of targeted therapies and more recently, of immunotherapy, has led to significant improvements in different outcomes of this malignant neoplasm. OBJECTIVE: The present review provides a balanced overview of most recent targeted therapies and immunotherapies patented for the treatment of lung cancer. METHODS: An extensive scientific literature and patent databases search were performed to identify peerreviewed studies containing information on recently patented drugs for the treatment of lung cancer, with a particular focus on their safety data and recently patented combinations. RESULTS: The development of therapies directed to different pathways involved in the tumor angiogenesis, proliferation, and metastasis has transformed the clinical practice of lung malignancies. Several clinical trials have shown an improvement in terms of progression-free survival and overall survival in patients with advanced/metastatic lung cancer. Safety data, extracted from clinical trials and from the WHO global database of adverse drug reactions (VigiAccessTM database), show that recently patented drugs for the treatment of lung cancer are well-tolerated and most of the adverse events reported are mild to moderate. CONCLUSION: Currently, a consistent number of new drugs and combinations have been introduced for the treatment of patients with advanced-stage lung cancer. Safety data remain essential to better assess the long-term risk/benefit ratio of these valuable emerging therapies. The new patents' development could provide further significant improvements for lung cancer treatment.

Safety Profiles and Pharmacovigilance Considerations for Recently Patented Anticancer Drugs: Advanced Thyroid Cancer.

BACKGROUND: Thyroid cancer is the most common endocrine neoplasia and represents approximately 1.5% to 2.1% of all cancers diagnosed annually worldwide. Iodine Refractory Differentiated Thyroid Carcinoma (RR-DTC) and advanced/metastatic medullary thyroid carcinoma are relatively uncommon yet prognostically significant thyroid cancers. Gene rearrangements resulting in the aberrant activity of tyrosine kinases have been identified as drivers of oncogenesis in a variety of cancers, including thyroid cancer. Many Multi-Kinase Inhibitors (MKIs) which are now FDA-/EMA approved for thyroid cancer have shown clinical benefit in patients with advanced cancer. Treatment related toxicities occur frequently with these drugs and can be severe or life-threatening. OBJECTIVES: This review summarizes the role of targeted therapy with MKIs in the management of RRDTC and advanced/metastatic MTC patients, focusing on side-effect profiles of these drugs, with a presentation of several recent patents published in this field. METHODS: We review the scientific literature on advanced thyroid cancer and analyze the International Pharmacovigilance database (FAERS, Eudravigilance, and WHO Vigibase) for adverse drug reactions. RESULTS: This systematic analysis highlights the difference in the safety profile of the recent drugs used in the treatment of advanced thyroid cancer and the recent discoveries for diagnosis or treatment of the thyroid cancer. CONCLUSION: It is essential to investigate the safety profile of recent anticancer drugs for advanced thyroid cancer to allow health professionals to make the best choice for each patient by conducting risk/benefit assessment.