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Systemic therapy improves the survival and quality of life of patients with advanced stage non-small cell lung cancer (NSCLC). Several new therapeutic options have emerged for advanced NSCLC, incorporating novel cytotoxic agents (taxanes, gemcitabine, pemetrexed) and molecular-targeted agents (erlotinib, bevacizumab). Efforts to improve the outcome of first-line therapy for advanced and metastatic NSCLC have primarily focused on the addition of targeted agents to platinum-based two-drug regimens. Bevacizumab, an antibody against vascular endothelial growth factor, is the first drug to demonstrate superior outcomes when added to systemic chemotherapy in advanced disease. Evaluation of the role of maintenance therapy following four to six cycles of first-line combination chemotherapy is ongoing. Both cytotoxic agents and targeted agents are suitable for evaluation in the maintenance setting. Promising results have been noted with single-agent paclitaxel as maintenance therapy following four cycles of combination therapy with carboplatin and paclitaxel. Phase III studies are now under way to evaluate the roles of gemcitabine, pemetrexed, and erlotinib as maintenance therapies for patients who experience a response or disease stabilization after four cycles of combination chemotherapy. Whether this approach will be successful in extending the survival of a select group of patients remains to be seen. [ABSTRACT FROM AUTHOR]

Cancer education merits a coordinated, vertical curriculum and an integrated planning strategy. It has become clear that it is as important to teach the techniques of supportive care in oncology as it is to teach the concepts of cancer biology, pathology, epidemiology, prevention, detection and aggressive treatments. Our aim is to determine whether the medical school and nursing school curricula give the students an introduction to the concepts of supportive care of the cancer patient. The spectrum of such supportive care encompasses a wide range of issues working towards a common goal of providing overall comfort with an emphasis on quality of life, and runs parallel with specific therapeutic strategies and associated problems. Do the graduate medical student and nursing student understand that cancer management is multidisciplinary and team-based? That the approach to pain management not only includes the administration of pain medications, but should also evaluate pain assessment and anesthetic, neurosurgical and behavioral approaches? That nausea and vomiting associated with chemotherapy can be ameliorated to a certain extent? That infections are common but algorithms exist for prevention and therapy? That certain metabolic complications are unique to cancer patients? That transfusions are vital procedures in patients with neoplasms undergoing aggressive treatments but are associated with certain risks and complications? That there are serious psychosocial, ethical and legal needs to be considered? To address these issues, the American Cancer Society Professors of Clinical Oncology, the American Cancer Society Professors of Oncology Nursing and the United States Cancer Center Directors were surveyed.(ABSTRACT TRUNCATED AT 250 WORDS) [ABSTRACT FROM AUTHOR]

Monika Joshi, Syed M Rizvi, Chandra P Belani Penn State Milton S Hershey Medical Center, Department of Medicine, Division of Hematology-Oncology, Hershey, PA, USA Abstract: Targeting the epidermal growth factor receptor (EGFR) in patients with non-small cell lung cancer (NSCLC) harboring sensitizing mutations in the tyrosine kinase (TKI) domain has led to a significant change in the management of this disease. The classic or sensitizing mutations are G719X mutation in exon 18, in-frame deletions or insertion of exon 19, L858R or L861Q mutation in exon 21. Approximately 90% of these mutations are exon 19 deletion or exon 21 L858R point mutation. Gefitinib and erlotinib are reversible first-generation inhibitors of mutant EGFR, and treatment with these agents in the first-line setting has demonstrated a progression-free survival of 9.5–13.7 months. However, the majority of these patients ultimately develop resistance to these drugs. Afatinib is an irreversible pan-ErbB inhibitor that was developed to circumvent the problem of resistance to first-generation TKIs. The LUX-Lung studies have evaluated the efficacy and toxicities of afatinib in treatment-naïve and refractory NSCLC patients. The promising results of some of these trials led to approval of afatinib by the US Food and Drug Administration for patients with advanced NSCLC and EGFR exon 19 deletions or exon 21 (L858R) substitution mutations. Afatinib causes toxicities similar to those of the first-generation EGFR TKIs, such as diarrhea, rash, acne, and stomatitis, and overall is well tolerated. This article focuses on the clinical studies of afatinib in patients with NSCLC. Keywords: afatinib, non-small cell lung cancer, epidermal growth factor receptor, tyrosine kinase inhibitor

Huali Wu,1 Ramesh K Ramanathan,2 Beth A Zamboni,3 Sandra Strychor,4 Suresh Ramalingam,5 Robert P Edwards,4 David M Friedland,4 Ronald G Stoller,4 Chandra P Belani,4 Lauren J Maruca,4 Yung-Jue Bang,6 William C Zamboni11UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC, USA; 2Translational Research Division, The Translational Genomics Research Institute, Scottsdale, AZ, USA; 3Department of Mathematics, Carlow University, Pittsburgh, PA, USA; 4School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA; 5Winship Cancer Institute, Emory University, Atlanta, GA, USA; 6College of Medicine, Seoul National University, Seoul, KoreaAbstract: S-CKD602 is a PEGylated liposomal formulation of CKD-602, a potent topoisomerase I inhibitor. The objective of this study was to characterize the bidirectional pharmacokinetic–pharmacodynamic (PK–PD) interaction between S-CKD602 and monocytes. Plasma concentrations of encapsulated CKD-602 and monocytes counts from 45 patients with solid tumors were collected following intravenous administration of S-CKD602 in the phase I study. The PK–PD models were developed and fit simultaneously to the PK–PD data, using NONMEM®. The monocytopenia after administration of S-CKD602 was described by direct toxicity to monocytes in a mechanism-based model, and by direct toxicity to progenitor cells in bone marrow in a myelosuppression-based model. The nonlinear PK disposition of S-CKD602 was described by linear degradation and irreversible binding to monocytes in the mechanism-based model, and Michaelis–Menten kinetics in the myelosuppression-based model. The mechanism-based PK–PD model characterized the nonlinear PK disposition, and the bidirectional PK–PD interaction between S-CKD602 and monocytes.Keywords: population pharmacokinetics, pharmacodynamics, PEGylated liposome, nonlinear kinetics

Abstract Vorinostat (Zolinza®), a histone deacetylase inhibitor, was approved by the US Food and Drug Administration in October 2006 for the treatment of cutaneous manifestations in patients with cutaneous T-cell lymphoma who have progressive, persistent or recurrent disease on or following two systemic therapies. This review summarizes evidence on the use of vorinostat in solid and hematologic malignancies and collated tolerability data from the vorinostat clinical trial program. Pooled vorinostat clinical trial data from 498 patients with solid or hematologic malignancies show that vorinostat was well tolerated as monotherapy or combination therapy. The most commonly reported drug-related adverse events (AEs) associated with monotherapy (n = 341) were fatigue (61.9%), nausea (55.7%), diarrhea (49.3%), anorexia (48.1%), and vomiting (32.8%), and Grade 3/4 drug-related AEs included fatigue (12.0%), thrombocytopenia (10.6%), dehydration (7.3%), and decreased platelet count (5.3%). The most common drug-related AEs observed with vorinostat in combination therapy (n = 157, most of whom received vorinostat 400 mg qd for 14 days) were nausea (48.4%), diarrhea (40.8%), fatigue (34.4%), vomiting (31.2%), and anorexia (20.4%), with the majority of AEs being Grade 2 or less. In Phase I trials, combinations with vorinostat were generally well tolerated and preliminary evidence of anticancer activity as monotherapy or in combination with other systemic therapies has been observed across a range of malignancies. Ongoing and planned studies will further evaluate the potential of vorinostat in combination therapy, including combinations with radiation, in patients with diverse malignancy types, including non-small-cell lung cancer, glioblastoma multiforme, multiple myeloma, and myelodysplastic syndrome.

Background: Ambulatory patients receiving systemic cancer therapy are at varying risk for venous thromboembolism. However, the benefit of thromboprophylaxis in these patients is uncertain.Methods: In this double-blind, randomized trial involving high-risk ambulatory patients with cancer (Khorana score of ≥2, on a scale from 0 to 6, with higher scores indicating a higher risk of venous thromboembolism), we randomly assigned patients without deep-vein thrombosis at screening to receive rivaroxaban (at a dose of 10 mg) or placebo daily for up to 180 days, with screening every 8 weeks. The primary efficacy end point was a composite of objectively confirmed proximal deep-vein thrombosis in a lower limb, pulmonary embolism, symptomatic deep-vein thrombosis in an upper limb or distal deep-vein thrombosis in a lower limb, and death from venous thromboembolism and was assessed up to day 180. In a prespecified supportive analysis involving the same population, the same end point was assessed during the intervention period (first receipt of trial agent to last dose plus 2 days). The primary safety end point was major bleeding.Results: Of 1080 enrolled patients, 49 (4.5%) had thrombosis at screening and did not undergo randomization. Of the 841 patients who underwent randomization, the primary end point occurred in 25 of 420 patients (6.0%) in the rivaroxaban group and in 37 of 421 (8.8%) in the placebo group (hazard ratio, 0.66; 95% confidence interval [CI], 0.40 to 1.09; P = 0.10) in the period up to day 180. In the prespecified intervention-period analysis, the primary end point occurred in 11 patients (2.6%) in the rivaroxaban group and in 27 (6.4%) in the placebo group (hazard ratio, 0.40; 95% CI, 0.20 to 0.80). Major bleeding occurred in 8 of 405 patients (2.0%) in the rivaroxaban group and in 4 of 404 (1.0%) in the placebo group (hazard ratio, 1.96; 95% CI, 0.59 to 6.49).Conclusions: In high-risk ambulatory patients with cancer, treatment with rivaroxaban did not result in a significantly lower incidence of venous thromboembolism or death due to venous thromboembolism in the 180-day trial period. During the intervention period, rivaroxaban led to a substantially lower incidence of such events, with a low incidence of major bleeding. (Funded by Janssen and others; CASSINI ClinicalTrials.gov number, NCT02555878.). [ABSTRACT FROM AUTHOR]