How we do it
Elizabeth Manchen RN, MS, OCN
Abstract
One significant toxicity associated with the anticancer tyrosine kinase inhibitors (TKIs) is hand–foot skin reaction (HFSR). We provide an overview of HFSR, emphasizing experience-based prevention techniques and nursing management strategies from the viewpoints of a medical oncologist, a dermatologist, and an oncology nurse. Supporting data include (1) published preclinical and phase I–III clinical studies and (2) published abstracts of phase II–III clinical trials of sorafenib and sunitinib. HFSR has been reported in up to 60% of patients treated with sorafenib or sunitinib. TKI-induced HFSR may lead to dose reductions or treatment interruptions and reduced quality of life. Symptoms of TKI-associated HFSR can be managed by implementing supportive measures and aggressive dose modification. Patients educated about HFSR can work with their health-care teams to proactively detect and help manage this cutaneous toxicity, thus preventing or reducing the severity of TKI-associated HFSR. Successful prevention and management of TKI-associated HFSR can help to ensure that patients achieve optimal therapeutic outcomes. Implementation of such measures may increase the likelihood that therapy is continued for the appropriate interval at an appropriate dose for each patient. Optimal management of TKI-associated HFSR is predicated on establishing appropriate partnerships among medical oncologists, dermatologists, oncology nurses, and patients.
Article Outline
This article reviews the mechanism of action, clinical trial results, and adverse effects of two molecularly targeted anticancer agents, the tyrosine kinase inhibitors (TKIs) sorafenib (Nexavar®; Bayer HealthCare Pharmaceuticals, Montville, NJ, and Onyx Pharmaceuticals, Emeryville, CA) and sunitinib (Sutent®; Pfizer Pharmaceuticals, New York, NY). This article specifically focuses on the diagnosis and management of TKI-associated hand–foot skin reaction (HFSR) from the perspectives of the medical oncologist, the dermatologist, and the oncology nurse. Data were derived from (1) published reports of preclinical and phase I–III clinical studies of sorafenib and sunitinib and (2) published abstracts of phase II–III clinical trials of sorafenib and sunitinib.
The Medical Oncologist's Viewpoint
Molecularly Targeted Agents
Molecularly targeted therapies are directed at specific mechanisms involved in cell division, invasion, and metastasis, as well as in cell survival mediated by avoidance of apoptosis and resistance to conventional treatments. Clinical trials in several cancer types have shown that these TKIs can inhibit these activities of cancer cells by either cytostatic or cytotoxic mechanisms.1 However, the ability of these agents to inhibit multiple cancer cell pathways via novel mechanisms of action may explain, at least in part, their apparent direct toxic effects.2 These include adverse events that, from a medical viewpoint, must be anticipated, promptly recognized, and properly treated. Doing so can help minimize disruption to the patient's quality of life and may reduce the need for dose reduction or treatment interruption.1
Both sorafenib and sunitinib are orally administered, small-molecule inhibitors of multiple kinases, some of which are common to both agents (Figure 2).3 Sorafenib has known effects on tumor-cell proliferation and angiogenesis. Its antiproliferative effects are exerted via inhibition of serine/threonine kinases of the RAF/MEK/ERK signaling pathway (also called the MAP-kinase pathway) that is found within tumor cells; specifically, sorafenib targets wild-type RAF gene products (CRAF, BRAF) and mutant BRAF. The antiangiogenic effects of sorafenib are exerted via its inhibition of extracellular vascular endothelial growth factor (VEGF) receptors 2 and 3 (VEGFR-2 and VEGFR-3) and platelet-derived growth factor receptor beta (PDGFR-β), which is found mainly in the tumor vasculature. Sorafenib also exerts broad-spectrum activity against the stem-cell growth factor receptor (c-KIT), FMS-like tyrosine kinase 3 (Flt3), and the receptor encoded by the ret proto-oncogene (RET).[4], [5], [6] and [7] Sunitinib has demonstrated effects on the growth, pathologic angiogenesis, and metastatic progression of cancer by inhibiting PDGFR-α and -β; VEGFR-1, -2, and -3; and colony-stimulating factor receptor (CSF-1R), c-KIT, Flt3, and RET.8