Seminars in oncology
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Seminars in oncology · Oct 2010
ReviewClinical development of the anti-CTLA-4 antibody tremelimumab.
Tremelimumab (formerly CP-675,206) is a fully human IgG2 monoclonal antibody tested in patients with cancer, of whom the majority have had metastatic melanoma. Clinical trials using tremelimumab demonstrate that this antibody can induce durable tumor regressions (up to 8 years at this time) in 7% to 10% of patients with metastatic melanoma. ⋯ Grade 3 or 4 toxicities in the range of 20% to 25% are mainly inflammatory or autoimmune in nature, which are on-target effects after inhibiting CTLA-4-mediated self-tolerance. The lack of survival advantage in the early analysis of a phase III clinical trial comparing tremelimumab with standard chemotherapy for metastatic melanoma highlights the importance of gaining a better understanding of how this antibody modulates the human immune system and how to better select patients for this mode of therapy.
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Seminars in oncology · Aug 2010
ReviewDrug development for cancer chemoprevention: focus on molecular targets.
With biomolecular evidence accumulating at an exponential rate, there will be a surge in the development of targeted cancer prevention drugs and interventions in the next decade. Promising results from clinical treatment trials identify a spectrum of targeted cancer therapies in several broad categories. These include both small molecule inhibitors of either key receptors or enzyme binding sites, as well as intravenously delivered monoclonal antibodies that block a specific binding interaction between ligands and their receptors. ⋯ The complementarities of target-related processes within tumors cells, in the tumor microenvironment, and beyond suggests that there is great potential for multi-targeted approaches that may be more effective than single agents and also less prone to resistance. Additional options, related to drug dose and schedule, remain to be established. As long as multiple agents can be used in combination for optimal effect with acceptable toxicity, the co-targeting of the epithelial cell compartment along with other compartments of oncogenic activity is expected to expand the dimensions of targeted prevention and enhance the overall opportunity to eliminate precancer or cells at risk of eventually transitioning to invasive cancer.
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Seminars in oncology · Dec 2009
ReviewClinical trial experience with temsirolimus in patients with advanced renal cell carcinoma.
Clinical trials have validated the importance of mammalian target of rapamycin (mTOR) as a therapeutic target in patients with advanced renal cell carcinoma (RCC). The TORC1 complex controls translation of key proteins involved in cell proliferation and regulates the expression and stability of hypoxia-inducible factor (HIF)-1alpha. Temsirolimus, the first mTOR inhibitor approved for treatment of advanced RCC, has demonstrated significantly longer overall survival (hazard ratio for death, 0.73; 95% confidence interval, 0.58-0.92, P = .008) and progression-free survival (P <.001) compared with interferon alfa (IFN) for patients with poor prognostic features. ⋯ Although development of symptomatic pneumonitis is rare, monitoring is recommended. Temsirolimus is now considered an important first-line treatment option for patients with advanced RCC and multiple factors predictive of short survival. Current trials are investigating the use of temsirolimus in sequence or in combination with other targeted agents to further improve outcomes.
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Seminars in oncology · Aug 2009
Review Randomized Controlled TrialShould intra-cerebrospinal fluid prophylaxis be part of initial therapy for patients with non-Hodgkin lymphoma: what we know, and how we can find out more.
Central nervous system (CNS) involvement is a serious complication of non-Hodgkin lymphoma (NHL), with an extremely poor outcome. In most cases, relapse in the CNS manifests as leptomeningeal disease. The relatively short interval between the initial diagnosis of NHL and CNS involvement implies that seeding of the cerebrospinal fluid occurs early in the natural history of the disease and suggests a role for CNS prophylaxis during initial treatment. ⋯ Risk factors for CNS relapse in patients with aggressive NHL have been identified and may help define a subpopulation of patients for whom CNS prophylaxis is justified. Because of variation in current practice and a paucity of high-quality evidence, well-designed and controlled trials are needed to assess the benefits of prophylactic treatment in such a population. This article reviews the current role of CNS prophylaxis in patients with NHL and discusses issues in the conception, design, and execution of a clinical trial to elucidate the role of CNS prophylaxis in patients with aggressive NHL.