Hand-foot Syndrome Due to Capecitabine: Report of Two Cases

Marsha Bianti, Aninda Marina, Wresti Indriatmi, Sandra Widaty

Department of Dermatology and Venereology, Faculty of Medicine Universitas Indonesia, Dr. Cipto Mangunkusumo

National General Hospital, Jakarta

Keywords: capecitabine, chemotherapy, hand-foot syndrome

Abstract: Capecitabine is one of the most common chemotherapy drugs known to cause hand-foot syndrome (HFS). It

is indicated as adjuvant therapy for the treatment of colorectal cancer, first-line therapy in metastatic colorectal

cancer, and as monotherapy or in combination with docetaxel in metastatic breast cancer. Although considered

to be safe, it has some adverse effect, such as HFS, which is a localized skin eruption associated with the

initiation of therapy with certain chemotherapeutic agents. It is considered common and mild thus frequently

but improperly self-managed and impaired quality of life. A fifty seven years old woman on treatment with

capecitabine for breast cancer and a 46-years-old woman on treatment with capecitabine for breast and thyroid

cancer presented with dry and fissured skin on both palms and soles. They also noted pain and discomfort

while doing their daily activities. On examination, there were multiple erythematous-hyperpigmented plaques,

with scales and fissures overlying it on both palms and soles. Both patients were diagnosed with hand-foot

syndrome due to capecitabine and responded well to topical emollients and steroid

1 INTRODUCTION

Hand-foot syndrome (HFS), also known as

palmoplantar erythrodysesthesia (PPE) or acral

erythema, is a localized skin eruption associated with

the initiation of therapy with certain

chemotherapeutic agents. It is considered a subtype

of toxic erythema of chemotherapy. The clinical

presentation of HFS is characterized by a prodrome

of dysesthesia followed by the development of

painful, symmetrical edema and erythema of the

palms, digits, and soles that may evolve into blisters

and erosions (Hoesly et al., 2011). Although HFS is

considered to affect quality of life, it is not a life-

threatening condition and rarely need hospitalization.

The incidence of HFS depends on the drug therapy,

dosage, and the manner in which the drug is

administered (Farr & Safwat, 2011).

The mechanism of HFS remains unclear. Based

on experience, HFS is considered to be dose-

dependent and probably related to drug metabolite

accumulation in the skin (Farr & Safwat, 2011).

Discontinuation of the offending agent generally

leads to skin regeneration over 1-2 weeks

(Abushullaih, 2002).

Some risk factors were identified to develop HFS,

including the type, dose and duration of

chemotherapy being used and this risk increases with

each dose of potential HFS inducing chemotherapy.

Other risk factors include advanced age, female,

performance status, and exposure to total body

irradiation (Farr & Safwat, 2011; Lassere & Hoff,

2004).

Capecitabine is one of the most common

chemotherapy drugs known to cause HFS. Other

drugs are 5-fluorouracil and liposomal doxorubicin.

Capecitabine is a fluoropyrimidine with

antineoplastic activity. It is a systemic prodrug of 5-

fluorouracil, which has advantage of being orally

administered and has better safety profile (Gressett,

2006). Currently, it is indicated as adjuvant therapy

for the treatment of colorectal cancer, first-line

therapy in metastatic colorectal cancer, and as

monotherapy or in combination with docetaxel in

metastatic breast cancer. Although it is considered to

be safe, capecitabine has side effects, such as nausea,

vomiting, diarrhea, stomatitis, and most commonly,

hand-foot syndrome. This condition is considered

mild thus frequently self-managed, instead of being

referred to Dermatologists. However, the

management is somewhat not proper and the

condition can be worsening and further impaired the

patient’s quality of life. This function impairment is

the main criteria in HFS severity classification. We

report two cases of hand-foot syndrome due to

Bianti, M., Marina, A., Indriatmi, W. and Widaty, S.

Hand-foot Syndrome Due to Capecitabine: Report of Two Cases.

DOI: 10.5220/0008158704150419

In Proceedings of the 23rd Regional Conference of Dermatology (RCD 2018), pages 415-419

ISBN: 978-989-758-494-7

415

capecitabine managed with topical emollients and

steroid.

2 CASE

First patient is a 57-years-old woman who was

consulted by Surgery Outpatient Clinic with right

breast cancer TxNxM1 and dry skin on July 12

2017. She came to our clinic with chief complaints of

dry and fissured skin, accompanied with pain on both

palms and soles since 1 year ago and got worsen

since. Capecitabine was taken daily since 1 year prior

to admission and 8 months ago she had mild redness,

dry, and flaky skin on both palms. However, it did not

impair her activities.

One month ago, she developed peeling of skin and

itch over both palms and soles. She overcame it by

rubbing skin with baby soap bar and warm water but

the condition didn’t improve. Two weeks ago, the

skin peeling worsen and accompanied by pain

everytime she walks or holds things.

History of contact with irritants, such as

detergents and dishwasher soap, was admitted but she

denied the usage of new brands or products. No

history of atopic and allergy were recorded on patient,

as well as on patient’s family. She bathes twice a day

with bar soap and regular temperature water. Patient

is planned to receive capecitabine for 6 more months.

On September 2012, patient was diagnosed with

right breast tumor suspect of malignancy and referred

to Cipto Mangunkusumo Hospital and then

underwent modified radical mastectomy of the right

breast. She started 25 radiotherapy sessions on July

2013 and 6 cycles of adjuvant chemotherapy on

November 2013. During that time, her laboratory

result showed bicytopenia (anemia and leukopenia)

with normal liver function, and normal renal function

(on August 2014, her estimated glomerular filtration

rate was 84.4 mL/min/1.73m

In 2015, multiple metastatic nodules on both lungs

were detected through chest radiography and multiple

slice CT scan (MSCT). Therefore, another 6 cycles of

second line chemotherapy (paclitaxel/cisplatin) were

initiated. On June 2016, blastic lesion on right

inferomedial caput femur were found and

capecitabine were started on July 2016. On follow-up

MSCT done on March 2017, multiple nodules on both

thyroid lobes were found, beside metastatic nodules

on both lungs and multiple mediastinal

lymphadenopathy. Treatment with capecitabine was

continued until present time.

During 2017, several abnormalities were found in

her laboratory result. She was pancytopenic and her

renal function was impaired. Her last laboratory test

on June 20

2017 showed hemoglobin 9.8 g/dL,

hematocrit 28.1%, leukocyte count 4.81 x 10

/μL,

platelet count 119.000/μL, and the estimated

glomerular filtration rate (eGFR) dropped to 42

mL/min/1.73m

From the physical examination, we found the

patient was fully conscious with normal vital signs.

On dermatological examination, we found multiple,

skin colored-erythematous-hyperpigmented plaques,

irregular in shape, plaque in size, circumscribed-

diffused border, with scales and fissures overlying it

on both palms and soles as well as lateral aspect of

the feet. On both back of her hand, on proximal

interphalangeal and metacarpal joints, and bilateral

lateral malleolus, we found multiple, erythematous-

hyperpigmented plaques, lenticular until nummular in

size, circumscribed, discrete, with lichenification,

scales, and fissured overlying it.

Patient was diagnosed with hand-foot syndrome

due to capecitabine and was treated with vaseline

album as emollient and clobetasole propionate 0.05%

ointment twice a day on palms and soles.

Our second patient was a 46-years-old woman

who was consulted by Hematology and Oncology

Division of Internal Medicine Department on

December 7

2017. She was consulted with breast

cancer, thyroid cancer, with metastasis to lungs,

brain, mediastinum, and respiratory tract, with chief

complaint of dry skin on palms and soles. She was

complaining of dry and fissured palms and soles since

2 months ago. It is accompanied with itch and pain

while walking.

She had history of prior treatment with

capecitabine from May 2009 to August 2012 but

experienced nothing unpleasant. Capecitabine

treatment was stopped and re-initiated on April 2016

due to respiratory tract metastasis. Two months prior

to admission, she complained redness on both palms

and soles, accompanied with itch and pain on fissured

skin. History of contact with irritants were denied.

She uses vinyl gloves everytime she wash clothes or

dishes. She overcome the complaints by applying

moisturizers and low potency topical corticosteroid

but no improvement were noted. She bathes twice a

day with baby bar soap and regular temperature

water. Patient is planned to receive capecitabine for 5

more years.

From the physical examination, we found the

patient was fully conscious with normal vital signs.

On dermatological examination, we found multiple,

erythematous-hyperpigmented plaques, irregular in

shape, plaque in size, circumscribed-diffused border,

with scales and fissures overlying it on both palms

and soles. Her laboratory test on October 23rd 2017

showed hemoglobin 13.7 g/dL, hematocrit 40.4%,

leukocyte count 4.04 x 103/μL, platelet count

303.000/μL. Her renal function were normal with the

eGFR 88.7 mL/min/1.73m2 and on December 11th

RCD 2018 - The 23rd Regional Conference of Dermatology 2018

416

2017 her eGFR increased to 104.2 mL/min/1.73m2.

Patient was diagnosed with hand-foot syndrome due

to capecitabine and was treated with vaseline album

as emollient and mometasone furoate 0.01% ointment

once a day on palms and soles.

Figure 1. First patient with erythematous-hyperpigmented plaques with scales and fissures on both palms, soles, and lateral

aspect of the feet

Figure 2. Second patient with erythematous-hyperpigmented plaques on both palms and soles

3 DISCUSSION

Various cytotoxic drugs have been reported to have

correlation with HFS. 5-fluorouracil (5-FU) has been

known to cause HFS since the first description in

1984 (Lokich & Moore, 1984). Occurrence of HFS

have been shown to be related to dose and prolonged

drug exposure during continuous intravenous

infusion, or daily ingestion as in capecitabine which

taken by our patients. Our patients were planned to

receive long-term maintenance treatment with

capecitabine, up to 5 years in our second patient.

Gresset reported that the median time of onset is 79

days, ranging from 11 to 360 days (Gressett et al.,

2006). In our first patient, the onset is around 1 year

prior to admission and in our second patient,

HFSoccurred on her second initiation of capecitabine

treatment after 3 years of previous cycle, so we can

conclude that the onset range of HFS is wide.

The mechanism of HFS remains unclear.

However, several theories have been postulated. First,

keratinocytes might have upgraded levels of the

enzyme thymidine phosphorylase which could lead to

capecitabine metabolite accumulation, causing

increased possibility of developing HFS. Second,

capecitabine may be eliminated by the eccrine glands,

which is numerous in palms and soles. Other theory

postulates HFS resulting from increased

vascularization and increased pressure and

temperature in the hands and feet.

From a meta-analysis reported in 1998, HFS

induced by 5-FU seems to be more common in elderly

female patients (Levy et al., 1998). Interestingly,

although our patients suit the gender profile and the

fact that capecitabine is a prodrug of 5-FU, the

relationship between age or gender and HFS seen

with 5-FU has not been clearly seen with

capecitabine.

Hand-foot Syndrome Due to Capecitabine: Report of Two Cases

417

The manifestations of HFS are classified

according to their severity by National Cancer

Institute (NCI) and World Health Organization

(WHO) as shown by Table 1.

Table 1. HFS Grading as defined by NCI and WHO (Webster et al., 2017)

Both of our patients experienced pain and

discomfort in holding objects and upon walking

besides skin changes, however no swelling or

periungual involvement in both patients, so we

classified their HFS as grade 2-3 according to WHO.

According to NCI, both patients classified as grade 3.

The treatment was tailored based on the clinical

manifestations on each patient. The histopathological

findings are nonspecific, therefore it was not

performed.

HFS is usually self-limiting and rarely leads to

life-threatening manifestations. Still, it interferes

treatment schedule and patient’s quality of life. Thus,

proper management is needed to prevent, as well as,

to treat HFS. Currently, the mainstay of the

management of HFS is interruption of therapy and

dose reduction, if necessary. Avoiding potential

irritants, including exposure to extreme changes in

temperature, ill-fitting shoes, tight-fitting clothing,

excessive exercise, and the use of topical anesthetic-

containing cream may prevent the development of

HFS.

Treatment is focused on supportive therapy to

reduce pain and discomfort, also to prevent

infections. Simple topical care with wet dressings,

topical steroids, and emollients are all that required to

clear the condition in some patients. Emollients and

creams have been used for prophylactic and

symptomatic treatment at first signs of grade 1 HFS.

Although the use of steroids for capecitabine-induced

HFS is not proven, steroids may acutely reduce

inflammation. Moreover, several studies reported that

topical or systemic corticosteroids have been useful

for prophylaxis and treatment of HFS for a wide

variety of different drugs. In our patients, the signs of

inflammation were visible, with thickening of the

skin. Therefore we gave high to very high potency

topical steroids, aiming to reduce the inflammation

and relieve symptoms.

In our patients, vaseline album were given. It acts

as occlusive agent that coat the stratum corneum to

retard transepidermal water loss, as well as provide an

emollient effects. In 2-weeks follow up, patients

report improvement in symptoms and skin lesions.

Pain were reduced and their daily activities are no

longer disrupted.

4 CONCLUSION

We report 2 cases of HFS due to capecitabine. Both

patients were diagnosed based on the history and

physical examination and were given topical

emollient and steroid. Both patients responded well

and reported improvement on skin lesions and quality

of life after 2-weeks treatment.

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