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First Published Online September 8, 2008
The Oncologist, Vol. 13, No. 9, 1001-1011, September 2008; doi:10.1634/theoncologist.2008-0131
© 2008 AlphaMed Press

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Symptom Management and Supportive Care

Evolving Strategies for the Management of Hand–Foot Skin Reaction Associated with the Multitargeted Kinase Inhibitors Sorafenib and Sunitinib

Mario E. Lacouturea, Shenhong Wub, Caroline Robertc, Michael B. Atkinsd, Heidi H. Konge, Joan Guitarta, Claus Garbef, Axel Hauschildg, Igor Puzanovh, Doru T. Alexandrescui, Roger T. Andersonj, Laura Woodk, Janice P. Dutcherl

aDepartment of Dermatology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA; bDivision of Medical Oncology, Department of Medicine, Stony Brook University Cancer Center, Stony Brook, New York, USA; cDermatology Unit, Gustave-Roussy Institute, Villejuif, France; dDivision of Hematology/Oncology, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA; eDermatology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA; fDepartment of Dermatology, Eberhard Karls University, Tübingen, Germany; gDepartment of Dermatology, University of Kiel, Kiel, Germany; hDivision of Hematology/Oncology, Vanderbilt-Ingram Cancer Center, Nashville, Tennessee, USA; iGeorgetown Dermatology, Washington, District of Columbia, USA; jPennsylvania State College of Medicine, Hershey, Pennsylvania, USA; kCleveland Clinic Taussig Cancer Center, Cleveland, Ohio, USA; lOur Lady of Mercy Medical Center, Comprehensive Cancer Center, New York Medical College, Bronx, New York, USA

Key Words. Sorafenib • Sunitinib • Hand–foot skin reaction • Forum consensus • Skin

Correspondence: Mario E. Lacouture, M.D., Department of Dermatology, Northwestern University Feinberg School of Medicine, 676 North St. Clair Street, Suite 1600, Chicago, Illinois 60611, USA. Telephone: 312-695-8106; Fax: 312-695-0537; e-mail: m-lacouture{at}northwestern.edu

Received June 11, 2008; accepted for publication July 30, 2008; first published online in THE ONCOLOGIST Express on September 8, 2008.

Disclosure: Employment/leadership position: None; Intellectual property rights/inventor/patent holder: None; Consultant/advisory role: Michael B. Atkins, Bayer/Onyx; Doru T. Alexandrescu, Bayer; Roger T. Anderson, Bayer; Claus Garbe, Bayer; Axel Hauschild, Bayer, Onyx; Janice P. Dutcher, Bayer/Onyx, Pfizer, Wyeth, Genentech; Mario E. Lacouture, Onyx, Bayer; Igor Puzanov, Spirogen; Caroline Robert, Bayer; Shenhong Wu, Onyx; Honoraria: Axel Hauschild, Bayer, Onyx; Laura Wood, Bayer/Onyx, Pfizer; Janice P. Dutcher, Bayer/Onyx, Pfizer, Wyeth, Novartis; Igor Puzanov, Pfizer, Novartis, Bayer; Shenhong Wu, Pfizer; Research funding/contracted research: Michael B. Atkins, Bayer/Onyx; Axel Hauschild, Bayer (Germany), Onyx (USA); Janice P. Dutcher, Bayer/Onyx, Pfizer, Wyeth, Genentech, Novartis; Mario E. Lacouture, Onyx; Ownership interest: None; Expert testimony: None; Other: None. The content of this article has been reviewed by independent peer reviewers to ensure that it is balanced, objective, and free from commercial bias. No financial relationships relevant to the content of this article have been disclosed by the authors, planners, independent peer reviewers, or staff managers.


   ABSTRACT
Top
 Abstract
Introduction
 MKIs
 Clinical Features and Incidence...
 Pathobiology of MKI-Induced HFSR
 Recommendations for Management...
 Conclusions
 Author Contributions
 Acknowledgments
 References
 
The multitargeted kinase inhibitors (MKIs) sorafenib and sunitinib have shown benefit in patients with renal cell carcinoma, hepatocellular carcinoma (sorafenib), and gastrointestinal stromal tumor (sunitinib). Their efficacy in other malignancies is currently being investigated because of their broad range of activity. The effectiveness of these drugs is somewhat diminished by the development of a variety of toxicities, most notably hand–foot skin reaction (HFSR). Although HFSR does not appear to directly affect survival, it can impact quality of life and lead to MKI dose modification or interruption, potentially limiting the antitumor effect. Currently, no standard guidelines exist for the prevention and management of MKI-associated HFSR. To address this issue, an international, interdisciplinary panel of experts gathered in January 2008 to discuss and evaluate the best-practice management of these reactions. Based on these proceedings, recommendations for the management of HFSR have been provided to offer patients the best possible quality of life while taking these drugs and to optimize the patient benefit associated with MKI therapy.


   INTRODUCTION
Top
 Abstract
 Introduction
MKIs
 Clinical Features and Incidence...
 Pathobiology of MKI-Induced HFSR
 Recommendations for Management...
 Conclusions
 Author Contributions
 Acknowledgments
 References
 
The advent of molecularly targeted therapies has changed the face of cancer treatment. These drugs enable the specific inhibition of cellular mechanisms, such as cell growth, differentiation, proliferation, and angiogenesis, to prevent tumor progression [1–3]. The multitargeted kinase inhibitors (MKIs) sorafenib and sunitinib have shown promising activity in renal cell carcinoma (RCC), hepatocellular carcinoma (HCC) (sorafenib), and gastrointestinal stromal tumor (GIST) (sunitinib) [3–7]; sorafenib and sunitinib have received regulatory approval for these malignancies by the U.S. Food and Drug Administration and the European Medicines Evaluation Agency [8–11]. However, these advances are somewhat diminished by the toxicities associated with these agents, including hand–foot skin reaction (HFSR) [12–14]. Although not life-threatening, HFSR can severely impact the physical, psychological, and social well-being of patients receiving these therapies and can lead to dose reductions and discontinuations that may potentially negate the life-prolonging effects of therapy [13, 14]. Therefore, appropriate methods of prophylaxis and management of HFSR are necessary to ensure proper administration of the drugs and to improve the health-related quality of life (HRQoL) of the patients who take them [13].

A forum to discuss the mechanisms behind MKI-associated HFSR, as well as existing management practices, was held January 21, 2008, in Chicago, Illinois. Medical oncologists and dermatologists from the U.S. and abroad attended this meeting with the objective of achieving a consensus about the management of HFSR. This article discusses the findings from this meeting.


   MKIS
Top
 Abstract
 Introduction
 MKIs
Clinical Features and Incidence...
 Pathobiology of MKI-Induced HFSR
 Recommendations for Management...
 Conclusions
 Author Contributions
 Acknowledgments
 References
 
The dysregulation of processes associated with cell growth and proliferation contributes to the development of tumors [15, 16]. Blocking or inhibiting the pathways responsible for these processes may prevent continued tumor growth [15, 17]. Several kinases involved in the potentiation of these pathways have been shown to be hyperactivated in various tumors, leading to increased cell proliferation and survival [7, 17]. Because of the important role played by several kinases in the perpetuation of tumor growth, targeting multiple kinases could provide more comprehensive antitumor protection [17].

In order for tumors to grow beyond 1 mm in size, new blood vessel formation is required; otherwise the tumors become necrotic or apoptotic [18]. This fact makes angiogenesis, the process by which new blood vessels are formed, a rational target for anticancer therapy [15]. The activation of vascular endothelial growth factor receptor (VEGFR) tyrosine kinase is responsible for binding proangiogenic factors and perpetuating signaling cascades that eventually result in the formation of new blood vessels [15]. Activation of another receptor tyrosine kinase, platelet-derived growth factor receptor (PDGFR), has been found to lead to the recruitment of pericytes, which stabilize growing vasculature; in the absence of proper PDGFR signaling, blood vessel maturation and stabilization are perturbed [17]. By blocking the activity of these receptors or by inhibiting members of their signaling pathways such as the RAF serine/threonine kinase, tumor vessel formation can be halted and even reversed [15, 17].

Another receptor tyrosine kinase, stem cell factor receptor (c-KIT), is well known for its role in hematopoiesis and melanocyte differentiation [2, 19]. Activating mutations in c-KIT often lead to increased signaling through the receptor, regardless of the presence of an appropriate ligand. Aberrant c-KIT signaling has been documented in GIST [7].

Targeting more than one kinase can be achieved through the use of several singly targeted agents or through the use of inhibitors that specifically target multiple kinases. The most well studied of these MKIs are the small-molecule inhibitors sorafenib and sunitinib. These inhibitors have been shown to specifically target the RAF (sorafenib only), c-KIT, fms-related tyrosine kinase receptor 3 (Flt3), VEGFR, and PDGFR kinases, inhibiting tumor-related angiogenesis and direct tumor growth (Fig. 1) [1, 2, 20, 21].


Figure 1
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  		Figure 1. Major pathways inhibited by sorafenib and sunitinib. Sorafenib and sunitinib specifically recognize and inhibit c-KIT, VEGFR, PDGFR-β, and Flt3 receptor tyrosine kinases. Sorafenib also inhibits RAF, a serine/threonine kinase involved in the MAPK/ERK kinase pathway [1, 2, 20, 21].

Abbreviations: c-KIT, stem cell factor receptor; ERK, extracellular signal–related kinase; Flt3, fms-related tyrosine kinase receptor 3; Flt3L, Flt3 ligand; KL, KIT ligand; MAPK, mitogen-activated protein kinase; MEK, mitogen-activated protein kinase–extracellular signal-related kinase kinase; PDGF-β, platelet-derived growth factor β; PDGFR-β, platelet-derived growth factor receptor β; VEGF, vascular endothelial growth factor; VEGFR, vascular endothelial growth factor receptor.

 
Sorafenib is a biaryl urea that is orally administered and has a half-life of 25–48 hours [3]. In clinical trials, patients with advanced RCC and unresectable HCC who were treated with sorafenib had a significantly longer progression-free survival (PFS) time than patients treated with observation (RCC) or standard therapies (HCC), leading to the approval of sorafenib in these disease settings; overall survival was also longer in patients with HCC [6, 8, 22]. The MKI sunitinib malate is also orally administered and has a half-life of 40–60 hours (metabolite half-life, 80–110 hours) [3]. It has been approved for use in patients with GIST who are refractory to or intolerant of imatinib mesylate and, more recently, in patients with advanced RCC [9]. In studies of sunitinib in patients with treatment-naïve and cytokine-refractory advanced RCC, treatment with sunitinib led to a significantly greater objective response rate (ORR) and PFS time [9, 23]. In patients with GIST, the ORR, PFS time, and time to tumor progression were all significantly greater with sunitinib therapy [7, 9].

In addition to their efficacy in often hard-to-treat malignancies [6, 7, 22, 23], and despite the incidence of side effects such as fatigue, hypertension, and diarrhea, sorafenib and sunitinib also have safety profiles that are generally more favorable than those of many standard chemotherapies [3]. However, sorafenib and sunitinib can also produce a series of cutaneous side effects, especially HFSR, which can negatively impact patient HRQoL and activities of daily living (ADL) [13, 24]. Although with adequate management of HFSR most patients can be maintained on their dosing schedule, no clear guidelines exist to direct clinicians in the proper treatment of HFSR [13].


   CLINICAL FEATURES AND INCIDENCE OF DERMATOLOGIC TOXICITIES ASSOCIATED WITH MKIS
Top
 Abstract
 Introduction
 MKIs
 Clinical Features and Incidence...
Pathobiology of MKI-Induced HFSR
 Recommendations for Management...
 Conclusions
 Author Contributions
 Acknowledgments
 References
 
Dermatologic toxicities are among the most commonly reported adverse events in patients receiving MKI therapy [3]. Several different cutaneous toxicities have been reported, which can range from mild to severe (Table 1) [1, 7, 22, 23, 25–27]. Seborrheic dermatitis-like rash, pruritus, erythema, xerosis, stomatitis, subungual splinter hemorrhages, alopecia, modification of hair growth or pigmentation, skin discoloration, and HFSR have been reported in clinical trials of sorafenib and sunitinib (Fig. 2) [2, 6, 7, 14, 22, 23, 26–31].


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  		Table 1. Dermatologic toxicities associated with multikinase inhibitor therapy [1, 7, 22, 23, 25–27]

 


Figure 2
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  		Figure 2. Common dermatologic toxicities associated with multitargeted kinase inhibitors and their locations [2, 6, 7, 14, 22, 23, 26–31].

 
The most clinically significant of these toxicities, HFSR, has also been referred to as hand–foot syndrome (HFS) and palmar–plantar erythrodysesthesia [14, 32], and has been shown to occur in anywhere from 9% to 62% of patients receiving sorafenib or sunitinib [1, 22, 25–27, 29]. A meta-analysis to study the incidence and risk of HFSR in patients enrolled in prospective clinical trials in which either sorafenib or sunitinib was examined as a single agent was performed using a random-effects or fixed-effects model based on the heterogeneity of the included studies [1, 33]. The studies included in the meta-analysis were single-arm phase II trials and randomized, controlled phase III trials. The summary incidence of HFSR in patients treated with sorafenib was 33.8% for grades 1–3 (95% confidence interval [CI], 24.5%–44.7%) and 8.9% for grade 3 (95% CI, 7.3%–10.7%) [1]. With sunitinib, the summary incidence was calculated at 18.9% for grades 1–3 (95% CI, 14.1%–24.8%) and 5.5% for grade 3 (95% CI, 3.9%–7.9%) [33]. The relative risk of developing HFSR based on data from randomized controlled clinical trials was 6.6 with sorafenib and 9.9 with sunitinib.

HFSR develops within the first 2–4 weeks of MKI administration in the majority of patients [13]. Lesions are tender and scaling, with a peripheral halo of erythema localized on areas of pressure (tips of fingers and toes, heels, and metatarsophalangeal skin areas) or flexure (skin overlying metacarpophalangeal or interphalangeal joints) [1, 13, 14, 34, 35]. After several weeks, the lesions, with or without blisters, are followed by areas of thickened or hyperkeratotic skin that is also painful, impairing range of motion, function, and weight bearing [36].

HFSR shares some clinical similarities with the HFS that occurs during the administration of cytotoxic chemotherapies such as cytarabine, capecitabine, 5-fluorouracil, or doxorubicin [1, 14]. These similarities include palmar–plantar localization, tenderness, pain, and resolution of the toxicity upon discontinuation of the drug [14, 37, 38]. However, the typical pattern of localized hyperkeratotic lesions surrounded by erythematous areas distinguishes HFSR from classic HFS, in which symmetric paresthesias, erythema, and edema occur [14]. The histopathology of HFSR also differs from that of HFS [1, 12].


   PATHOBIOLOGY OF MKI-INDUCED HFSR
Top
 Abstract
 Introduction
 MKIs
 Clinical Features and Incidence...
 Pathobiology of MKI-Induced HFSR
Recommendations for Management...
 Conclusions
 Author Contributions
 Acknowledgments
 References
 
Investigating the histology of HFSR lesions may reveal insights about the pathogenesis of the toxicity. Histologic changes can been seen in the epidermal and dermal layers and followed throughout the course of HFSR [12, 39] (Fig. 3a). Extensive and linear layers of keratinocyte necrosis are observed, which correlate with the time of initial exposure to the MKI [36]. Histologic examination reveals necrotic subepidermal, intraepidermal, or subcorneal blister formation that is followed by acanthosis with hyperkeratosis or parakeratosis [12, 39]. Few cases show mild cystic degenerative changes of the eccrine coil; in rare cases, some squamous metaplasia of these glands has also been observed [34, 40]. Because of the erythematous and tender nature of the HFSR lesions, some postulate that an inflammatory infiltrate must be present [12]; however, histologic findings indicate a mild lymphoid infiltrate usually devoid of eosinophils and rather prominent dilated capillaries (telangiectasias) [36].


Figure 3
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  		Figure 3. Examples of MKI-associated HFSR. (A) Histologic alterations in HFSR affected skin. Linear necrosis with a subcorneal blister is observed in the epidermis, and telangiectasia with a mild perivascular mononuclear cell infiltrate is evidenced in the dermis. (B) Grade 1 HFSR: minimal skin changes without pain. (C) Grade 2 HFSR: skin changes or pain that do not interfere with the patient's ADL. (D) Grade 3 HFSR: ulcerative dermatitis or skin changes with pain that interfere with the patient's ADL [24].

Abbreviations: ADL, activities of daily living; HFSR, hand–foot skin reaction; MKI, multitargeted kinase inhibitor.

 
The exact mechanism of the pathogenesis of HFSR is unknown, but some postulate that secretion of the MKI into the eccrine glands results in direct toxicity of the MKI to the skin, as is the case in doxorubicin-associated HFS [12, 13, 35, 41]. However, no direct evidence exists that either sorafenib or sunitinib is secreted by the eccrine glands, making this theory unlikely. Furthermore, the lack of cytotoxic, metaplastic, or structural changes of the eccrine units also weighs against skin damage secondary to local sweat secretion [36]. Epidermal keratinocytes synthesize PDGF-{alpha} and PDGF-β, which are activating ligands for PDGFR in dermal capillaries and fibroblasts, as well as eccrine glands [42]. In addition, eccrine glands express c-KIT and PDGFR, which are both targets of sorafenib and sunitinib [19, 43]. Because an overlap in targets for sorafenib and sunitinib lies in VEGFR and PDGFR inhibition, HFSR may be an indirect effect of the inhibition of these proangiogenic pathways [14, 34, 39]. Inhibition of VEGFR and PDGFR could potentially prevent vascular repair mechanisms from functioning properly, thereby causing HFSR in high-pressure areas, such as the palms and soles, which may be repeatedly exposed to subclinical trauma [14]. The combined inhibition of these receptors appears to be essential because PDGFR (imatinib) or VEGF (bevacizumab) inhibition alone does not result in HFSR [11]. In addition, greater blockade of VEGF results in greater HFSR, as shown with the combination of sorafenib and bevacizumab, which produced grade 2 HFSR in 18 of 38 patients [10].


   RECOMMENDATIONS FOR MANAGEMENT OF MKI-ASSOCIATED HFSR
Top
 Abstract
 Introduction
 MKIs
 Clinical Features and Incidence...
 Pathobiology of MKI-Induced HFSR
 Recommendations for Management...
Conclusions
 Author Contributions
 Acknowledgments
 References
 
No prospective, randomized trials have been undertaken to determine the best management strategy for HFSR. Therefore, the following recommendations represent a compilation of expert opinions from medical oncologists and dermatologists that are based on individual clinical experience and qualitative information. Further recommendations could arise after the completion of trials designed to formally determine the efficacy of these management strategies for HFSR.

Grading of HFSR
Accurate grading of HFSR allows for appropriate follow-up of the toxicity and may also correlate with its impact on HRQoL. The main goal of all intervention strategies is to maintain or recover comfort and HRQoL for the patient while continuing a potentially life-prolonging therapy for as long as possible. Therefore, accurate grading of the toxicity in the clinical setting is critical to its management.

The National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0 (NCI-CTCAE v3.0) is the most widely used method of grading HFSR (Table 2) [24]. Grade 1 HFSR is described as having minimal skin changes or dermatitis with no pain. Grade 2 is indicated by skin changes, such as blisters and peeling, with some pain; these changes still do not interfere with the patient's ADL. Grade 3, the most severe, is described as skin changes with pain that affect the patient's ADL (Fig. 3B–D) [24]. ADL are comprised of the activities of daily living, or the tasks of everyday life. Basic ADL include eating, dressing, getting into or out of a bed or chair, taking a bath or shower, and using the toilet [44]. Instrumental activities of daily living are activities related to independent living and include preparing meals, managing money, shopping, doing housework, and using a telephone [45–47]. However, other important considerations not included in this definition that are an important part of patients' lives include (but are not limited to) the ability to groom, do hobbies, work, and exercise.


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  		Table 2. NCI-CTCAE version 3.0 grading of HFSR [24]

 
Effective Management of HFSR
Management of HFSR can begin before any symptoms occur. Several prophylactic measures may be taken to prevent or reduce the severity of HFSR. Before therapy with an MKI begins, a full-body skin exam should be performed, with a special emphasis on hyperkeratotic areas on palms and soles and any deformities. Patients can receive a pedicure, using properly sterilized utensils, to remove any preexisting hyperkeratotic areas or calluses that may predispose them to developing HFSR. For patients with evidence of abnormal weight-bearing, evaluation by an orthotist for an orthotic device is encouraged. Patients should be advised to reduce the exposure of their hands and feet to hot water, either through dishwashing or hot baths and showers, because this is believed to exacerbate symptoms, and patients frequently report symptomatic relief with cold water. Because the majority of patients develop HFSR within the first 2–4 weeks of MKI therapy, prevention of traumatic activity and rest are critical in order to minimize development during this period. Patients should also avoid constrictive footwear; care should also be taken to avoid excessive friction on the skin when applying lotion, during massages, or in the process of everyday tasks, such as typing. Vigorous exercise or activities that place undue stress on the hands and feet should also be avoided, especially during the first month. Thick cotton gloves or socks can be worn to prevent injury and keep palms and soles dry. Shoes with padded insoles should be worn throughout treatment to reduce pressure on the feet. Frequent communication between patients and health care professionals is encouraged; maintaining contact at weeks 2–4 of MKI therapy initiation is recommended to ensure that symptoms of HFSR are detected at the earliest possible stage. Such frequent contact also enables health care professionals to screen their patients for hypertension or other side effects of MKIs [8, 9]. Distributing a pamphlet pertaining to the early signs and symptoms of HFSR could encourage patients to be proactive about detecting HFSR at an early stage and promptly instituting management.

If HFSR does develop, the following management strategies are suggested, depending on the grade of HFSR (Fig. 4):


Figure 4
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  		Figure 4. Algorithm for the management of MKI-associated HFSR.

Abbreviations: HFSR, hand–foot skin reaction; MKI, multitargeted kinase inhibitor.

 
Grade 1: Patients should avoid hot water and use moisturizing creams for relief. Keratolytics, such as urea 20%–40%, or salicylic acid 6% may be indicated. Cotton gloves and socks can be worn at night to prevent further injury and to help retain moisture. No dose modifications of the MKI are recommended at this level of toxicity. A 2-week follow-up in the clinic is recommended; special attention should be paid to palms and soles.

Grade 2: Treatment should continue as for grade 1 toxicity with the following additions. Consider applying clobetasol 0.05% ointment to erythematous areas twice daily. For pain control, consider using topical analgesics such as lidocaine 2% and assess for bleeding and kidney function before prescribing any systemic pain medications (e.g., nonsteroidal anti-inflammatory drugs, codeine, pregabalin). If necessary, consider a dose reduction to 50% of the full dose for a minimum of 7 days, up to 28 days, until the HFSR reaches grade 1 or 0, and then resume full dosing [8]. For subsequent grade 2 recurrences, please refer to Table 3.


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  		Table 3. Suggested dose modifications for sorafenib and sunitinib for HFSR based on prescribing information and 2008 consensus panel recommendations [8]

 
Grade 3: Provide treatment as indicated for grades 1 and 2 and include the following. Interrupt treatment for a minimum of 7 days until the HFSR reaches grade 1 or 0, and then resume treatment at 50% of the full dose. Monitor the patient for toxicity. If toxicity does not recur, it may be possible to escalate doses until the full dose is reached. For a second or third recurrence, follow the dose modifications listed in Table 3 [8].

Once the acute episode of erythema with or without blisters improves, patients may develop hyperkeratotic, tender lesions. In these cases, topical agents that inhibit keratinocyte proliferation that have shown anecdotal benefit include urea 40% cream, tazarotene 0.1% cream, and fluorouracil 5% cream [48–51]. Urea is a keratolytic, which dissolves the intracellular matrix, softening hyperkeratosis and decreasing epidermal thickness and proliferation. Tazarotene is a retinoid that also decreases proliferation, normalizes differentiation, and reduces dermal inflammation. Fluorouracil is an antifolate that inhibits proliferation and has shown anecdotal benefit in inherited conditions characterized by hyperkeratotic lesions in palms and soles. These topical agents are applied twice daily only to affected areas because they may be irritating to unaffected skin.

With MKIs, the total dose seems to correlate with the occurrence and severity of HFSR [36, 52]. Although therapeutic response to other targeted agents, such as epidermal growth factor receptor inhibitors, is correlated with the occurrence of dermatologic toxicity, no evidence exists to indicate that the same is true for MKIs (J.P.D., unpublished data, May 2008) [29, 53]. Patients should be aware that the development of HFSR does not mean that their treatment is "working."

Impact of HFSR on HRQoL
Patient HRQoL is always an important consideration in the treatment of cancer. Therefore, maintaining the best possible HRQoL should be a treatment goal. Supporting HRQoL in patients receiving MKI therapy is essential to continuously promote patient well-being as well as reduce the need for dose reductions or interruptions. Therefore, properly assessing patient HRQoL, combined with therapeutic efficacy, can help to determine the most effective HFSR management strategies. Skin toxicities, including those resulting from MKI therapy, while not life-threatening, can adversely impact a patient's HRQoL by impairing their ability to perform ADL and impacting their social functioning and emotional well-being [54]. Unfortunately, the literature on the effects of HFSR on HRQoL is very sparse. Recently, a small study was the first to directly assess the effects of HFSR on HRQoL [55]. In 11 patients with HFSR after sorafenib or sunitinib therapy, pain (3.45 on a scale of 0–6; standard deviation [SD], 2.50) was the most significant complaint, as assessed by a dermatologic HRQoL patient-reported questionnaire, the Skindex-16 [56]. The median overall Skindex-16 score among these patients was 28 (SD, 25.9; out of a total of 96). Other highly rated items included irritation (3.18; SD, 2.7) and the persistence of skin condition (3.36; SD, 2.1). Using the Pearson correlation coefficient, emotional symptoms were correlated with physical symptoms at r = 0.86 (p < .005) and functioning at r = 0.73 (p = .01). The severity of the HFSR, graded by the physician using the NCI-CTCAE v3.0, correlated with its impact on patient-reported HRQoL; the more severe the HFSR, the greater the impact on HRQoL as measured by the Skindex-16 [56]. The Skindex-16 is a HRQoL measure that specifically addresses HRQoL issues in patients with skin disease and has been shown to accurately assess the self-reported condition of the skin as well as the disfigurement from skin disease [55, 56]. Currently available HRQoL measures such as the Skindex-16 and the Dermatology Specific Quality of Life Questionnaire can be valuable tools in monitoring skin-related HRQoL in patients receiving MKI therapy [57]; however, these questionnaires have not been developed for this specific patient population and may fail to address differences between the effects of therapy and the effects of the original illness on HRQoL beyond those common to skin disease [57]. Alternatively, measures of cancer-related HRQoL address some of the core areas relevant to HFSR but typically do not address upper and lower extremities or skin reaction symptoms. Therefore, it may be necessary to develop a measure of HRQoL that assesses the effects of MKI therapy on HRQoL separately from the effects of cancer.


   CONCLUSIONS
Top
 Abstract
 Introduction
 MKIs
 Clinical Features and Incidence...
 Pathobiology of MKI-Induced HFSR
 Recommendations for Management...
 Conclusions
Author Contributions
 Acknowledgments
 References
 
The introduction of MKIs into the therapy of GIST, HCC, and RCC has significantly impacted patients with these diseases, for which there were few available therapies. However, the resultant dermatologic toxicities from these drugs, particularly HFSR, can sometimes prevent patients from receiving MKI therapy, even when it may prove beneficial. Management of the symptoms of HFSR at its earliest signs is the only available means to prevent the dose reduction or interruption of MKI therapy.

Because of the recent introduction of MKIs into cancer therapy, no randomized, controlled clinical trials have been performed to address the management of MKI-related dermatologic toxicities, so health care professionals must rely on anecdotal reports of successful management strategies. Until clinical trials that examine the effective management of HFSR are completed, these guidelines for HFSR management, developed by a multidisciplinary expert panel, can serve as a proxy for more detailed, clinically tested recommendations.

The main goal of any anticancer therapy is a favorable outcome for the patient. The reduction or interruption of MKI therapy can adversely affect patient outcomes through the removal of a potentially life-sparing therapy. Therefore, the symptoms of HFSR should be recognized as early as possible to initiate therapeutic management before withholding therapy becomes necessary. The ultimate goal is the elimination of the need for treatment withdrawal or interruption, optimizing the chance for these agents to improve overall survival.


   AUTHOR CONTRIBUTIONS
Top
 Abstract
 Introduction
 MKIs
 Clinical Features and Incidence...
 Pathobiology of MKI-Induced HFSR
 Recommendations for Management...
 Conclusions
 Author Contributions
Acknowledgments
 References
 
Conception/design: Mario E. Lacouture

Provision of study materials or patients: Mario E. Lacouture, Shenhong Wu, Caroline Robert, Heidi H. Kong, Joan Guitart, Roger T. Anderson

Collection/assembly of data: Mario E. Lacouture

Data analysis and interpretation: Mario E. Lacouture, Shenhong Wu, Caroline Robert, Michael B. Atkins, Heidi H. Kong, Joan Guitart, Claus Garbe, Axel Hauschild, Igor Puzanov, Doru T. Alexandrescu, Roger T. Anderson, Laura Wood, Janice P. Dutcher

Manuscript writing: Mario E. Lacouture, Shenhong Wu, Caroline Robert, Michael B. Atkins, Heidi H. Kong, Joan Guitart, Claus Garbe, Axel Hauschild, Igor Puzanov, Doru T. Alexandrescu, Roger T. Anderson, Laura Wood, Janice P. Dutcher

Final approval of manuscript: Mario E. Lacouture, Shenhong Wu, Caroline Robert, Michael B. Atkins, Heidi H. Kong, Joan Guitart, Claus Garbe, Axel Hauschild, Igor Puzanov, Doru T. Alexandrescu, Roger T. Anderson, Laura Wood, Janice P. Dutcher


   ACKNOWLEDGMENTS
Top
 Abstract
 Introduction
 MKIs
 Clinical Features and Incidence...
 Pathobiology of MKI-Induced HFSR
 Recommendations for Management...
 Conclusions
 Author Contributions
 Acknowledgments
References
 
The authors take full responsibility for the content of the paper but thank Leslie A. Moody, Ph.D., from the Center for Biomedical Continuing Education, supported by an educational grant from Onyx Pharmaceuticals, Inc., and Bayer HealthCare Pharmaceuticals, for her assistance in organizing the published literature, preparing the initial draft of the manuscript, and collating the comments of the authors. M.E.L. is supported by a Zell Scholarship from the Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, Illinois.


   REFERENCES
Top
 Abstract
 Introduction
 MKIs
 Clinical Features and Incidence...
 Pathobiology of MKI-Induced HFSR
 Recommendations for Management...
 Conclusions
 Author Contributions
 Acknowledgments
 References
 

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