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Dermatologic Effects of Cancer Therapy by jianglifang

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                           Dermatologic Effects of Cancer Therapy

                                Susan Moore, RN, MSN, ANP-BC, AOCN®

                         Pamela Hallquist Viale, RN, MS, CS, ANP, AOCNP®



Introduction

Changes in treatment of solid tumors over the past decade have led to new side effects
not often seen with treatments in the past. Over a decade ago, capecitabine, an oral
fluoropyrimidine prodrug, was introduced. More recently, epidermal growth factor
receptor inhibitors (EGFRIs) and multikinase inhibitors (MKIs) have become the
standard of care in treating certain solid tumors. These new drugs have introduced a
variety of dermatologic side effects, and nurses need to be prepared to educate and
treat patients experiencing these side effects. This CE module addresses the following
dermatologic side effects commonly associated with cancer therapy:
         Section 1.       Cutaneous Toxicities Associated With EGFR Inhibitor Therapy
         Section 2.       Hand-Foot Syndrome
         Section 3.       Ocular Changes
         Section 4.       Hand-Foot Skin Reaction


Section 1. Cutaneous Toxicities Associated With EGFR Inhibitor Therapy


Background
   • Skin rash associated with EGFRI therapy is generally considered mild to moderate in
     nature1,2 and affects more than 50% of patients receiving treatment. The incidence of
     severe rash (grade 3) reported is up to 16% to 18% of patients.2,3 The cutaneous
     eruptions appear primarily on the face, neck, and upper torso, as seen in Figure 1.1,
     and the face is often the first area affected by the rash4-7
   • The rash is characterized by interfollicular- and follicular-based erythematous
     papules and pustules and is usually seen during the first 2 weeks of therapy1,2
   • The follicular skin lesions are without microcomedones and comedones
     characteristic of acne, thus indicating that this rash in not acne vulgaris1,2,4

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   • The rash tends to wax and wane during therapy, with “flare ups” occasionally
     noted following infusions 3,5
   • Rash symptoms typically resolve without scarring within 1 to 2 months of
     stopping treatment 3
   • Several studies have demonstrated a positive correlation between rash and
     tumor response and/or survival with cetuximab and erlotinib; findings are less
     consistent with gefitinib1-3

   Figure 1.1. Clinical Presentation of EGFRI-Associated Skin Rash




   Photos courtesy of Pamela Hallquist Viale.


Pathophysiology
The pathophysiology of EGFRI-associated skin rash is not completely understood,
but interference with the proliferation, differentiation, migration, and attachment of
keratinocytes is believed to occur with EGFRI therapy, resulting in recruitment of
inflammatory cells and injury to the cutaneous tissues.8 Since EGFR is highly
expressed in the epidermal keratinocytes, sebaceous glands, and epithelium of the
hair follicle, inhibition of these receptors can produce characteristic dermatologic
effects.9


Guidelines
There are no established evidence-based guidelines for the treatment of rash
symptoms associated with EGFRIs, and many interventions are based on
anecdotal reports or our colleagues’ experience. Many were based primarily on
effectiveness noted with anti-acne strategies.

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A National Comprehensive Cancer Network (NCCN) consensus panel report10
published treatment recommendations for the rash based on expert opinion. These
recommendations are that
    •    Patients should use emollients for the dry skin, or xerosis, that accompanies
         EGFRI therapies
    •    Sunscreen should be employed early on, as inhibition of the receptors for
         EGF lessens the protective nature of the receptors, allowing sun exposure to
         worsen rash symptoms. Sunscreen products should have a high sun
         protection factor (SPF)
Mild rash symptoms may not require intervention; if needed, clindamycin gel and/or
topical hydrocortisone may be adequate. Moderate rash symptoms may require the
previous treatments, or consideration of pimecrolimus 1%, plus a tetracycline
analog agent, such as oral doxycycline 100 mg twice daily or minocycline 100 mg
twice daily. Severe rash requires dose interruption of the EGFRI agent, tetracycline
analog treatment, and application of hydrocortisone cream, clindamycin gel, or
pimecrolimus, plus a steroid dose pack given orally.11 Figure 1.2 shows rash
before and after treatment. Each tier of care requires careful assessment of patient
response to therapeutic strategies for treatment of rash.10 Dermatologic
consultation is advisable for refractory or severe cases.

Limited evidence exists in the form of randomized, controlled trials for management
of EGFRI-associated rash; however, several studies were reported in the last 2
years regarding rash treatment. The results of selected studies are listed in Table
1.1.

Table 1.1. Recent Studies: Management of EGFRI-Associated Rash
 Study                   Study Design                           Study Results               Recommendations
 Author
 Kozloff et al,          Pilot, randomized,                     Of 11 patients              100% of patients
 200712                  prospective single-                    meeting criteria, 8         would recommend
                         center observational                   completed                   product to others
                         study of 20 patients (8                evaluation after 4
                         reported) on                           weeks of
                         cetuximab or other                     Regenecare
                         EGFRI therapy                          application for
                         receiving Regenecare                   cutaneous toxicity.
                         for cutaneous toxicity.                The study data
                         Regenecare contains                    indicated that
                         collagen/lidocaine/aloe                Regenecare was
                                                                effective in reducing
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                                                                itching and pain
                                                                associated with
                                                                rash; Relief
                                                                occurred within 15-
                                                                30 minutes
 Alexandrescu Pilot study of 11                                 Of 10 assessable            Treatment with
 et al, 200713 patients (10                                     patients, 6 had             colloidal oatmeal
               assessable) on EGFR                              complete response,          lotion is efficient in
               moAbs and TKI oral                               and 4 had partial           controlling EGFRI
               agents receiving                                 responses (100%             rash with no
               colloidal oatmeal                                response rate) with         associated
               lotion for dermatologic                          no associated               toxicities and 100%
               toxicity                                         toxicities. Colloidal       response rate,
                                                                oatmeal lotion              allowing
                                                                demonstrates                continuation of
                                                                multiple anti-              therapy
                                                                inflammatory
                                                                properties on
                                                                arachidonic acid and
                                                                TNF-α pathways
 Ocvirk et al,           Pilot trial of 30                      Of the 30 patients, 6       Further studies are
 200814                  patients on cetuximab                  had grade 3 rash,           needed to evaluate
                         plus chemotherapy                      18 grade 2, and 6           the impact on the
                         with rash treated with                 grade 1. Cream was          response rate of
                         topical cream                          used twice daily. All       cetuximab and
                         containing urea and                    patients had                quality of life
                         0.1% K1 vitamin                        reduction in
                         (Reconval K1) started                  cutaneous toxicity,
                         after the first                        with median time to
                         cutaneous toxicity                     improvement of 8
                         noted                                  days, and 18 days
                                                                to downstage rash
                                                                one grade. No
                                                                toxicity noted with
                                                                therapy
 Scope et al,            Randomized, double-                    Total facial lesion         Prophylaxis with
 200715                  blind trial of                         counts were                 oral minocycline
                         prophylactic oral                      significantly lower in      may be useful in
                         minocycline and                        patients receiving          decreasing severity
                         topical tazarotene for                 minocycline at              of acneiform rash

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                         cetuximab                              weeks 1 through 4.          during first month
                         dermatologic toxicity;                 At week 4, 20% of           of treatment; topical
                         48 patients were                       patients reported           tazarotene is not
                         randomized to either                   moderate to severe          recommended
                         minocycline or                         itch vs placebo
                         placebo, with                          (50%). No benefits
                         tazarotene on either                   with tazarotene
                         left or right side of the              application, and
                         face                                   treatment was
                                                                associated with
                                                                significant irritation
 Jatoi et al,            Placebo-controlled,                    Incidence of rash           Tetracycline was
 200816                  double-blind trial                     was comparable              not found to
                         enrolled patients                      across treatment            prevent EGFRI
                         starting therapy with                  arms: 70% in                rash and cannot be
                         an EGFRI. A total of                   tetracycline group          clinically
                         61 evaluable patients                  vs 76% in placebo           recommended for
                         were enrolled;                         group. Tetracycline         this purpose;
                         patients were                          appeared to have            however,
                         randomly assigned                      lessened rash               diminished rash
                         either to tetracycline                 severity; by week 4,        severity and
                         500 mg orally twice a                  grade 2 rash was            improved quality of
                         day for 28 days or to                  present in 17% of           life in tetracycline
                         placebo                                tetracycline patients       patients suggest
                                                                vs 55% of placebo           further study
                                                                patients. Symptoms          warranted
                                                                were improved in
                                                                tetracycline group
 Lacouture et            Prospective trial                      Only 29% of                 Preemptive therapy
 al, 200817              (STEPP) of 95                          patients in the             for skin reactions
                         patients on                            preemptive group            appears to
                         panitumumab                            experienced serious         significantly reduce
                         receiving either                       skin reactions vs           rate of skin
                         preemptive or reactive                 62% in the reactive         reactions
                         treatment with                         group; effectiveness        associated with
                         doxycycline for EGFRI                  of chemo/EGFRI              treatment with
                         rash                                   therapy was not             panitumumab
                                                                affected by                 without affecting
                                                                preemptive therapy          effectiveness of
                                                                                            therapy

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 Scope et al,            Prospective                            Treatment sides had         Pimecrolimus
 200918                  randomized trial of                    greater decrease in         application did not
                         topical pimecrolimus                   facial lesion counts,       translate into
                         for cetuximab-                         vs observation              clinically
                         associated acnelike                    sides, at weeks 2           meaningful benefit
                         eruption; 24 patients                  and 5 (P < .001             for patients with
                         received twice-daily                   and P = .02,                cetuximab-
                         pimecrolimus for 5                     respectively);              associated facial
                         weeks                                  however, no                 rash
                                                                significant
                                                                differences in
                                                                patients’ symptoms
                                                                and review of facial
                                                                photographs for
                                                                severity
 Jatoi et al,            Prospective                            Cumulative                  Use of tetracycline
 201019                  randomized trial of 65                 incidences of grade         is not helpful in
                         patients receiving                     2 or worse rash             management of
                         either tetracycline 500                were comparable             EGFRI rash
                         mg bid or placebo for                  across both groups
                         28 days
 Jatoi et al,            110 patients                           No differences in           Sunscreen does
 201020                  randomized to receive                  rash severity were          not have efficacy in
                         sunscreen bid or                       noted between the 2         reduction of either
                         placebo for 4 weeks                    study arms                  incidence or
                                                                                            severity of EGFRI
                                                                                            rash

Based on the information from the trials in Table 1.1, clinicians should consider
preemptive therapy with a tetracycline analog agent. The action of the tetracycline
analog agents is primarily anti-inflammatory.16,17,19,21 Topical anti-acne therapies
were not considered helpful and should be avoided. Regenecare gel may be helpful
in reducing symptoms, although larger trials are necessary to confirm usefulness of
this treatment.12 Colloidal oatmeal lotion may be useful in reducing inflammation
associated with the rash, although additional studies are needed to confirm the role
of this therapy. 13




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Figure 1.2. Papulopustular Rash Before and After Topical Treatment. Patient
presented after erlotinib therapy with confluent pruritic pustules on the glabella,
nose, and chin (left). After 2 weeks of doxycycline 50 mg twice daily and topical
pimecrolimus twice daily, there was marked improvement, with no pustules and
only residual macules with no pruritus (right).7




Photos courtesy of Mario E. Lacouture.

Grading and Management of EGFRI-Associated Rash
Although grading of the EGFRI rash has typically been done with the National
Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE
v4.03) scales,22 recent proposals from consensus panels of experts have identified
the limitations of the CTCAE, as it is subject to variable interpretation and calls for
involvement of body surface area in calculating different grades of rash.11,23
Recommendations for simplifying the approach to grading, for ease of clinicians
taking care of these patients and for more accuracy, now exist. This simplified
approach calls for 3 categories: mild, moderate, and severe (Table 1.2).11
Table 1.2. Recommendations for Management of EGFRI Rash
   Category                    Description                              Interventions
     Mild              Generalized localized                            • Mild soaps
                       papulopustular reaction with                     • Sunblock
                       minimal symptoms                                 • Emollients
                                                                        • Clindamycin gel
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                                                                        • Colloidal oatmeal lotion
                                                                        • Topical steroid as indicated
   Moderate    Generalized papulopustular                               • Interventions as in grade 1, mild,
               rash that is pruritic or tender                            plus
               but minimally affects                                    • Oral tetracycline analog
               activities of daily living                                 (doxycycline or minocycline)
               (ADLs)
   Severe      Generalized papulopustular                               • Interventions as in grade 2,
               rash with severe pruritus or                               moderate, plus
               tenderness that significantly                            • Consider short-term course of oral
               affects ADLs and may be                                    steroids
               infected
Based on information from Lynch et al.11

Other Cutaneous Toxicities
There are other cutaneous toxicities associated with HER1/EGFR-targeted therapy.
These include nail bed toxicity (paronychia), hair alterations, xerosis,
telangiectasia, nasal mucositis, and ocular irritation.1,2,4
Paronychia2,4,7
   • Described as painful inflammation of tissue around fingernails and toenails,
     more commonly seen in the big toe and thumbs; observed in 12% to 16% of
     patients (Figure 1.3, left)
   • Often delayed, developing after 4 to 8 weeks of treatment
   • Symptoms may be improved by wearing shoes that are not too tight and
     avoiding friction; hot soaks and cushioning provide comfort; Epsom salt
     soaks help promote drainage; topical antiseptic or antibiotic ointments may
     help
Hair Alterations2,4
   • Hair changes may occur 2 to 3 months after initiation of therapy, with hair
      thinning and developing dry, brittle, or curly texture
   • Trichomegaly (increased hair growth of the eyelashes and eyebrows) may
      occur, although it is rare (Figure 1.3, right)
   • Waxing or electrolysis may be recommended
Xerosis and Related Changes, Skin Fissures2,4
   • Xerosis (abnormally dry skin) is a common side effect of HER1/EGFR-
      targeted therapy
   • Painful fissures may develop on the fingers and toes, in the nail folds, and
      over the interphalangeal joints

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    •    Hydration of the skin with the use of bath oil or shower oil may help alleviate
         symptoms. Gels and soap should be avoided because they may exacerbate
         dryness; dryness may be alleviated by using emollient creams
    •    Liquid BandAid may be helpful in protecting fissures
Telangiectasia4
   • Defined as chronic dilation of groups of capillaries, leading to elevated dark
      red blotches on the skin
   • May be seen in early onset of rash symptoms, appearing on the face, nose,
      chest, back, and limbs around a follicular pustule
   • Tend to fade in time, leaving some hyperpigmentation
   • Consider dermatology consult for possible laser therapy
Nasal Mucositis1
  • Sores and irritation may develop inside the nostrils, and may become
      uncomfortable
  • Bactroban Nasal can be applied to help prevent secondary infection
Ocular Irritation7
  • Manifests as dry eyes, progressing to erythematous lids and crusting in the
      eyelash follicles; looks like blepharitis or conjunctivitis
  • Rare, but if it occurs, it usually appears within the first 4 weeks of therapy
  • Treatment may consist of ophthalmic antibiotic ointment, warm soaks,
      natural tears

Figure 1.3. Other EGFRI-Associated Cutaneous Toxicities. Left, Paronychia and
pyogenic granuloma of the nail fold of the big toe. Right, Trichomegaly (long curly
eyelashes).




Left, M. Lawrenson, Wikipedia. Right, Criado and Rocha Lima.24

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Assessment Tools
The different scales and description of the rash make it difficult to compare the
severity of rashes.8 Table 1.3 is commonly used to grade adverse events
associated with papulopustular rash, the most common type of EGFRI-associated
skin rash.

Table 1.3. Grading Skin Rash: Papulopustular Rash
     Grade     Description
       1       Papules and/or pustules covering < 10% BSA, which may or may
               not be associated with symptoms of pruritus or tenderness
     2         Papules and/or pustules covering 10%-30% BSA, which may or may
               not be associated with symptoms of pruritus or tenderness;
               associated with psychosocial impact; limiting instrumental ADL
     3         Papules and/or pustules covering > 30% BSA, which may or may
               not be associated with symptoms of pruritus or tenderness; limiting
               self-care ADL; associated with local superinfection with oral
               antibiotics indicated
     4         Papules and/or pustules covering any % BSA, which may or may
               not be associated with symptoms of pruritus or tenderness and are
               associated with extensive superinfection with IV antibiotics
               indicated; life-threatening consequences
     5         Death
Based on information from Oishi, 4 Lacouture et al,7 and NCI.22
ADL = activities of daily living; BSA = body surface area; IV = intravenous.

An alternate grading scale for EGFRI-associated skin toxicity is the MASCC EGFR
Inhibitor Skin Toxicity Tool (MESTT) available through the Multinational Association
of Supportive Care in Cancer (MASCC) Web site at
http://www.mascc.org/mc/page.do?sitePageId=98483.

Implications for Health Care Professionals
Health care professionals caring for patients on EGFRI therapy need to become
competent in treatment of these common dermatologic toxicities. Because rash
indicates a probable response to therapy, it is incumbent on the health care
professional to implement care strategies for these toxicities, helping patients to
maintain therapy for longer periods of time. Education of the patient regarding the
characteristics and time course of the rash and associated toxicities is crucial.4
Care strategies should be instituted early and based on the expert
recommendations and clinical trial results of EGFRI rash treatment.25,26
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When necessary, dose modifications are important; however, this option is not
considered optimal, as the goal of therapy is to keep patients on therapy when
responding.4 Prescribing information for the EGFRI drug should be consulted for
dose modification recommendations. EGFRI therapy is an integral part of cancer
treatment today, and management of the dermatologic toxicities associated with
this therapy is crucial to achieving good patient outcomes.




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References
1. Perez-Soler R, Delord J, Halpern A, et al. HER1/EGFR inhibitor-associated rash:
    future directions for management and investigation outcomes from the management
    forum. Oncologist. 2005;10:345-356.
2. Dick S, Crawford G. Managing cutaneous side effects of epidermal growth factor
    receptor (HER1/EGFR) inhibitors. Community Oncol. 2005;2:492-496.
3. Sipples R. Common side effects of anti-EGFR therapy: acneiform rash. Semin Oncol
    Nurs. 2006;22(suppl 1):28-34.
4. Oishi K. Clinical approaches to minimize rash associated with EGFR
    inhibitors. Oncol Nurs Forum. 2008;35:103-111.
5. Segaert S, Van Cutsem E. Clinical signs, pathophysiology and management of skin
    toxicity during therapy with epidermal growth factor inhibitors. Ann Oncol.
    2005;16:1425-1433.
6. Fish-Steagall A, Searcy P, Sipples R. Clinical experience with anti-EGFR
    therapy. Semin Oncol Nurs. 2006;22(1 suppl 1):10-19.
7. Lacouture M, Basti S, Patel J, Benson A. The SERIES Clinic: an interdisciplinary
    approach to the management of toxicities of EGFR inhibitors. J Support Oncol.
    2006;4:236-238.
8. Eaby B, Culkin A, Lacouture M. An interdisciplinary consensus on managing skin
    reactions associated with human epidermal growth factor receptor inhibitors. Clin J
    Oncol Nurs. 2007;12:283-290.
9. Galimont-Collen AFS, Vos LE, Lavrijsen APM, et al. Classification and management
    of skin, hair, nail and mucosal side-effects of epidermal growth factor receptor
    (EGFR) inhibitors. Eur J Cancer. 2007;43:845-851.
10. Burtness B, Anadkat M, Basti S, et al. NCCN task force report: management of
    dermatologic and other toxicities associated with EGFR inhibition in patients with
    cancer. J Natl Compr Canc Netw. 2009:7(suppl 1):S5-S21.
11. Lynch TJ Jr, Kim ES, Eaby B, et al. Epidermal growth factor receptor inhibitor-
    associated cutaneous toxicities: an evolving paradigm in clinical
    management. Oncologist. 2007;12:610-621.
12. Kozloff MF, Gowlande PA, Vlamakis J, et al. Evaluation of Regenecare™ Topical
    Gel in the treatment of skin rash associated with cetuximab (Erbitux®), Tarceva®
    and other EGFR inhibitor-treated cancer patients.
    http://www.mpmmedicalinc.com/pdf/Regenecare_Study_Ingalls_April07.pdf
13. Alexandrescu DT, Vaillant JG, Dasanu CA. Effect of treatment with a colloidal
    oatmeal lotion on the acneform eruption induced by epidermal growth factor receptor
    and multiple tyrosine-kinase inhibitors. Clin Exp Dermatol. 2007;32:71-74.
14. Ocvirk J, Rebersek M. Managing cutaneous side effects with K1 vitamin crème
    reduces cutaneous toxicities induced by cetuximab. J Clin Oncol. 2008;26(suppl).
    Abstract 20750.

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15. Scope A, Agero AL, Dusza SW, et al. Randomized double-blind trial of prophylactic
    oral minocycline and topical tazarotene for cetuximab-associated acne-like
    eruption. J Clin Oncol. 2007;25:5390-5396.
16. Jatoi A, Rowland K, Sloan JA, et al. Tetracycline to prevent epidermal growth factor
    receptor inhibitor-induced skin rashes: results of a placebo-controlled trial from the
    North Central Cancer Treatment Group (N03CB). Cancer. 2008;113:847-853.
17. Lacouture MC, Mitchell EP, Piperdi B, et al. Skin toxicity evaluation protocol with
    panitumumab (STEPP), a phase II, open-label, randomized trial evaluating the
    impact of a pre-emptive skin treatment regimen on skin toxicities and quality of life in
    patients with metastatic colorectal cancer. J Clin Oncol. 2010;28:1351-1357.
18. Scope A, Lieb JA, Dusza SW, et al. A prospective randomized trial of topical
    pimecrolimus for cetuximab-associated acnelike eruption. J Am Acad Dermatol.
    2009;61:614-620.
19. Jatoi A, Dakhil SR, Sloan JA, et al. Prophylactic tetracycline does not diminish
    the severity of epidermal growth factor receptor (EGFR) inhibitor-induced rash:
    results from the North Central Cancer Treatment Group (Supplementary
    N03CB). Support Care Cancer. 2010;[Epub ahead of print September 6, 2011].
20. Jatoi A, Thrower A, Sloan JA et al. Does sunscreen prevent epidermal growth
    factor receptor (EGFR) inhibitor-induced rash? Results of a placebo-controlled
    trial from the North Central Cancer Treatment Group (N05C4). Oncologist.
    2010;15:1016-1022.
21. Sapadin AN, Fleischmajer R. Tetracyclines: nonantibiotic properties and their clinical
    implications. J Am Acad Dermatol. 2006;54:258-265.
22. National Cancer Institute, Cancer Therapy Evaluation Program, Common
    Terminology Criteria for Adverse Events (CTCAE)
    v4.03. http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-
    14_QuickReference_8.5x11.pdf.
23. Agero ALC, Dusza SW, Benvenuto-Andrade C, et al. Dermatologic side effects
    associated with the epidermal growth factor receptor inhibitors. J Am Acad Dermatol.
    2006;55:657-670.
24. Criado PR, Rocha Lima AA. Blepharitis and trichomegaly induced by detuximab. An
    Bras Dermatol. 2010;85:919-920.
25. Morse L, Calarese P. EGFR-targeted therapy and related skin toxicity. Semin Oncol
    Nurs. 2006;22:152-162.
26. Viale PH. Management of EGFRI associated toxicities: rash, pruritus, xerosis. Oncol
    Nurse. 2008;1:10-11.




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Section 2. Hand-Foot Syndrome


Background
Hand-foot syndrome (HFS), also called palmar-plantar erythrodysesthesia (PPE), is a
cutaneous complication associated with continuous fluorouracil (5-FU) therapy, oral
capecitabine, and liposomal doxorubicin. First reported in 1974, this complication was
noted in patients receiving antimetabolites and some chemotherapy antibiotics.1 The
median time to onset of HFS with capecitabine is approximately 79 days, ranging from
11 to 360 days. HFS is the most frequently reported side effect of oral capecitabine (>
50% of patients) and is the dose-limiting side effect for this agent.2,3


Pathophysiology
Although the exact mechanism of action is not known, some researchers have
theorized that HFS may be related to the crushing of deep capillaries in the soles of
the feet and palms of the hands, which may cause drug extravasation into those
same capillaries, leading to the symptoms of this condition. Another report by Lin et
al4 describes a different mechanism of action, relating HFS as a consequence of an
inflammatory reaction, which might result from overexpression of COX-2. These
researchers note that COX-2 is upregulated with the administration of
chemotherapy, possibly leading to a COX inflammatory-type reaction.4
Because the condition primarily affects the palms of the hands and the soles of the
feet, researchers have also postulated a theory that HFS is caused by the
accumulation of drug in the eccrine sweat or the eccrine sweat glands of the hands
and feet, causing the damage characteristic of this toxicity.1 Histologically, changes
in keratinocytes and vacuolar degeneration of the basal layer are seen with
scattered necrotic areas noted.5 Dilated blood vessels and papillary edema may
also be seen. More research is needed to determine the complete
pathophysiology/pathobiology of this common cutaneous side effect.




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Physical Presentation
Symptoms may include
  • Numbness
  • Tingling
  • Swelling
  • Dryness, cracking, edema
  • Erythema
  • Pain, blistering, or even desquamation (Figure 2.1)
Skin reactions may not be noted until the second week of therapy. To control or
relieve symptoms, dose reduction or temporary drug cessation may be required
(Table 2.1).
Figure 2.1 Toxicity Grading Scale*: HFS/PPE.




Photos courtesy of Susan Moore.
*Grading and descriptions based on information from NCI CTCAE v4.03.6



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Few randomized clinical trials have looked at prevention and management of HFS.
Selected trials of treatments studied in HFS are listed in Table 2.1.
Table 2.1 Selected Treatment Trials for Management of Hand-Foot Syndrome

 Study Author                   Study Design                         Study Results           Recommendations

 Lauman et al,                  Retrospective                        Patients who took       Patients may need
 20017                          study in which                       pyridoxine > 200        higher doses of
                                patients were                        mg/d had better         pyridoxine to
                                evaluated in 3                       symptom control of      ameliorate the
                                arms: capecitabine                   their HFS than          symptoms of HFS
                                alone, pyridoxine                    patients who took
                                prophylaxis with                     less than that
                                capecitabine, and                    amount
                                pyridoxine to
                                alleviate symptoms
                                of HFS

 Karo et al, 20068              Small trial of 5                     After 1 week, PPE       May be of interest
                                patients with MBC                    symptoms began          to consider vitamin
                                treated with                         to disappear            E as a preventive
                                docetaxel and                                                drug with agents
                                capecitabine; all                                            associated with
                                patients developed                                           PPE
                                grade 2-3 PPE.
                                Vitamin E therapy
                                at 300 mg/d PO
                                was given without
                                dose reduction of
                                therapy

 Yamamoto et al,                Patients on                          Reduction in            Vitamin E minimized
 20089                          capecitabine were                    desquamation,           drug delays and
                                followed for HFS                     pain, and improved      schedule
                                symptoms; 42                         comfort level in all    interruptions, and
                                episodes of grade                    patients; neurologic    maintained dose
                                2 toxicity were                      symptoms improved       density of therapy
                                identified; all                      as well. All patients
                                patients received                    were able to
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                                oral vitamin E bid                   complete
                                during                               chemotherapy
                                chemotherapy                         without interruption
                                                                     or delay; 38/42 did
                                                                     not develop
                                                                     cutaneous
                                                                     manifestation, and
                                                                     4 had grade I
                                                                     toxicity

 Cin et al, 200110              13 patients with                     12 of 13 reported      Large placebo-
                                HFS used bag                         improvement of         controlled trials are
                                balm topically in a                  symptoms after         needed to
                                nonblinded study                     bag balm; 55%          determine
                                                                     were able to           effectiveness of
                                                                     continue               bag balm
                                                                     chemotherapy
                                                                     without dose
                                                                     delays or dose
                                                                     reductions

 Lopez et al,                   Topical DMSO was                     When given topical     Small study;
 199911                         given to 2 patients                  DMSO 4 times           patients must be
                                undergoing                           daily for 14 days,     treated in a
                                chemotherapy with                    the PPE resolved       prospective trial to
                                liposomal                            over a period of 1-    definitively
                                doxorubicin who                      3 weeks                document
                                developed grade 3                                           therapeutic efficacy
                                PPE

 Lee et al, 200712              Prospective,                         Pyridoxine was not     No clinical benefit
                                randomized,                          effective for          to administration of
                                placebo-controlled                   prevention of HFS      pyridoxine
                                trial (N = 360) of                   associated with
                                pyridoxine (vitamin                  capecitabine
                                B6) for prevention                   therapy
                                of HFS/PPE

DMSO = dimethyl sulfoxide; HFS = hand-foot syndrome; MBC = metastatic breast
cancer; PPE = palmar-plantar erythrodysesthesia.

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Small case reports of treatment with oral corticosteroids, COX-2 inhibitor agents,
and topical nicotine patch have also been reported as interventions to ameliorate
the symptoms of HFS; however, large prospective trials are needed to help refine
the optimal therapy of this often-seen side effect. Therefore, treatment of HFS is
largely symptomatic (Tables 2.2 and 2.3). Patients should be instructed to
    •    Avoid immersion in hot water, which could exacerbate symptoms
    •    Avoid activities that may increase pressure in affected areas, such as
         high-impact exercise
    •    Avoid tight clothing, vigorous skin rubbing and sun exposure13
    •    Try cold compresses, which may be helpful
    •    Use topical emollients or other preparations containing urea or lanolin 2,3,14
    •    Use protective gloves if needed15


Additional Clinical Information
Several case reports have been published recently regarding another complication
as a sequela of HFS with capecitabine. Two cases of acquired palmoplantar
keratoderma were noted in patients with metastatic breast cancer; this was thought
to be a sequential event of HFS.16 Another published report described HFS with
scleroderma-like changes, also thought to be linked to the administration of oral
capecitabine, with hyperpigmentation of the palms and soles.17 These cases should
be noted as single reports, and more information is needed before these side
effects can be conclusively linked to capecitabine. Nurses should continue to be
vigilant and report all new effects and toxicities thought to be drug related to FDA
MedWatch (http://www.fda.gov/medwatch/).
Drs Saif and Elfiky18 report on differentiating between the presentation of
fluoropyrimidine-associated HFS in white and non-white patients. Three cases
illustrating the disparities in white and non-white patients are discussed. The
authors suggest a modified grading schema for non-white patients. An algorithm
outlines pretreatment patient education and monitoring of skin changes during
therapy.


Implications for Health Care Professionals
HFS can be painful and disruptive to patients’quality of life. However, the current
literature on HFS is limited to the identification and treatment of HFS, with no
existing reports on the effect of HFS on patients’ quality of life (QOL).19 More
research is needed on the effect of HFS and QOL. Oncology health care providers
should instruct patients regarding the possibility of HFS and the need for early
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communication of symptoms. Because capecitabine is an oral therapy administered
at home, this communication of symptoms is crucial. Early reporting of HFS
symptoms can assist nursing and physician staff in appropriate identification and
grading of PPE, allowing care interventions to be implemented sooner. In most
patients, the syndrome is completely reversible.20 However, significant HFS usually
requires dose interruption and if the syndrome persists, dose modification becomes
necessary (Table 2.2).21 Although pyridoxine (50-150 mg/d) has been of use in
some patient populations, others receive no benefit from the addition of this
therapy.12,20 Table 2.3 outlines patient education for managing capecitabine-
associated HFS.
Table 2.2 Capecitabine Dose Modification

                                                                                    Dose Adjustment for Next
                                                                                        Treatment Cycle
 Toxicity                          During a Course of Therapy                         (% of Starting Dose)
 Grade 1                       Maintain dose level                                          Maintain dose level

 Grade 2

 1st appearance                Interrupt until resolved to grade 0-1                              100%

 2nd appearance                Interrupt until resolved to grade 0-1                               75%

 3rd appearance                Interrupt until resolved to grade 0-1                               50%

 4th appearance                Discontinue treatment permanently


 Grade 3

 1st appearance                Interrupt until resolved to grade 0-1                               75%

 2nd appearance                Interrupt until resolved to grade 0-1                               50%

 3rd appearance                Discontinue treatment permanently



Data from Xeloda prescribing information. 22

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Table 2.3. Patient Education for Management of Capecitabine-Associated Hand-
Foot Syndrome

 Grade         Clinical Feature               Functional Status Suggested Interventions
     1       Numbness,              Activities of daily                   Call nurse or doctor when symptoms first
             paresthesia,           living generally                      appear. Do not “wait and see.”
             dysesthesia, tingling, unaffected
             painless swelling or                                         Skin care:
             erythema of the
             hands and/or feet                                                Reduce friction and pressure:
                                                                              kneeling for long periods of time;
     2       Painful erythema                Activities of daily              leaning on elbows; power walking,
             and swelling of the             living more difficult            jogging, or regular walking for long
             hands and/or feet,                                               periods of time; using hand tools;
             skin remains intact                                              gardening
                                                                              Wear sunscreen; avoid exposure to
     3       Moist                         Activities of daily living         heat
             desquamation,                 interrupted: unable to
             ulceration,                   work; difficulty walking           Use mild soap to bathe; pat (don’t
             blistering, or                and using hands                    rub) skin dry
             severe pain of the                                               Keep shower and bath water
             hands and/or feet,                                               lukewarm to cool; avoid hot tubs
             tissue breakdown                                                 and long exposure to hot water
                                                                              Keep skin moist; gently apply
                                                                              moisturizing creams or topical
                                                                              emollients. Apply at night and wear
                                                                              loose-fitting cotton gloves; avoid
                                                                              rubber ones (dishwashing gloves),
                                                                              since they retain heat
                                                                              Put hands and feet in cool water to
                                                                              relieve symptoms

                                                                          Clothing:

                                                                              Wear comfortable, loose-fitting
                                                                              clothes, shoes, and gloves
                                                                              Do not go barefoot; wear shoes or
                                                                              slippers when possible

Based on information from NCI CTCAE v4.03 (page 18)6 and Wilkes and Doyle.23


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Assessment Tools
Polovich et al include a description of HFS under Cutaneous Toxicity in Side
Effects of
Cancer Therapy.24
Patient information for coping with HFS skin problems is available here.


Clinical Practice Guidelines
There are no evidence-based national clinical practice guidelines for the
management of HFS.




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References

1. Clark AS, Vahdat LT. Chemotherapy-induced palmar-plantar erythrodysesthesia
   syndrome: etiology and emerging therapies. Support Cancer Ther. 2004;1:213-
   218.
2. Viale PH, Fung A, Zitella L. Advanced colorectal cancer: current treatment and
   nursing management with economic considerations. Clin J Oncol Nurs.
   2005;9:541-552.
3. Berg D. Capecitabine: a new adjuvant option for colorectal cancer. Clin J Oncol
   Nurs. 2006;10:479-486.
4. Lin E, Morris JS, Ayers GD. Effect of celecoxib on capectabine-induced hand-
   foot syndrome and antitumor activity. Oncology (Williston Park).
   2002;16(suppl):31-37.
5. Nagore E, Insa A, Sanmartin O. Antineoplastic therapy-induced palmar plantar
   erythrodysesthesia (“hand-foot”) syndrome. Incidence, recognition and
   management. Am J Clin Dermatol. 2000;1:225-234.
6. National Cancer Institute, Cancer Therapy Evaluation Program, Common
   Terminology Criteria for Adverse Events v4.03 (CTCAE).
   http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-
   14_QuickReference_8.5x11.pdf.
7. Lauman MK, Mortimer J. Effect of pyridoxine on the incidence of palmar plantar
   erythrodysesthesia (PPE) in patients receiving capecitabine. Proc Am Soc Clin
   Oncol. 2001;20:392a. Abstract 1565.
8. Karo IO, Sahin B, Erkisi M. Palmar-plantar erythrodysesthesia due to docetaxel-
   capecitabine therapy is treated with vitamin E without dose reduction. Breast.
   2006;5:414-424.
9. Yamamoto D, Yamamoto C, Tanaka K. Novel and effective management of
   capecitabine induced hand foot syndrome. J Clin Oncol. 2008;26(suppl):734s.
   Abstract 20615.
10. Cin SF, Tchen N, Oza AM, et al. Use of “bag balm” as topical treatment of
    palmar-plantar erythrodysesthesia syndrome (PPES) in patients receiving
    selected chemotherapeutic agents. Proc Am Soc Clin Oncol. 2001;20:409a.
    Abstract 1632.
11. Lopez A, Wallace L, Dorr R, et al. Topical DMSO treatment for pegylated liposomal
    doxorubicin-induced palmar-plantar erythrodysesthesia. Cancer Chemother
    Pharmacol. 1999;44:303-306.


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12. Lee S, Lee S, Chun Y, et al. Pyridoxine is not effective for the prevention of
    hand foot syndrome (HFS) associated with capecitabine therapy: results of a
    randomized double-blind placebo-controlled study. J Clin Oncol. 2007;25(18
    suppl). Abstract 9007.
13. Morse MA. Supportive care in the management of colon cancer. Support Cancer
    Ther. 2006;3:158-170.
14. Wilkes GM. Therapeutic options in the management of colon cancer: 2005
    update. Clin J Oncol Nurs. 2005;9:31-44.
15. Viale PH. Chemotherapy and cutaneous toxicities: implications for oncology
    nurses. Semin Oncol Nurs. 2006;22:144-151.
16. Do JE, Kim YC. Capecitabine-induced diffuse palmoplantar keratoderma: is it a
    sequential event of hand-foot syndrome? Clin Exp Dermatol. 2007;32:519-521.
17. Lee SD, Kim HJ, Hwang SJ, et al. Hand-foot syndrome with scleroderma-like
    change induced by the oral capecitabine: a case report. Korean J Intern Med.
    2007;22:109-112.
18. Saif MW, Elfiky AA. Identifying and treating fluoropyrimidine-associated hand-
    and-foot syndrome in whites and non-white patients. J Support Oncol.
    2007;5:337-343.
    http://www.supportiveoncology.net/journal/articles/0507337.pdf.
19. Keating KN, Anderson RT, O’Leary JJ. Hand-foot syndrome: symptom
    assessment and the impact on quality of life—a review of the peer-reviewed
    literature. J Clin Oncol. 2008;26(suppl):739s. Abstract 20685.
20. Janusch M, Fischer M, Marsch WCH. et al. The hand-foot syndrome: a frequent
    secondary manifestation in antineoplastic chemotherapy. Eur J Dermatol.
    2006;16:494-499.
21. Gressett SM, Stanford BL, Hardwicke F. Management of hand-foot syndrome
    induced by capecitabine. J Oncol Pharm Pract. 2006;12:131-141.
22. Genentech USA, Inc. Xeloda prescribing information; 2010.
    http://www.gene.com/gene/products/information/xeloda/pdf/pi.pdf.
23. Wilkes GM, Doyle D. Palmar-plantar erythrodysesthesia. Clin J Oncol Nurs.
    2005;9:103-106.
24. Polovich M, White JM, Kelleher LO, eds. Chemotherapy and Biotherapy
    Guidelines and Recommendations for Practice. 3rd ed. Pittsburgh, PA:
    Oncology Nursing Society; 2009.




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Section 3. Ocular Changes


Background
For more than a decade, articles have documented ocular changes believed to be
related to the administration of certain chemotherapeutic drugs. An article by O’Dea and
colleagues reported historical and current knowledge on the subject, components of a
comprehensive visual assessment, and 4 case studies of patients who experienced
visual changes while receiving therapy with oxaliplatin.1 Changes in visual fields and
acuity have been attributed to a number of pharmaceutical agents, including allopurinol,
cephalosporins, and narcotics, as well as to chemotherapeutic agents such as the
antimetabolites, alkylating agents, taxanes, and platinum agents. Patients undergoing
treatment for breast cancer often report changes in visual acuity and dry-eye syndrome.
Agents targeting the epidermal growth factor receptor (EGFR) also are reported to
cause ocular toxicity.2

Antineoplastic chemotherapy, especially carmustine, vinblastine, and vincristine, may
cause damage to the optic nerve and the ocular motor nerves. Interferon may cause
neuro-ophthalmic lesions. Ischemic optic neuropathy, which may be bilateral, presenting
with optic disc edema and progressing to optic atrophy, has been reported with the use
of interferon. Interferon α treatment may cause, or aggravate the risk of developing,
anterior ischemic optic neuropathy, and vulnerable patients should be advised of this
potential complication.

Reported adverse effects vary from mild changes, such as dry eyes and blurred vision,
to more severe and sometimes permanent changes, such as retinal damage, glaucoma,
and cataracts. Medications taken for comorbid conditions may also cause ocular
changes; therefore, a full medication assessment should be undertaken when a patient
reports visual changes. Comorbid conditions, such as diabetes mellitus, lupus, multiple
sclerosis, and pheochromocytoma, may also cause visual changes. In certain types of
cancer known to metastasize to the brain, persistent visual changes should prompt
radiologic examination of the brain to rule out brain metastases.

Case reports of blepharitis related to long-term (> 15 weeks) cetuximab monotherapy
were reported by Dranko et al.2 Another chemotherapy agent, specific to the care of
patients with colorectal cancer (CRC), that may cause visual changes is oxaliplatin.
Leonard and coworkers conducted a survey to evaluate neurotoxicity secondary to
oxaliplatin therapy.3 Eighty-six patients with metastatic CRC being treated with
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oxaliplatin plus capecitabine were interviewed. The participants reported blurred vision,
eye pain, and visual field cuts. The incidence rates were < 20%, and all changes were
transient and resolved after discontinuing oxaliplatin therapy. The prescribing
information for oxaliplatin reports low rates (< 20% for all grades) of visual disturbances,
including tearing, conjunctivitis, and abnormal lacrimation.4

Fluorouracil (5-FU) and the oral 5-FU prodrug, capecitabine, may cause dry eyes and/or
excessive tearing.5 In a 2000 case report, Waikhom and colleagues6 reported severe
ocular irritation associated with capecitabine therapy; the package insert for
capecitabine reports a 5% to 15% incidence for all types of visual disturbance.7 Irritation
of the anterior (corneal) surface leading to ocular surface lesions can result from the
systemic administration of 5-FU. The calculated prevalence rates of ocular surface
lesions with use of systemic 5-FU are ocular irritation, 5.8%; conjunctivitis, 3.8%;
keratitis, 3.8%; tearing, 26.9%; and blurred vision, 11.5%.8

Ocular toxicity has been reported with EGFRIs (eg, cetuximab, panitumumab) used in
treatment of CRC and other solid tumors.2 Panitumumab administration resulted in
ocular toxicities in 15% of patients, which included, but were not limited to, conjunctivitis
(4%), ocular hyperemia (3%), increased lacrimation (2%), and eye or eyelid irritation
(1%).9 Cetuximab administration reports blepharitis (erythema of the eyelids),
conjunctivitis, keratitis (inflammation of the cornea), cheilitis (inflammation of the lip),
and hypertrichosis (abnormal hair growth) in patients receiving cetuximab therapy,
although specific percentages are not reported in the prescribing information.10
Bevacizumab has not been reported to cause visual changes or abnormalities.11

Cataracts have been reported with use of tamoxifen, a selective estrogen receptor
modulator (SERM), commonly used in treatment of breast cancer, and with high-dose
corticosteroids, such as dexamethasone and prednisone, commonly used in treatment
of hematologic malignancies or for symptom management of conditions such as
cerebral edema secondary to brain metastases.12

Pathophysiology
Ocular toxicity induced by cancer chemotherapy includes a broad spectrum of
disorders, reflecting the unique anatomic, physiologic, and biochemical features of the
eye. Structures of the skin, including the face, eyelids, and eyebrows, may be affected
by side effects of chemotherapy. Epiphora (watery eyes) resulting from permanent
lacrimal gland stenosis has been reported in patients receiving combination
chemotherapy of cyclophosphamide, methotrexate, 5-FU, and docetaxel.12 5-FU may
produce lacrimal gland irritation in some patients, leading to excessive lacrimation.12

The mechanism of visual toxicity induced by cisplatin is unknown, but it may result from
central nervous system accumulation of drug after repeated doses, especially with high-
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dose platinum-containing regimens. Toxic neuropathies, including disc edema, retinal
edema, and optic neuritis, are rare but have been described as occasional side effects
of treatment with cisplatin. Tamoxifen has been reported to cause bilateral optic neuritis
followed by optic atrophy and visual loss. This effect is dose related.12


Physical Presentation
Ocular changes may include areas just outside the eye itself, commonly called the
ocular adnexa, which clinicians may consider part of the dermatologic system.
Structures of the skin, including the eyelids and eyebrows, may be affected by side
effects of antineoplastic chemotherapy, resulting in blepharitis (Figure 3.1), eyelid
dermatitis, and excessive tearing. Excessive tearing that resolves on cessation of
treatment is a reported side effect of 5-FU.12 A National Comprehensive Cancer
Network (NCCN) multidisciplinary task force compiled a report that describes commonly
used therapies for the management of dermatologic and ophthalmologic toxicities
associated with EGFRIs.13


Figure 3.1. Blepharitis.




Photo courtesy of Susan Moore.




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Grading Ocular Changes
Many visual changes, covering a wide range of symptoms and eye disorders, may
occur as a side effect of cancer therapy. Readers are advised to consult the NCI
CTCAE v4.03 (pages 10-11) for definitions and specific criteria for each grade of ocular
toxicity.14 Grade refers to the severity of the adverse event. The CTCAE displays grades
1 through 5 with unique clinical descriptions of severity for each adverse event based on
this general guideline (Table 3.1).14

Table 3.1. General Adverse Event Grading Criteria
    Grade      Description
          1            Mild; asymptomatic or mild symptoms; clinical or diagnostic
                       observations only; intervention not indicated
          2            Moderate; minimal, local, or noninvasive intervention indicated; limiting
                       age-appropriate instrumental ADL
          3            Severe or medically significant but not immediately life threatening;
                       hospitalization or prolongation of hospitalization indicated; disabling;
                       limiting self-care ADL
          4            Life-threatening consequences; urgent intervention indicated
          5            Death related to AE
ADL = activities of daily living.
Based on information from the National Cancer Institute.14


Management of Ocular Changes
It is easy to miss the association between chemotherapy and visual changes because
the incidence is relatively uncommon and many other conditions can cause ocular
changes, especially in older adults. Hazin et al15 and Schmid et al16 suggest that
ophthalmologists should be part of a multidisciplinary team caring for patients
undergoing systemic chemotherapy to provide the following:
   • Baseline examination to evaluate for preexisting eye disorders
   • Evaluate for dry-eye syndrome
   • Ongoing consultation for eye problems that present during systemic chemotherapy

Omoti and Omoti12 recommend a baseline exam and ongoing follow-up every 3 months
thereafter during active therapy.12 Other than recommending over-the-counter eye
lubricants, patients reporting visual changes should be referred to an ophthalmologist
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immediately to preserve vision. Ophthalmalogic intervention may include topical or
systemic medication or, in the case of excessive tearing, the insertion of lacrimal stents.

Implications for Health Care Professionals
Ophthalmologic side effects are generally uncommon, but important to note because of
the extreme debility produced by loss of vision. Although most chemotherapeutic agents
seem to be relatively free of ocular toxicity, certain drugs carry a significant risk of visual
changes. Long-term effects of chemotherapy are of increasing importance as survival of
patients with cancer improves. The long-term ocular effects of most chemotherapeutic
agents are unknown. Nurses caring for patients with cancer can assist them in
protecting their visual health by doing a thorough review of systems related to visual
changes during therapy, and referring patients to an ophthalmologist for a baseline
exam and complete visual assessment when they report these changes.

Assessment and Patient Care Management Tools
National Cancer Institute, Cancer Therapy Evaluation Program. Common Terminology
Criteria for Adverse Events (CTCAE) v4.03 (pp 10-11).
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-
14_QuickReference_8.5x11.pdf .

Health on the Net Foundation. Vision FAQ, section 5: disease of the eye (posterior eye
disease).
http://www.hon.ch/Library/Theme/VisionFaq/section5.html.

Optometric clinical practice recommendations for monitoring ocular toxicity of selected
medications can be viewed online at http://www.aoa.org/documents/Ocular-Toxicity.pdf.




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References
1. O’Dea D, Handy C, Wexler A. Ocular changes with oxaliplatin. Clin J Oncol Nurs.
    2006;10:227-229.
2. Dranko S, Kinney C, Ramanathan RK. Ocular toxicity related to cetuximab
    monotherapy in patients with colorectal cancer. Clin Colorectal Cancer. 2006;6:224-
    225.
3. Leonard G, Wright M, Quinn M. Survey of oxaliplatin-associated neurotoxicity using
    an interview-based questionnaire in patients with metastatic colorectal cancer. BMC
    Cancer. 2005;5:116-125.
4. Eloxatin (oxaliplatin for injection) prescribing information. http://products.sanofi-
    aventis.us/eloxatin/eloxatin.html.
5. Wilkes G, Barton-Burke M. 2006 Oncology Nursing Drug Handbook. Boston, MA:
    Jones & Bartlett Publishers; 2005.
6. Waikhom B, Fraunfelder F, Henner W. Severe ocular irritation and corneal deposits
    associated with capecitabine use. N Engl J Med. 2000;343:740-741.
7. Xeloda (capecitabine) tablets prescribing information; 2010.
    http://www.gene.com/gene/products/information/xeloda/
8. Eiseman AS, Flanagan JC, Brooks AB, Mitchell EP, Pemberton CH. Ocular surface,
    ocular adnexal, and lacrimal complications associated with the use of systemic 5-
    fluorouracil. Ophthal Plast Reconstr Surg. 2003;19:216-224.
9. Amgen, Inc. Vectibix prescribing information; 2010.
    http://pi.amgen.com/united_states/vectibix/vectibix_pi.pdf.
10. Bristol-Myers Squibb, Inc. Erbitux prescribing information; 2010.
    http://packageinserts.bms.com/pi/pi_erbitux.pdf.
11. Genentech, Inc. Avastin prescribing information. 2011. Retrieved from
    http://www.gene.com/gene/products/information/pdf/avastin-prescribing.pdf.
12. Omoti AE, Omoti CE. Ocular toxicity of systemic anticancer chemotherapy. Pharm
    Pract. 2006; 4: 55-59.
13. Burtness B, Anadkat M. Basti S, et al. NCCN Task Force Report: Management of
    Dermatologic and Other Toxicities Associated With EGFR Inhibition in Patients with
    Cancer. J Natl Compr Canc Netw. 2009;7(suppl 1):S5-S22.
14. National Cancer Institute, Cancer Therapy Evaluation Program, Common
    Terminology Criteria for Adverse Events (CTCAE) v4.03 (pp 10-11).
    http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-
    14_QuickReference_8.5x11.pdf.
15. Hazin R, Abuzetun JY, Daoud YJ, Abu-Khalaf MM. Ocular complications of cancer
    therapy: a primer for the ophthalmologist treating cancer patients. Curr Opin
    Ophthalmol. 2009; 20:308-317.
16. Schmid KE, Kornek GV, Scheithauer W, Binder S. Update on ocular complications
    of systemic cancer chemotherapy. Surv Ophthalmol. 2006;51:19-40.

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Section 4. Hand-Foot Skin Reaction


Background
Multitargeted kinase inhibitors (MKIs) have shown promising activity in renal cell
carcinoma (RCC), hepatocellular carcinoma (HCC), and gastrointestinal stromal tumor
(GIST). A common dermatologic toxicity of MKIs is hand-foot skin reaction (HFSR).
HFSR is not life threatening; however, 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. HFSR has been shown to occur in anywhere from 9% to 62% of
patients receiving MKIs. Appropriate methods of prevention and management of HFSR
are necessary to ensure proper administration of the drugs and to improve the health-
related quality of life of the patients who take them.1

HFSR, which is also termed keratosis, is a separate condition from, and should not be
confused with, hand-foot syndrome, which is often seen in patients receiving
capecitabine, fluorouracil (5-FU), and liposomal doxorubicin.

Pathophysiology
The most relevant histopathologic finding of HFSR is keratinocyte damage.2 The rate of
epidermal cell replication is markedly accelerated in active HFSR lesions.2 The exact
mechanism by which MKIs produce painful palm and sole blisters remains unclear, but
increased incidence and more severe rashes at higher doses suggest that it is dose
related and is not due to an allergic reaction.2 An increase in drug concentrations in the
rich capillary network at the thickened papillary dermis, combined with increased blood
flow, is one of the proposed mechanisms, as the palms, soles, and fingertips are areas
of repeated friction, grasping, or trauma. However, HFSR on non–pressure-bearing
skin, such as finger webs, lateral aspects of the sole, and perianal area, is also a
relatively common presentation. Other speculative mechanisms include the direct
cytotoxic effect of the drug in eccrine sweat glands.1,2

Physical Presentation
HFSR develops within the first 2 to 4 weeks of MKI administration in the majority of
patients and may initially present as paresthesia (tingling and burning sensation) of
fingers and palms of the hands or padded areas of the feet bilaterally. Lesions are
tender and scaling, with a peripheral halo of erythema localized on areas of pressure
(tips of fingers and toes, heels) or points of flexure (Figure 4.1).1 In fully developed
lesions, large blisters may develop on lesional skin. Similar cutaneous reactions were

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occasionally noted over the distal phalanges and the fingertips, particularly in the area
around the nails.2 After several weeks, the lesions, with or without blisters, are followed
by areas of thickened or hyperkeratotic skin (calluses) that are painful, requiring
analgesic intervention. At this stage, HFSR can lead to marked disruptions in activities
of daily living, including inability to ambulate and impaired range of motion, function, and
weight bearing.1

Figure 4.1. Hand-Foot Skin Reaction.




Photos courtesy of Susan Moore.



Differentiating HFSR From HFS
HFSR shares some clinical similarities with the HFS that occurs during the
administration of cytotoxic chemotherapies such as cytarabine, capecitabine, 5-FU, or
liposomal doxorubicin. These similarities include the palms and soles as the primary
location, tenderness, pain, and resolution of the toxicity on discontinuation of the drug.
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 (Table 4.1).1




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Table 4.1. Differentiating Between HFSR and HFS

 Symptom/Presentation                                                                       HFSR   HFS
 Erythema
 Edema (swelling)
 Blisters
 Desquamation
 Affects palmar-plantar (palms and soles) surfaces
 Affects nonpressure areas (finger webs, lateral feet, perianal
 skin)
 Hyperkeratotic calluses
HFS = hand-foot syndrome; HFSR = hand-foot skin reaction.
Based on information from Lacouture et al,1 Yang et al.2

Assessment Tools

National Cancer Institute, Cancer Therapy Evaluation Program. Common
Terminology Criteria for Adverse Events (CTCAE)
v4.03. http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-
14_QuickReference_8.5x11.pdf. (Table 4.2 provides a description of HFSR
grades.)

Table 4.2. Grading HFSR
  Grade    Description
    1      • Minimal skin changes or dermatitis
           • No pain
   2       • Skin changes (blisters, peeling, bleeding, edema) or
               pain
           • No interference with patient’s ADL
   3       • Ulcerating dermatitis or skin changes with pain
           • Interferes with patient’s ADL
ADL = activities of daily living; HFSR = hand-foot skin reaction.
Based on information from NCI CTCAE v4.03.3

Clinical Guidelines for Management of HFSR
No prospective, randomized trials have been undertaken to determine the best
management strategy for HFSR. There are no evidence-based national clinical
guidelines available.

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Management of HFSR

Preventive Measures1,2,4
  • Management of HFSR can begin at the initiation of MKI therapy, before any
    symptoms occur
  • 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 by a podiatrist, 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
  • Prevention of traumatic activity and rest during the first 2 to 4 weeks of MKI
    therapy are critical to minimizing development during this period
  • Avoid constrictive footwear
  • 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
  • Twice-daily topical applications of nonprescription-strength salicylic acid and/or
    urea-containing lotions should be initiated at the first complaint of paresthesias to
    help with natural exfoliation and chemical debridement of hyperkeratotic areas
    such as calluses




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Management by Grade of HFSR
With MKIs, the total dose seems to correlate with the occurrence and severity of HFSR.
If HFSR does develop, the following management strategies are suggested, depending
on the grade of HFSR (Table 4.3).1,4

Table 4.3. Management of HFSR
    Grade           Intervention                                                                Dose
                                                                                             Modification
                                                                                            Recommended
                    •   Full-body skin exam
 Prophylaxis        •   Pedicure                                                             Not applicable
                    •   Wearing thick cotton gloves and socks
                    •   Avoiding hot water and constrictive footwear
                    •   Patients should avoid hot water and use moisturizing
                        creams for relief
                    • Keratolytics, such as urea 20%-40% or salicylic acid
        1               6%, may be indicated                                                      No
                    • Cotton gloves and socks can be worn at night to
                        prevent further injury and to help retain moisture
                    • 2-week follow-up in the clinic is recommended; special
                        attention should be paid to palms and soles
                    Treatment should continue as for grade 1 toxicity with the
                    following additions:
                    • Consider applying clobetasol 0.05% ointment to
                        erythematous areas twice daily
        2           • For pain control, consider using topical analgesics,                       Yes *
                        such as lidocaine 2%
                    • Assess for bleeding and kidney function before
                        prescribing any systemic pain medications (eg,
                        nonsteroidal anti-inflammatory drugs, codeine,
                        pregabalin)
                    Provide treatment as indicated for grades 1 and 2, and
                    include the following:
                    • Interrupt treatment for a minimum of 7 days until the
        3               HFSR reaches grade 1 or 0, then resume treatment at                      Yes *
                        50% of full dose
                    • Monitor the patient for toxicity. If toxicity does not
                        recur, it may be possible to escalate doses until full
                        dose is reached
*Refer to specific drug prescribing information for dose modifications.
Based on information from Lacouture et al,1 Yang et al,2 NCI,3 Wood and Manchen,4
Bayer Pharmaceuticals, Inc,5 and Pfizer.6
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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 and have shown anecdotal benefit include urea 40% cream,
tazarotene 0.1% cream, and 5-FU 5% cream. 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. 5-FU 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.1

Other recommendations for managing HFSR include wearing cotton socks, using gel
inserts, avoiding pressure points by wearing soft or tennis shoes, limiting standing for
long periods of time, soaking the affected skin in a solution of magnesium sulfate and
lukewarm water, and applying sunburn-relief spray to affected areas when needed.1

Implications for Health Care Professionals
Frequent communication between patients and health care professionals is
encouraged; maintaining contact at weeks 2 to 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 patients
for hypertension or other MKI side effects.1 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.1




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References

1. Lacouture ME, Wu S, Robert C, et al. Evolving strategies for the management of
   hand foot skin reaction associated with the multitargeted kinase inhibitors sorafenib
   and sunitinib. Oncologist. 2008;13:1001-1011.
2. Yang CH, Lin WC, Chuang CK, et al. Hand-foot skin reaction in patients treated
   with sorafenib: a clinicopathological study of cutaneous manifestations due to
   multitargeted kinase inhibitor therapy. Br J Dermatol. 2008; 158:592-596.
3. National Cancer Institute, Cancer Therapy Evaluation Program. Common
   Terminology Criteria for Adverse Events v4.03
   (CTCAE). http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-
   14_QuickReference_8.5x11.pdf.

4. Wood LS, Manchen B. Sorafenib: a promising new targeted therapy for renal cell
   carcinoma. Clin J Oncol Nurs. 2007;11:649-656.

5. Bayer Healthcare Pharmaceuticals, Inc. Nexavar Prescribing Information; 2010.
   http://berlex.bayerhealthcare.com/html/products/pi/Nexavar_PI.pdf.

6. Pfizer Labs. Sutent Prescribing Information; 2010.
   http://www.pfizer.com/files/products/uspi_sutent.pdf.




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Learning Assessment

To successfully complete this activity and receive continuing education credit, you must
read the text and score at least 70% on the learning assessment, and complete the
evaluation form. You can access the learning assessment and evaluation form by
selecting the link below. If you provide your e-mail address, you will receive an
immediate e-mail notification with a link to your printable statement of credit.

Click on the link below to register and submit your evaluation form online
http://managecrc.cme360.net/default.aspx

    1. Erythema is a common presenting symptom for which of the following?
          a. Hand-foot syndrome
          b. Blepharitis
          c. Hand-foot skin reaction (HFSR)
          d. All of the above

    2. Skin rash is one of the most common toxicities during capecitabine therapy
          a. True
          b. False

    3. Dose modification is the first intervention for grade 1 toxicities for cutaneous
       toxicities
           a. True
           b. False

    4. Visual changes have not been reported to occur with administration of
          a. Cetuximab
          b. Bevacizumab
          c. Fluorouracil (5-FU)
          d. Oxaliplatin

    5. Dose modification for management of hand-foot syndrome (HFS) begins at the
       appearance of grade 3 toxicity
          a. True
          b. False

    6. A clinical finding that can help differentiate HFSR from HFS is
          a. Localized hyperkeratotic lesions surrounded by erythema
          b. Erythema
          c. Pain
          d. Limitation in activities of daily living (ADL)
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    7. Urea and salicylic acid can be used to manage which of the following?
          a. Blepharitis
          b. Blisters
          c. Calluses
          d. None of the above

    8. Urea and salicylic acid provide which of the following actions on the skin?
          a. Debridement
          b. Moisturization
          c. Anti-inflammatory
          d. Antimicrobial

    9. Skin rash is one of the most common toxicities during cetuximab therapy.
          a. True
          b. False

    10. Patients should be advised to avoid exposure to hot water to avoid HFS or
        HFSR.
           a. True
           b. False




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