Temisorlimus in the treatment of advanced renal cell carcinoma
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Bernard J. Escudier
Received: 21 May 2007 Accepted in revised form: 8 June 2007
B.J. Escudier (쾷) Institut Gustave Roussy 39 rue Camille Desmoulins F-94805 Villejuif, France Tel.: +33-1-42-11-54-10 Fax: +33-1-42-11-52-11 e-mail: [email protected]
REVIEW
Temsirolimus in the treatment of advanced renal cell carcinoma
Abstract Temsirolimus is a novel inhibitor of mammalian target of rapamycin (mTOR), which is a central regulator of the response of tumour cells to growth and survival signals. When heavily pretreated patients with advanced solid tumours received intravenous (IV) temsirolimus over a broad dose range, antitumour activity was observed in various tumour types, including advanced renal cell carcinoma (RCC). A study of singleagent temsirolimus in patients with cytokine-refractory metastatic RCC subsequently demonstrated antitumour activity and encouraging progression-free survival and overall survival. Temsirolimus was generally well tolerated over the 3 dose levels tested (25 mg, 75 mg or 250 mg weekly as a 30-minute IV infusion). The most frequent grade 3 or 4 treatment-related adverse events
Introduction Metastatic renal cell carcinoma (RCC) is notably unresponsive to chemotherapy and radiation and is only modestly responsive to cytokine therapy with interferon-alpha (IFN) or interleukin-2 [1–4]. However, targeted therapies have recently led to a revolution in the treatment of advanced RCC [5, 6]. The multikinase inhibitors sorafenib and sunitinib inhibit vascular endothelial growth factor (VEGF) receptor and tumour angio-
reported (n=110) were hyperglycemia (17%), hypophosphatemia (13%), anemia (9%), and hypertriglyceridemia (6%). Results from a randomized phase III study that enrolled previously untreated patients with advanced RCC and poor-prognostic features have recently demonstrated a significant increase in overall survival (p=0.0089) for patients who received temsirolimus 25 mg IV, 30-minute infusion once weekly compared with those who received interferon-alpha up to 18 million units subcutaneously thrice weekly. On the basis of improved survival, temsirolimus can be considered a first-line treatment for patients with advanced RCC. Key words Temsirolimus • Kidney cancer • Renal cell carcinoma • mTOR • Targeted therapy
genesis and have significantly improved progression-free survival for patients with advanced or metastatic RCC [7, 8]. Treatment strategies are continuing to evolve with the emergence of temsirolimus, a novel targeted agent with a mechanism of action different from that of multikinase inhibitors, cytokines, and chemotherapy. Temsirolimus specifically inhibits the mammalian target of rapamycin (mTOR), which is a central mediator of tumour cell response to multiple growth and survival signaling pathways [9–12]. Whereas many chemotherapeutic agents inhibit DNA synthesis or metabolic
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pathways, temsirolimus acts at the level of mRNA translation to inhibit or reduce the production of proteins that are required for tumour cell growth and angiogenesis [13, 14]. This article reviews
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