The
Oncologist
®
Symptom Management and Supportive Care
ROGER ANDERSON,a AMINAH JATOI,b CAROLINE ROBERT,c LAURA S. WOOD,d KAREN N. KEATING,e
MARIO E. LACOUTUREf
a
Penn State University College of Medicine, Hershey, Pennsylvania, USA; bMayo Clinic Cancer Center,
Rochester Minnesota, USA; cInstitut Gustav Roussy, Villejuif, France; dCleveland Clinic Taussig Cancer
Institute, Cleveland, Ohio, USA; eBayer Healthcare Pharmaceuticals, Montville, New Jersey, USA;
f
Robert H. Lurie Comprehensive Cancer Center, Chicago, Illinois, USA
Key Words. Hand–foot skin reaction • Acral erythema • Palmar–plantar erythrodysesthesia • Multikinase inhibitors
Disclosures: Roger Anderson: Consultant/advisory role: Bayer Healthcare; Aminah Jatoi: None; Caroline Robert: Consultant/
advisory role: Pfizer-Bayer; Laura S. Wood: Honoraria: Bayer, Onyx, Pfizer, Wyeth; Karen N. Keating: Employment/leadership
position: Bayer Healthcare; Mario E. Lacouture: Consultant/advisory role: Bayer, Onyx; Research funding/contracted research:
Bayer, Onyx.
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 independent peer reviewers.
ABSTRACT
Background. The anticancer multikinase inhibitors
(MKIs) are associated with cutaneous adverse events,
including hand–foot skin reaction (HFSR), a condition
affecting 20%– 40% of patients. Symptoms are usually
mild, but can evolve into a painful condition that limits
function and impacts quality of life (QoL), resulting in
shortened cancer treatment duration or intensity. The
goal of this study was to systematically review the literature on the prevention and palliation of MKI-associated HFSR, to identify areas for further clinical study,
and to provide a foundation for evidence-based guidelines for HFSR management.
Methods. Systematic searches of the National Library of Medicine’s PubMed database, Cochrane Reviews, BIOSIS, CancerLit, and the American Society
of Clinical Oncology website were conducted using
search terms for cutaneous toxicities associated with
chemotherapeutic agents. Articles were categorized
(C) based on type of agent and cutaneous reaction as:
C1 (MKI and HFSR); C2 (MKI and other cutaneous
toxicity); C3 (other antineoplastic agents and HFSR);
and C4, other.
Results. Of the 2,069 abstracts screened, 350 (17%)
met the criteria for C1–C4, with 56 (16%) coded as C1
with details of HFSR histology, pathogenesis, clinical
outcome, QoL impact, and/or prevention and treatment
approaches in MKI-treated patients. No randomized,
controlled trials (RCTs) on prevention/palliation of
HFSR were identified. Anecdotal evidence or expert
opinion advocated protective measures, preventive and
therapeutic skin care, systemic analgesics for pain, vitamin B6, and MKI dose modification.
Conclusion. No articles containing evidence from
RCTs on preventive/palliative approaches to MKI-asso-
Correspondence: Roger Anderson, Ph.D., A210 Public Health Sciences, Penn State University College of Medicine, 500 University
Drive, Hershey, Pennsylvania, USA. Telephone: 717-531-2044; Fax: 717-531-4359; e-mail: randerso@hes.hmc.psu.edu Received November 1, 2008; accepted for publication February 2, 2009; first published online in The Oncologist Express on March 10, 2009. ©AlphaMed Press 1083-7159/2009/$30.00/0 doi: 10.1634/theoncologist.2008-0237
The Oncologist 2009;14:291–302 www.TheOncologist.com
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Search for Evidence-Based Approaches for the Prevention and
Palliation of Hand–Foot Skin Reaction (HFSR) Caused by the
Multikinase Inhibitors (MKIs)
292
Treatment Strategies for Hand–Foot Skin Reaction
vance development of evidence-based treatment guidelines. The Oncologist 2009;14:291–302
INTRODUCTION
17]. The primary objective of this literature review study
was to determine the extent of evidence-based treatment for
MKI-associated HFSR available in the peer-reviewed literature. A systematic and intensive review revealed that no
evidence-based treatment algorithms exist for the effective
prevention and treatment of cutaneous toxicities from
MKIs [15]. Several experience-based practices are consistently seen and reported in the literature; these practices
were presented in a recent publication summarizing the proceedings of an expert panel [5].
Chemotherapeutic agents such as capecitabine and doxorubicin have long been noted for their potential to cause skin
toxicities that affect the hands and feet, varying in occurrence and severity by type of agent and dosing schedule
[1–5]. Novel targeted therapies have recently demonstrated
efficacy against several tumor types; however, use of several of the multikinase inhibitors (MKIs), such as sorafenib
or sunitinib, has also led to the cutaneous toxicity known as
hand–foot skin reaction (HFSR) in 20%– 40% of treated patients [1, 2, 5]. The appearance of MKI-associated HFSR
differs from the hand–foot skin toxicities (i.e., hand–foot
syndrome [HFS]) seen with older chemotherapeutic agents
[6, 7]. It usually presents as a mild-to-moderate cutaneous
reaction [5, 8], is not age limited [3], and may evolve into a
painful condition that limits daily functioning and affects
quality of life (QoL) [1, 2, 4, 5]. The HFSR symptom burden experienced by the patient may eventually cause the oncologist to limit or reduce MKI treatment duration or
intensity, or to end treatment. Signs and symptoms of HFSR
may include pain, swelling, numbness, tingling, redness of
the skin of the hands or feet, and flat blisters or hyperkeratotic lesions [9 –12]. As the hyperkeratotic areas thicken,
scaly lesions resembling skin calluses surmount the erythematous patches. In high-grade, fully developed lesions,
large tense blisters can develop [12].
The National Cancer Institute Common Terminology
Criteria for Adverse Events (NCI-CTCAE, v3.0) grading
system for dermatologic toxicities [13], the most widely
used method of grading for HFSR [3, 5], is shown in Table 1. The grading system used in the sorafenib U.S. prescribing information, which is more descriptive and
specific to HFSR symptoms reported with sorafenib, also
is shown [14]. Grade 1 HFSR is characterized by numbness, dysesthesia, paresthesia, tingling, painless swelling, and erythema or discomfort of the hands or feet that
does not disrupt the patient’s normal activities. Characteristics of grade 2 HFSR include painful erythema and
swelling of the hands or feet and/or discomfort affecting
the patient’s normal activities. Grade 3 HFSR is characterized by moist desquamation, ulceration, blistering, or
severe pain of the hands or feet, or severe discomfort that
causes the patient to be unable to work or perform activities of daily living.
Prompt identification and management of HFSR may be
essential to facilitate the continuation of MKI therapy [15–
METHODS
Searches of the peer-reviewed literature were conducted
via the National Library of Medicine’s PubMed database, the Cochrane Database of Systematic Reviews, and
the BIOSIS and CancerLit databases listed in the archives through August 31, 2008. Literature search terms
were broad based to capture skin toxicities associated
with chemotherapy and were not specific to a certain
agent or treatment approach. The searches used variations and synonyms of the key word “hand–foot syndrome”
including hand–foot skin reaction, acral erythema, palmar–
plantar erythrodysesthesia, acral erythema, acral erythrodysesthesia, Burgdorf reaction, and toxic erythema of
the palms and soles, among other variations of the terms
already stated. Medical subject heading (MeSH)
searches were conducted using the terms skin disease,
hand injuries– chemically induced, and erythema and
were combined with MeSH terms, including antineoplastic agents and protein kinase inhibitors. The names of
specific agents entered into the MeSH search included:
sorafenib, sunitinib, gefitinib, erlotinib, temsirolimus,
capecitabine, gemcitabine, 5-fluorouracil, tegafur,
emitefur, vinorelbine, liposome-encapsulated or continuous-infusion doxorubicin, floxuridine, cytarabine,
methotrexate, palifermin, docetaxel, cisplatin, clofarabine, cyclophosphamide, daunorubicin, etoposide, fluorouracil, hydroxyurea, 6-mercaptopurine, paclitaxel,
6-thioguanine, and troxacitabine [18]. Additional
searches focused on the toxicity of anticancer agents, patient management, and general cutaneous reactions to kinase inhibitors. When retrieval results exceeded 1,000
records, queries were limited to recent English-language
clinical studies, meta-analyses, reviews, or practice
guidelines. Additional articles that were similar or related to those already found were either brought to our
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ciated HFSR have been published. Systematic study of
optimal treatment strategies for HFSR is needed to ad-
Anderson, Jatoi, Robert et al.
293
Table 1. Clinical features of HFSR and patient-reported symptoms [13, 14, 24]
NCI-CTCAE v3.0 grading for
Skin toxicity grade (sorafenib PI)
Grade
HFSR [13]
[14]
Minimal skin changes or dermatitis
(e.g., erythema) without pain
Numbness, dysesthesia, paresthesia,
tingling, painless swelling,
erythema or discomfort of the hands
or feet that does not disrupt the
patient’s normal ADLs
Grade 2
Skin changes (e.g., peeling,
blisters, bleeding, edema) or pain,
not interfering with function
Painful erythema and swelling of
the hands or feet and/or discomfort
affecting the patient’s ADLs
Grade 3
Ulcerative dermatitis or skin
changes with pain interfering with
function
Moist desquamation, ulceration,
blistering, or severe pain of the
hands or feet or severe discomfort
that causes the patient to be unable
to work or perform ADLs
● Numbness
● Unpleasant sensations when
touching ordinary things
● A burning or prickly feeling
● Tingling
● Painless swelling
● Redness or discomfort of
hands or feet
● None of these symptoms
affect the patient’s ADLs
One or more of the following:
● Painful redness
● Swelling
● Skin thickening of the
hands or feet
● Symptoms create
discomfort, but do not
affect the patient’s ADLs
One or more of the following:
● Scaling or shedding of the
skin
● Open sores
● Blistering
● Skin thickening
● Severe pain of the hands or
feet
● Severe discomfort that
causes the patient to be
unable to work or perform
ADLs
Abbreviations: ADL, activity of daily living; HFSR, hand–foot skin reaction; NCI-CTCAE, National Cancer Institute
Common Terminology Criteria for Adverse Events; PI, prescribing information.
attention by expert panel members for further scrutiny or
appeared in abstracts presented at recent American Society of Clinical Oncology congresses. Included for review
in this study were all citations categorized (C) as C1 (pertaining to MKI-associated HFSR) and containing details
on histology, pathogenesis, incidence, QoL, impact,
treatment, or prevention. This literature was distinguished from related published material categorized as:
C2 (citations that focused on MKI-associated skin reactions other than HFSR such as acneiform eruptions or
skin rash histology, pathogenesis, incidence, treatment,
or prevention); C3 (citations that focused on antineoplastic agents other than MKIs, such as capecitabine, doxorubicin, etc.); or C4 (citations that did not focus on
clinical details of pathophysiology or treatment of
HFSR/HFS but on other issues related to HFSR such as
complications, study design issues, health care policy, or
patient needs). Copies of articles were obtained and reviewed for all retained citations reporting clinical results
of patient treatment approaches regardless of: (a) sample
size or study design, (b) whether they were reviews of the
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scientific literature on HFSR treatment or outcomes, and
(c) whether they were case studies. Excluded from further review were C1 articles that solely presented attitudes or opinions regarding HFSR without reference to
any of the above inclusion criteria. Each citation was
judged independently by two reviewers. Any discrepancies that arose regarding inclusion were resolved either
by clarification followed by unanimous agreement or after review of the full article in question. Finally, we considered “evidence” as data or information that originated
from objective tests of efficacy in clinical or case studies
published in the scientific literature rather than from anecdotal observations.
RESULTS
In total, 2,069 abstracts were identified. All were screened
for consistency with the search objectives. Abstracts covering the wrong condition or topics unrelated to antineoplastic therapy were eliminated. A total of 350 abstracts (16%)
met the criteria for inclusion in C1–C4 (Fig. 1) and were
stored in a reference database. Fifty-six (16%) were in-
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Grade 1
Symptoms [24]
Treatment Strategies for Hand–Foot Skin Reaction
294
Database Literature Search
NLM PubMed Database, Cochrane Database of Systematic Reviews,
BIOSIS and CancerLit Databases, ASCO Congress Abstracts
Search terms: hand-foot skin reaction, hand-foot skin
syndrome, etc., AND antineoplastic agents, protein kinase
inhibitors, multikinase inhibitors, etc.
2,069 Citations
350a Citations
MKI-Associated Skin
Reactions
Category 1 (C1)
56 Citations
a
Category 2 (C2)
12 Citations
Cytotoxic ChemotherapyInduced Skin Reactions
Category 3 (C3)
270 Citations
Category 4 (C4)
19 Citations
7 articles contained content that required that they be placed into more than 1 category.
Figure 1. Classification of retrieved articles.
Abbreviations: ASCO, American Society of Clinical Oncology; MKI, multikinase inhibitor; NLM, National Library of Medicine.
cluded in C1, and 270 (80%) were included in C3. None of
the C1 or C3 articles on prevention/palliation approaches to
HFSR were reports from randomized, controlled trials.
Findings from the C1 articles follow.
Prevention Approaches for MKI-Associated HFSR
Evidence and reports on prevention and palliation of
HFSR relevant to developing evidence-based clinical
practice guidelines are shown in Table 2. Recommendations for the prevention and treatment of MKI-associated
HFSR in the examined literature were based on: practices
implemented during clinical trials of MKI agents, postmarketing practices, approaches derived from personal
clinical experiences of the authors, and strategies used
for chemotherapy-induced HFS (non-MKI agents) but
applied to HFSR resulting from MKI therapy. The range
of treatment goals and prophylactic recommendations
identified included: (a) controlling the presence of plantar hyperkeratosis, a putative risk factor for HFSR, by
prophylactic removal of the hyperkeratotic areas followed by application of a moisturizing cream; (b) pedicures; and (c) the cushioning of callused areas by means
of soft or padded shoes [19, 20]. Among other approaches were the prophylactic use of exfoliating products applied to the calluses [17] and administration of
prophylactic pyridoxine (vitamin B6). The role of these
recommendations in preventing chemotherapy-induced
HFS remains under debate [21–23].
Recommendations on Patient Education Prior to
Initiation of Drug Therapy
Because most MKIs are self-administered oral medications, effective patient education about HFSR prior to commencement of therapy and guidance on skin care and
protection is another strategy for prevention [4]. Oncology
providers are encouraged to listen to patients’ concerns, offer options to enhance patient comfort, and identify treatment issues early [17]. No studies were found that tested the
efficacy of patient education approaches for HFSR (e.g.,
printed material, video or photographic aides, or other media) [15, 24] on the likelihood of developing HFSR, or the
severity of symptoms.
Treatment/Palliation Approaches for
Management of Symptoms of MKI-Associated
HFSR
Grade 1
Clinical goals for grade 1 HFSR (Table 3) as cited in the
literature included instituting supportive measures, con-
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Independent Reviewer Screening
Anderson, Jatoi, Robert et al.
295
Table 2. Recommendations for prophylactic management of hand-foot skin reaction
Clinical goals/objectives
Recommendations
Source
Screen for pre-existing
plantar hyperkeratosis
Prophylactic removal of the
hyperkeratotic areas
Prophylactic skin care
Prophylactic systemic
treatments
Manicure or pedicure before
and during treatment to
remove hyperkeratosis
● Emollients
● Topical exfoliating
products (salicylic acid
and urea-based; e.g.,
Kerasal威; Alterna LLC,
Whippany, NJ); ureacontaining prescription
agents (e.g., Keralac威;
Doak Dermatologics,
Fairfield, NJ) to treat
hyperkeratotic calluses
● Pedicure before treatment;
manicure and pedicure
before and during
treatment with follow-up
emollient; Keralac威 to
treat hyperkeratotic
calluses
Wear well-fitting, soft shoes
(e.g., sandals), foam-type
absorbing soles, and shock
absorbers to relieve painful
pressure points
Preventive administration of
pyridoxine (doses of 50–150
mg/day)
Glucocorticoidsa
Cyclooxygenase-2
inhibitorsb
Personal experience or recommendation
of the authors
Personal experience or recommendation
of the authors
[8, 10, 11, 19]
Personal experience or recommendation
of the authors
Personal experience or recommendation
of the authors
[7, 11, 15, 17, 20,
25, 38, 45]
Personal experience or recommendation
of the authors
[2, 8, 17]
Personal experience or recommendation
of the authors
[3, 10, 19, 20]
Work of Vukelja et al. [46] in a patient
with 5-FU–induced PPE; cited by
others
Opinion of the author
Work of Lin et al. [47] with
capecitabine and celecoxib; cited by
others
[3, 16, 46, 47]
[7–11, 19]
a
Route of administration is not identified; no evidence of successful use.
Effective as a systemic approach for prophylaxis of chemotherapy-associated hand–foot syndrome (5-FU, capecitabine,
tegafur, emitefur, vinorelbine, doxorubicin, irinotecan, cytarabine, floxuridine), as well as sorafenib.
Abbreviations: 5-FU, 5-fluorouracil; PPE, palmar–plantar erythrodysesthesia.
b
tinuation of MKI treatment, control of hyperkeratotic areas, maintaining the moisture of the skin, and continuing
patient education on skin care and protection. Specific
approaches employed to achieve these goals included the
use of keratolytics such as 40% urea and/or salicylic acid
to aid in the natural exfoliation of the callused areas followed by cushioning of the affected regions with gel inserts or the use of soft shoes. Frequent application of
emollients and creams may be important to maintain
moisture of the skin and to prevent cracks or breaks in
dermal integrity. A dermatologic referral of patients with
unique skin presentations or those who fail to respond to
HFSR treatment, combined with active collaboration
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among dermatologists, podiatrists, oncologists, and oncology nurses, was recommended. Unfortunately, none
of the C1 publications covering recommendations for
grade 1 MKI-associated HFSR presented scientifically
collected evidence on the benefits of adherence to these
general treatment strategies. All of the recommendations
were based on the personal experience of the authors or
case studies.
Grade 2
No recommendations are cited in the literature for management approaches specific to grade 2 MKI-associated HFSR
involving compounds or procedures for skin care or symp-
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Protection of pressuresensitive areas of the hands
and feet
Suitable podiatry care
Reference(s)
Treatment Strategies for Hand–Foot Skin Reaction
296
Table 3. Recommendations for management of grade 1 hand–foot skin reaction (HFSR)
Clinical goals/objectives
Recommendations
Source
Dermatology referral and
management
Highly inflammatory
lesions
Cushioning the callused
areas to relieve discomfort
Local application of
occlusive emollients to
maintain moisture and
treat dry skin
Dose adjustment for
grade 1 HFSR seen
with sorafenib
Footwear: gel inserts may provide some
relief; loose-fitting shoes or slippers
Analgesics: low- to moderate-dose
analgesics; applying sunburn-relief spray to
affected areas when needed
Local/regional cooling, cold compresses:
cold compresses/ice packs for pain relief;
cooling battery or cooling hand and foot
baths to relieve the symptoms
Foot soaks: soaking feet in magnesium
sulfate to soften calluses and reduce pain
upon pressure
Frequent application of highly occlusive
emollients
Emollient and urea-based creams may
provide comfort and softening of the lesions
Diligent application of creams and lotions
especially to palms and soles
Keep affected areas soft and pliable to
prevent cracks or breaks in skin integrity
Continue treatment with sorafenib and
consider topical therapy for symptomatic
relief
tom control. Clinical goals for grade 2 HFSR included controlling hyperkeratosis, cushioning callused areas,
moisturizing the skin, controlling symptoms, and relieving
discomfort. The specific treatment approaches cited for
grade 1 HFSR also applied to grade 2 HFSR (Table 4). The
major approach used to control grade 2 HFSR is described
in the reviewed literature as dose adjustment of MKIs. Recommendations for dosage or regimen adjustments for sorafenib were based on the proceedings from the expert panel
[5] and were based on whether this was the first occurrence
of grade 2 HFSR or a second, third, or fourth occurrence
(Table 4).
Personal experience of
the authors
[3, 36, 45]
Personal experience of
the author
[4]
Personal experience of
the authors
[4, 7, 8, 11, 14,
19, 37, 38, 48]
Cited work of others
[11]
Personal experience of
author
Case study cited by the
author [34, 36]; cited
work of others [2,12]
Personal experience of
the author
[15, 19]
[3, 4, 7, 8, 11,
34, 36, 49, 50]
Personal experience of
the authors
[11, 36]
Expert panel
[5]
Grade 3
Clinical goals for grade 3 HFSR included symptom reduction and prevention of further progression [3, 25–27]. Specific supportive measures included topical therapies such as
cortisone creams and topical antibiotics. Systemic strategies to reduce symptoms and prevent further progression
included pyridoxine in doses of 50 –150 mg/day [3, 25–27].
The efficacy of corticosteroids has not been established.
The cornerstone of the treatment recommendations is interruption of MKI treatment for a minimum of 7 days until toxicity has resolved to grade 0 or 1 (Table 5) and a decrease by
one dose level (sorafenib, 400 mg daily or 400 mg every
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Local control of symptoms
at first signs of
paresthesias
Control hyperkeratosis
through products that aid
in natural exfoliation
Early and appropriate dermatologic
management
Active collaboration between dermatologists
and medical oncologists or urologists
Over-the-counter products help patients
maintain a sense of control over their
treatment plan
Decrease thickness of hyperkeratotic areas
with keratolytics, such as 40% urea and/or
salicylic acid
Nonprescription emollient
Twice-daily application of the products
appears adequate
Dermocorticoids are unproven
Reference(s)
Anderson, Jatoi, Robert et al.
297
Table 4. Recommendations for management of grade 2 hand–foot skin reaction (HFSR)
Clinical goals/objectives
Recommendations
Reference(s)
Expert panel
[5]
See recommendations for grade 1 HFSR (Table 3)
On the first occurrence of grade 2 HFSR, promptly
institute supportive measures such as topical
therapy for symptomatic relief and consider a dose
decrease of sorafenib to 400 mg daily for a
minimum of 7 days and up to 28 days
If toxicity resolves to grade 0 or 1 after dose
reduction, increase to registration dose: sorafenib,
400 mg twice daily
If toxicity does not resolve to grade 0 or 1 despite
dose reduction, interrupt MKI treatment for a
minimum of 7 days and until toxicity has resolved
to grade 0 or 1
When resuming treatment after dose interruption,
begin at reduced dose: sorafenib, 400 mg daily
If toxicity is maintained at grade 0 or 1 at reduced
dose for a minimum of 7 days, increase to
registration dose
On the second or third occurrence of grade 2
HFSR, follow steps for first occurrence; upon
resuming MKI treatment, decrease dose by one
dose level (sorafenib, 400 mg daily or 400 mg
every other day); decision whether to re-escalate
dose should be based on clinical judgment and
patient preference
On the fourth occurrence of grade 2 HFSR, the
decision whether to discontinue MKI treatment
should be based on clinical judgment and patient
preference
Abbreviation: MKI, multikinase inhibitor.
other day) when resuming treatment. Specific recommendations for resumption of treatment and for a second or third
occurrence of grade 3 HFSR can be found in Table 5 [5].
Overall, there are limited evidence-based data to guide selection of the most effective and specific measures on the
management of MKI-associated grade 3 HFSR. The literature search identified a single uncontrolled HFSR
treatment study of 12 patients predominantly with grade
3 toxicity [26], and reported improvement in skin toxicity with treatments including single-agent 40% urea cream,
0.1% tazarotene cream, and 5% fluorouracil cream. The recommendations and treatment approaches listed in Table 5 are
based solely on clinical experience, case studies, or uncontrolled trial designs. In a case study of three patients on a
sunitinib treatment regimen, the occurrence of adverse effects
diminished during the rest period within the treatment cycle
[28] and/or upon dose reduction of sunitinib [29].
Clinical reports of grade 3 HFSR treatment [4, 19] have
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observed that toxicity may resolve within a few days by employing approaches such as dose interruption/reduction and
systemic or local supportive measures, after which treatment with MKIs can be resumed. In a dermatologic subanalysis of the Treatment Approaches in Renal Cancer
Global Evaluation Trial [30], grade 3 HFSR resulted in
50% dose reductions in two of the 43 renal cell carcinoma
(RCC) patients receiving sorafenib, and toxicity resolved in
3– 4 weeks without long-term sequelae [31]. Upon restoration of full-dose sorafenib, HFSR recurred in only one of
those patients. No sorafenib-induced nevi modifications
were observed; however, since this study, several nevi
eruptions have occurred in patients treated with sorafenib
[32, 33]. In a single case study of a patient with RCC who
presented with HFSR after treatment with sorafenib, discontinuation of treatment for 14 days combined with topical
treatment and mild analgesics for pain led to resolution of
the HFSR [34]. After the HFSR had resolved, sorafenib was
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General goals for controlling
hyperkeratosis, cushioning
callused areas, moisturizing
the skin, controlling the
symptoms, relieving
discomfort
Dose adjustment for grade 2
HFSR seen with sorafenib
Source
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298
Table 5. Recommendations for management of grade 3 hand–foot skin reaction (HFSR)
Clinical goals/objectives Recommendations
Source
Local topical strategies to
reduce symptoms and
prevent further
progression
Dose adjustment
recommendations for
grade 3 HFSR seen with
sorafenib
Personal experience or recommendation [3, 7, 20, 51]
of the authors
Uncontrolled observational study
[26]
Work of Vukelja et al. [46] in a patient
with 5-FU–induced PPE; cited by
others
[3, 15, 20, 46]
Mechanism of action is still
Personal experience or recommendation
unknown
of the authors
Only in a few exceptional cases is
systemic administration of
corticosteroids or antihistamines
indicated to complement therapy
Efficacy of corticosteroids has not
been established
On the first occurrence of grade 3
Expert panel
[5]
HFSR, institute supportive measures
such as topical therapy for symptomatic
relief and interrupt MKI treatment for a
minimum of 7 days and until toxicity has
resolved to grade 0 or 1
When resuming treatment after dose
interruption, decrease by one dose
level (sorafenib, 400 mg daily or 400
mg every other day)
If toxicity is maintained at grade 0 or 1
at reduced dose for a minimum of 7
days, increase by one dose level
(sorafenib, 400 mg twice daily or 400
mg daily)
On the second occurrence of grade 3
HFSR, follow steps for first
occurrence; upon resuming MKI
treatment, decrease dose by one dose
level (sorafenib, 400 mg daily or 400
mg every other day); decision whether
to re-escalate dose should be based on
clinical judgment and patient
preference
On the third occurrence of grade 3
HFSR, the decision whether to
discontinue MKI therapy should be
based on clinical judgment and patient
preference
Abbreviation: 5-FU, 5-fluorouracil; MKI, multikinase inhibitor; PPE, palmar–plantar erythrodysesthesia.
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Systemic strategies to
reduce symptoms and
prevent further
progression
Treatment of blisters and erosions with
a wet disinfectant
Emollient and urea-based creams may
provide comfort and softening of the
lesions
Diligent application of creams and
lotions especially to palms and soles
For severe forms of HFSR, the
combination of a cortisone cream and
topical antibiotic such as fluconazole
or gentamicin is recommended
Efficacy of dimethylsulfoxide has not
been substantiated
Pyridoxine may be beneficial (doses of
50–150 mg/day)
Reference(s)
Anderson, Jatoi, Robert et al.
299
Table 6. Skin care products for use in hand–foot skin reactions (HFSR) (adapted from [17, 36])
Skin care products for acral erythema/xerosis
Product information
Cetaphil威 (Galderma Laboratories, Ft. Worth, TX) skin cleaners,
Aveeno威 (Johnson & Johnson, New Brunswick, NJ) shower gel
Udderly Smooth威 (Redex Industries, Salem, OH), Gold Bond威
(Chattem, Chattanooga, TN), Aveeno威
Bag Balm威 (Dairy Association Co., Lyndonville, VT)
Eucerin威 (Beiersdorf AG, Hamburg, Germany) Cream
Eucerin威 Dry Skin Therapy
Aquaphor威 (Beiersdorf AG, Hamburg, Germany) Healing
Ointment
Kerasal威 (Alterna LLC, Whippany, NJ)
Blue Lizard威 (Crown Laboratories, Johnson City, TN)
resumed at a 50% dose reduction without any further incidence of toxicity.
The range and variety of skin care products that have
been cited in the literature as having treatment potential for
the management of HFSR are listed in Table 6.
DISCUSSION
No evidence-based treatment algorithms exist for cutaneous toxicities of the MKIs in the dermatologic or oncologic
literature [17, 35]. Our systematic review of the published
literature through August 31, 2008, revealed that current
recommendations on the clinical approaches to HFSR prevention and treatment are largely anecdotal, derived from
case reports, based on practices implemented during clinical trials to optimize MKI treatment duration, culled from
postmarketing practices, or extrapolated from approaches
used for chemotherapy-induced HFS (e.g., capecitabine,
5-fluorouracil [5-FU], doxorubicin) rather than specifically
from MKIs. The literature on treatment of HFS stemming
from the use of chemotherapeutic agents and the current
recommendations may or may not be appropriate in treating
the side effects of newer agents [36]. Although HFSR in patients treated with MKIs may resemble the more commonly
known presentation seen in patients receiving capecitabine,
fluorouracil, or doxorubicin [4], when the condition is associated with MKI treatment it is thought to be a distinct
entity [1, 5]. Time to onset of MKI-associated HFSR is
noted to be much shorter (14 –28 days) [11, 37, 38] than for
chemotherapy-induced HFS; MKI-associated HFSR is typically more localized than HFS from other antineoplastic
www.TheOncologist.com
Thicker products with more intense moisturizing
properties than basic lotions; anti-itch
formulations are available
Contains dimethicone 1%, camphor 0.1%, and
lidocaine
Contains cetearyl alcohol, dimethicone,
menthol, and urea
May provide “cooling” effect from eucalyptus
Best used at night due to greasy formulation
Contains urea and alpha hydroxy acid
Petrolatum 41%
Salicylic acid 5% exfoliates and softens skin;
urea 10% moisturizes skin
UV A and B sunblock, water resistant
agents and most often affects the pressure zones of the feet
(e.g., the skin facing the heels, heads of the metatarsals, areas of friction with shoes) in a symmetrical pattern [1, 4].
Thus far, there is no evidence-based rationale to advocate
for any of the preventive measures for chemotherapyinduced HFS for prophylaxis of MKI-associated HFSR [25,
36]. Therefore, it will be important to understand the similarities and differences between the pathogenesis, histology, clinical course, and complications of dermatologic
reactions (HFS) induced by traditional agents, such as capecitabine and 5-FU, and those induced by MKIs (HFSR) to
develop appropriate, rationally developed interventions [36].
Among the C1 articles reviewed, none were randomized, controlled trials designed to test HFSR management
approaches. In addition, none of the ancillary, prospective,
observational, or case– control studies described in the literature had been designed to test the efficacy of distinct
treatment approaches in the management of HFSR on either
clinical or patient-reported outcomes. The phase I–III studies that have thus far established MKIs, such as sorafenib,
as effective therapeutic agents for metastatic cancers have
not included the systematic study of HFSR management approaches [30, 39, 40]. Thus, a major conclusion from our
study points to the need for additional research to test and
compare the various recommendations for prevention and
treatment of HFSR and to further elucidate the most efficacious methods for treating the side effects observed with
newer targeted therapies [36]. Specifically, research is
needed on: (a) appropriate patient education on prophylaxis
for HFSR and its effects on patient outcomes; (b) how often
Downloaded from www.TheOncologist.com at EBSCO PUBLISHING DATA DELIVERY on April 7, 2009
Norwegian Formula: Smoothing Relief Anti-Itch Moisturizer
by Neutrogena威 (Neutrogena, Los Angeles, CA)
Norwegian Formula: Foot Cream by Neutrogena威
Nondeodorant, fragrance-free products
300
conjunction with accepted criteria, such as the NCICTCAE v3.0 [13, 41].
In order to apply a systematic approach to future research and development of evidence-based solutions for
HFSR, it is essential to develop an evidence base for HFSR
prevention and management goals and endpoints from rigorous study designs comparing clinical treatment alternatives or patient management strategies recommended in the
scientific literature [44]. With regard to treatment goals, it
was noted in our review that there is general consensus that
hyperkeratosis is a risk factor for MKI-associated HFSR,
and that these areas should be removed prophylactically before and during treatment, cushioned for orthopedic redistribution, and covered with emollient and/or keratolytic
creams to moisturize and aid in natural exfoliation, respectively. However, the literature does not contain details on
how to remove the hyperkeratosis or how to cushion these
areas. Nor is there consensus on which specific agents to
use, strength of the agent, dosage, duration or frequency,
and supportive care practices. Thus, prospective studies,
preferably randomized, double-blind, controlled designs of
adequate size to detect meaningful effects, are needed to
identify optimal treatment approaches developed though
clinical experience to control the risk for HFSR, and to benefit patients. In addition to guideline evidence on effective
treatments, prospective studies with health services research designs will be informative to identify optimal initiation of treatment: prophylaxis versus reactive treatment
(waiting until symptoms arise and treating them reactively)
as well as other elements of clinical practice that support
clinical management of HFSR. Some of these considerations include identifying effective care processes such as
the scheduling of visits with an oncologist for HFSR
screening and monitoring, how to best deliver effective patient education, and the value of referrals for specialist care.
For patients with extensive hyperkeratosis prior to initiating
MKI treatment, comparisons of “standard” optimal care by
an oncology team versus an approach supplemented by specialist care from dermatologic or podiatric consults (e.g., to
remove hyperkeratosis and advise on cushioning of pressure areas and proper footwear) merit study for effects on
the development or progression of HFSR. For patients with
mild disability related to skin toxicity, studies are needed to
weigh the benefit of traditional therapeutic approaches such
as referrals to allied health for evaluation for adaptive
equipment and assistance with independent living in prolonging treatment and reducing disability. Finally, HFSR
outcomes should not only include consensus ratings on
grade or severity, but also ratings from the patient’s perspective on tolerability and health-related QoL. With the
advancements noted above, clinicians will have a scientific
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the patient should be seen by an oncologist or dermatologist
after beginning treatment with MKIs; (c) how to accurately
diagnose HFSR in its mild forms and recognize subsequent
dermatologic complications; (d) how to effectively treat
and remove the calluses on hands and feet without leading
to increased HFSR damage and symptom burden; (e) providing guidance to both patients and providers on the best
types of gel inserts, cushions, and soft footwear; (f) identifying the treatment strategies that are most effective at each
grade of toxicity or severity; and (g) testing the effectiveness of specific emollients and keratolytic creams for preemptive or reactive treatment of MKI-associated HFSR.
Efficacy studies on novel mechanism-based prophylactic or palliative therapy are needed to provide the data that
may ultimately lead to the development of better tolerance
of novel antineoplastic or targeted therapies with reduced
dermatologic side effects [41]. A major pitfall of conducting such trials is the risk of ascribing an improvement to the
palliative agent, when that improvement may represent the
natural history of the dermatologic reaction or poor compliance with the inciting agent (MKI) [41]. Because dose reductions can postpone or undermine optimal anticancer
treatment efficacy, the prevention and minimization of dermatologic adverse events through prompt recognition and
management is an important goal. Treatment options will
need to be adapted according to the availability of agents,
reimbursement patterns, and national and international
treatment guidelines [15].
Another important need is a better understanding of the
psychological and social implications that dermatologic reactions have on patients receiving cancer treatment. Brief
toxicity screens serve as poor substitutes for the measurement of patient well-being. None of the studies or reports in
the reviewed literature included a detailed assessment of
QoL and patient symptom burden. Tools for the assessment
of patient response to preventive and palliative measures,
whether newly developed or adapted, are required to advance research on HFSR outcomes; such tools are essential
for clinicians to gain an understanding of the full burden
that HFSR imposes on daily life and whether the condition
is moderated by patient characteristics, location of HFSR,
and other comorbidities. In this regard, the dermatology literature shows that several questionnaires are available for
patients to complete on a regular basis and thus provide information about their condition to aid investigators in understanding whether the dermatologic symptoms are
worsening or improving and their impact on the patient’s
QoL [42, 43]; however, none of the available measurement
tools were developed to specifically assess HFSR. Detailed
questionnaires for patient completion should be used in
Treatment Strategies for Hand–Foot Skin Reaction
Anderson, Jatoi, Robert et al.
basis for selecting and delivering the most effective therapy
to prevent and manage HFSR.
SUMMARY AND CONCLUSIONS
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ACKNOWLEDGMENTS
This study has been supported by an educational grant from
Bayer Healthcare Pharmaceuticals, Montville, NJ.
AUTHOR CONTRIBUTIONS
Conception/design: Roger Anderson, Karen N. Keating, Mario E.
Lacouture
Collection/assembly of data: Roger Anderson, Karen N. Keating
Data analysis: Roger Anderson, Karen N. Keating
Manuscript writing: Roger Anderson, Aminah Jatoi, Caroline Robert, Laura
S. Wood, Karen N. Keating, Mario E. Lacouture
Final approval of manuscript: Roger Anderson, Aminah Jatoi, Caroline Robert,
Laura S. Wood, Karen N. Keating, Mario E. Lacouture
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published literature/preparing the initial and all subsequent drafts of the manuscript/collating the comments of authors), but thank Aurora O’Brate, Ph.D.,
from Ogilvy Healthworld, supported by Bayer Healthcare, for her assistance in
copyediting the manuscript (ensuring correct grammar, spelling, and readability), in preparing the manuscript for submission to The Oncologist (ensuring
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