Charles J. Nock

Diagnosis and Treatment of Melanoma Brain Metastasis: A Literature Review

BACKGROUND Brain metastasis is common in patients with malignant melanoma and represents a significant cause of morbidity and mortality. Nearly 37% of patients with malignant melanoma eventually develop brain metastasis, and autopsy reports show that 75% of those who died of this disease developed brain metastasis. METHODS We review the level I and level II evidence that guides indications for treatment with surgery, stereotactic radiosurgery, chemotherapy, and immunotherapy for patients with melanoma brain metastasis. RESULTS Level I evidence supports the role of whole brain radiotherapy, microsurgery, and radiosurgery alone or in combination for the treatment of patients with melanoma brain metastasis. Chemotherapy has been ineffective. Ongoing studies continue to assess the effects of immunotherapy and agents in development. CONCLUSIONS Brain metastasis is a common and formidable challenge in patients with malignant melanoma. Although there have been no randomized controlled trials exclusively in patients with melanoma brain metastasis, care can be guided by the application of level I evidence for the treatment of brain metastasis in general and phase II studies focusing specifically on melanoma brain metastasis. Promising new agents and approaches are needed and will hopefully be identified in the near future.

Phase II Study of Dasatinib (BMS-354825) in Patients With Metastatic Adenocarcinoma of the Pancreas

BACKGROUND Src, EphA2, and platelet-derived growth factor receptors α and β are dysregulated in pancreatic ductal adenocarcinoma (PDAC). METHODS Dasatinib is an oral multitarget tyrosine kinase inhibitor that targets BCR-ABL, c-Src, c-KIT, platelet-derived growth factor receptor β, and EphA2. We conducted a phase II, single-arm study of dasatinib as first-line therapy in patients with metastatic PDAC. METHODS Dasatinib (100 mg twice a day, later reduced to 70 mg twice a day because of toxicities) was orally administered continuously on a 28-day cycle. The primary endpoint was overall survival (OS). Response was measured using the Response Evaluation Criteria in Solid Tumors. Circulating tumor cells (CTCs) were also collected. RESULTS Fifty-one patients enrolled in this study. The median OS was 4.7 months (95% confidence interval [CI]: 2.8-6.9 months). Median progression-free survival was 2.1 months (95% CI: 1.6-3.2 months). In 34 evaluable patients, the best response achieved was stable disease in 10 patients (29.4%). One patient had stable disease while on treatment for 20 months. The most common nonhematologic toxicities were fatigue and nausea. Edema and pleural effusions occurred in 29% and 6% of patients, respectively. The number of CTCs did not correlate with survival. CONCLUSION Single-agent dasatinib does not have clinical activity in metastatic PDAC.

Phase I trial of docetaxel and thalidomide: a regimen based on metronomic therapeutic principles

SummaryPurpose: Pre-clinical models have demonstrated the benefit of metronomic schedules of cytotoxic chemotherapy combined with anti-angiogenic compounds. This trial was undertaken to determine the toxicity of a low dose regimen using docetaxel and thalidomide. Patients and Methods: Patients with advanced solid tumors were enrolled. Thalidomide 100mg twice daily was given with escalating doses of docetaxel from 10 to 30mg/m2/week. One cycle consisted of 12 consecutive weeks of therapy. The maximal tolerated dose (MTD) was defined as the dose of thalidomide along with docetaxel that caused ≤grade 1 non-hematologic or ≤grade 2 hematologic toxicity for cycle one. Results: Twenty-six patients were enrolled. Dose-limiting toxicities (DLTs) were bradycardia, fatigue, fever, hyperbilirubinemia, leukopenia, myocardial infarction, and neutropenia. Prolonged freedom from disease progression was observed in 44.4% of the evaluable patients. Conclusions: This anti-angiogenic regimen was well tolerated and demonstrated clinical benefit. The recommended phase II dosing schedule is thalidomide 100mg twice daily with docetaxel 25mg/m2/week.