Molecular and clinical features of second-generation anaplastic lymphoma kinase inhibitors: ceritinib.

The discovery of ALK rearrangement in non-small-cell lung cancer (NSCLC) triggered rapid clinical development of a family of specific drugs targeting this alteration, called ALK inhibitors. Despite high rate of responses, the vast majority of patients treated with first-generation ALK inhibitor crizotinib will ultimately develop disease progression. The second-generation ALK inhibitor, ceritinib, is an oral, small-molecule that inhibits the ALK kinase activity with a potency 20-fold greater than crizotinib, being able to tackle some of the principal mechanisms of resistance to crizotinib. Evidences from five large prospective clinical trials have so far showed impressive activity of ceritinib in ALK inhibitor pretreated and naive NSCLC patients. This review will focus on the preclinical and clinical data available regarding ceritinib pharmacology, clinical efficacy and safety profile.

Phase ib of sorafenib in combination with everolimus in patients with advanced solid tumors, selected on the basis of molecular targets.

BACKGROUND: Molecular alterations of the PI3K and Ras pathways often occur in human cancer. In this trial, the pharmacokinetics, toxicity, and activity of two drugs inhibiting these pathways-everolimus and sorafenib-were investigated. METHODS: Thirteen patients with progressing solid tumors were treated with everolimus and sorafenib, according to a 3+3 scheme. Patients were selected on the basis of immunohistochemical expression of tumor molecular targets, including phospho-AKT, -p70S6K, and -ERK1/2. RESULTS: The daily recommended dose identified was 2.5 mg of everolimus and 600 mg of sorafenib. Dose-limiting toxicities included grade 3 asthenia and hand-foot skin reaction. No grade 4 adverse events were observed. The most frequent grade 3 toxicities were hypophosphatemia (30.8%), alanine aminotransferase level increase, asthenia, and anorexia (14%). No pharmacokinetic interactions were identified between everolimus and sorafenib. Of 12 evaluable patients, we observed 2 partial responses, with greater than 10% shrinkage in an additional 5 patients. Objective responses were observed in one patient with a thymoma and in one patient with a lung adenocarcinoma. Tumor shrinkage that did not qualify as a partial response was seen in an abdominal leiomyosarcoma and in adenoid cystic carcinomas. CONCLUSION: The combination of everolimus and sorafenib is safe. The tumor activity observed in different tumor types could be the result of the combined action of these drugs as well as the molecular selection of the treated population. Further research is warranted to better investigate drugs simultaneously blocking the PI3K and the Ras pathways and to refine patient selection.

"Waiting and the waiting room: how do you experience them?" emotional implications and suggestions from patients with cancer.

Waiting can increase discomfort. The goal of this study was to identify moods and fears of cancer patients while in a waiting room and to capture their concrete suggestions for an anthropocentric transformation of waiting itself. A 15-item questionnaire was given to 355 patients who came to our Out-patient Oncology Clinic. Eighty-three percent of patients felt that waiting has an emotional cost, 35% were upset by talking about their condition with others while waiting, and 26% suffered a major emotional impact seeing other sick people and witnessing their clinical decline. Eighty-nine percent of patients suggested that alternative activities, such as meetings with professionals, doctors, and psychologists, be organized during the waiting period; 65% suggested fun activities (music therapy, drawing courses, library, TV). Most patients asked to have the freedom to leave the waiting room. This option, feasibly by means of IMs/"beepers," would limit their sense of having a lack of freedom or being robbed of their time. This study highlighted the complexity and heterogeneity of emotional implications that waiting causes in patients with cancer and collected many patients' suggestions about how to create a constructive, free, and personalized waiting period, overcoming the boredom, distress, and psychological suffering it causes.

Breast cancer and pregnancy: how safe is trastuzumab?

BACKGROUND: A 29-year-old woman was diagnosed with lymph-node-positive, steroid-hormone-receptor-negative and HER2/neu-positive breast cancer. She underwent surgery followed by cyclophosphamide, epirubicin, and 5-fluorouracil chemotherapy, and received radiotherapy followed by trastuzumab therapy for 1 year. During the tenth month of trastuzumab therapy, the patient reported a missed period and had a positive pregnancy test. INVESTIGATIONS: Physical examination, pregnancy test, echocardiography. DIAGNOSIS: Unintended pregnancy during adjuvant trastuzumab therapy. MANAGEMENT: Cessation of trastuzumab and close monitoring of mother and fetus during pregnancy.