http://informahealthcare.com/cotISSN: 1556-9527 (print), 1556-9535 (electronic)

Cutan Ocul Toxicol, Early Online: 1–3! 2013 Informa Healthcare USA, Inc. DOI: 10.3109/15569527.2013.832280

CASE REPORT

Topical henna ameliorated capecitabine-induced hand-foot syndrome

Saher Ilyas, Komal Wasif, and Muhammad Wasif Saif

Section of GI Cancers and Experimental Therapeutics, Tufts University School of Medicine, Boston, MA, USA

Abstract

Background: Hand-foot syndrome (HFS) is the most frequently reported side effect of oralcapecitabine therapy. In addition to treatment interruption and dose reduction, supportivetreatments can help alleviate symptoms. Although its efficacy has not been proven in clinicalstudies, certain authors report on the use of prophylactic or therapeutic pyridoxinesupplementation for the prevention of minimization to be useful in preventing worsening ofHFS but are no substitute for dose modifications.Case report: We report a case of an interesting observation in a patient with pancreatic cancerreceiving capecitabine whose HFS was improved with the use of ‘‘henna’’.Discussion: Henna has been used for histories as a medicine, preservative, and cosmetic. Ourcase underlines the basis to further evaluate the anti-inflammatory, antipyretic, and analgesiceffects of henna. We encourage other investigators to publish any similar cases or any otherherbal or non-drug therapies. HFS is a common side effect of many drugs, includingcapecitabine, sorafinib and regorafenib. HFS is bothersome for patients even in low grades andimpacts quality of life of patients. HFS cannot be prevented and currently the treatments aimedat controlling syndrome are not very effective. Exploring other potential treatment ormanagement options such as henna is of high value.

Keywords

Capecitabine, diarrhea, hand-foot syndrome(HFS), pancreatic cancer

History

Received 30 April 2013Revised 30 July 2013Accepted 31 July 2013Published online 9 September 2013

Introduction

Capecitabine is an oral flouoropyrimidine lactic carbmate

rationally designed to allow for selective 5-FU (Fluorouracil)

activation in tumor tissue. Capecitabine is metabolized to

5-FU within the tumor, allowing higher concentration and less

systemic side effects1,2. Although capecitabine is generally

well tolerated as side effects such as diarrhea, nausea,

vomiting, and mucositis are particularly less frequent than

with intravenous 5-FU1–3. However, palmer-plantar erythro-

dysesthesia or hand-foot syndrome (HFS) is reported in450%

of patients receiving capecitabine4. HFS is also seen in

patients receiving other drugs such as liposomal doxorubicin

and infusional 5-FU5,6. The pathogenesis of HFS is not fully

understood, but it may be due related to damage to deep

capillaries in the soles of the feet and palms of the hands,

COX inflammatory-type reaction, or related to enzymes

involved in the metabolism of capecitabine, especially,

thymidine phosphorylase (TP) and dihydropyrimidine

dehydrogenase (DPD)1,7–9. In addition, the increased

number of eccrine glands on the hands and feet may have

major role in pathogenesis. Ethnic variations in the clinical

manifestation of HFS have also been reported by our group

and others. Higher toxicity is seen in the US patients

compared to East Asian patients. In addition, there is a

discrepancy in tolerance of dose among patients treated in the

US versus Europe10,11.

The most common management includes treatment inter-

ruption and dose reduction4. However, supportive treatments

can help alleviate symptoms, such as use of emollients

(udderly smooth). Although its efficacy has not been proven

in clinical studies, certain authors as well as our group report

on the use of prophylactic or therapeutic pyridoxine supple-

mentation for the prevention and treatment of HFS1,4.

We here report a case report of a patient in whom topical

use of henna ameliorated HFS and we were able to continue

capecitabine at the current dose for six cycles. Henna has been

commonly used in south-Asian countries as decorative

paintings for hands, nails, feet, as well as a dye for hair and

body painting.

Case report

A 53-year-old Indian woman was diagnosed with Stage II

pancreatic adenocarcinoma in 2008. She underwent

Whipple’s procedure that showed moderately differentiated

adenocarcinoma, 1/6 lymph node positive, and negative

margins. The patient was offered adjuvant chemotherapy,

but she declined. She was followed up at 3-months interval by

CT scan of abdomen, pelvis and chest. At 18th month follow-

up, she was found to have a solitary liver metastasis. A PET

scan was performed that revealed no other metastases. She

underwent liver resection with negative margins. She was

Address for correspondence: Muhammad Wasif Saif, MD, MBBS,Director, Section of GI Cancers and Experimental Therapeutics, TuftsUniversity School of Medicine, 800 Washington Street, Boston, MA02111, USA. Tel: + 1 (617-636-5627). Fax: + 1 (617-636-8535). E-mail:wsaif@tuftsmedicalcenter.org

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again offered adjuvant chemotherapy. After multiple discus-

sions, she agreed to receive only oral therapy. Capecitabine

was offered. She received 1500 mg PO BID for 14 days

followed by 7 days rest. At the end of second cycle, she

developed grade 2 HFS. Capecitabine was withheld and

supportive therapy with emollients and pyridoxine was

offered. She decided to use none of them but applied henna

to her soles and palms. The patient was suggested by her close

friend to apply henna to help healing and that it might

decrease the burning sensation. Her friend, herself was using

henna for diabetic neuropathy and found it to be beneficial.

Therefore, she applied henna in a traditional manner. She

poured henna powder in a small, non-metallic mixing bowl.

Then she stirred with a plastic spoon until the mixture is the

consistency of thin mashed potatoes. She covered the mixture

closely with plastic wrap and let it sit for almost 24 h until the

dye released from the henna powder. ‘‘Reshma Mehndi’’ can

take up to 24 hours for dye release. After washing her hands

with water and soap, she placed the henna paste on the palms

of both hands as well as the soles of both feet using a foam

paint brush. All the areas were covered with plastic bags or an

old towel (henna stains). She kept henna on her hands and feet

overnight and washed away with water in the morning. Per

patient, henna relieved her burning sensations immediately.

Though commonly people use lemon juice (a very small

amount) to adjust the consistency of the henna paste but she

did not add it because of the concern of irritation secondary to

few cracks on her hands. At her next follow-up in 2 weeks, her

HFS was improved to grade 0. On further questioning, she

narrated that she used henna twice a week. Patient has no HFS

at the time at the time of MD’s visit and she completed a total

of 6 cycles without any dose reduction or interruption.

Discussion

Henna is a dye extracted from the dried leaves and skin of

branches of plant from lythracea family named ‘‘Lawsonia

inermis (Henna)’’ shown in Figures 1 and 212. Use of henna is

very common in the eastern cultures, especially Indian,

Pakistan, Turkey, Bangaladesh, as well and some places in

Middle East. The most common use is cosmetic, especially at

the weddings or major religious ceremonies but it has some

medical use too as a preservative, as an astringent, as a

purgative, and as an abortifacient. Literature also reveals the

use of topical henna for the treatment of seborrhea and fungal

infections. Lawsone and six extracts of L. inermis plant,

used by Algerian traditional healers to treat infectious

diseases, were screened for their antifungal activity against

filamentous fungi13. The investigators found that the com-

mercial lawsone showed potentially interesting MICs against

the strains Fusarium oxysporum (12 Jg/mL) and Aspergillus

flavus (50 Jg/mL).

The exact mechanism of action of henna has not been

elucidated but animal data suggest an antioxidant as well as

an immune-modulatory effect in rats14. It is suggested that the

henna, a natural dye like indigo can stain skin for a prolonged

duration because the dye molecules are small, thereby, absorb

into the dead cells at the surface of the skin. This leads the

stain to remain visible until the affected cells are exfoliated.

Some mythologists believe that the first step to mixing henna

is to get the dye released from the plant matter, and mixing it

with an acidic liquid like lemon juice, strong coffee, or even

pop can facilitate. Investigators have tried to isolate the

constituents and found that among many others, two com-

pounds (4-hydroxy coumarin and 7- hydroxy-4-methyl cou-

marin) showed a moderate inhibition of urease activity15.

Although the data are anecdotal, we reviewed the literature

and the web sites and generally the basic recipe about henna

includes: 25–30 g (2–3 heaping Tbsp) henna powder, lemon

juice, 2–3 ml (1/2 tsp), boiled water (must be cooled down to

room temperature), bowl, spoon, and plastic wrap. Pour henna

powder in a small, non-metallic mixing bowl. Slowly add

room temperature lemon juice and stir with a plastic spoon

until the mixture is the consistency of thin mashed potatoes.

Cover mixture closely with plastic wrap and let sit 12–24 h or

more until the dye releases from the henna powder. Keep out

of direct sunlight. Dye release will occur faster in warmer

weather. After dye release, the henna paste is ready for use.

Now you will adjust the consistency to allow for easy

application. Start adding lemon juice A LITTLE AT A TIME

until the paste is thin enough to SLOWLY fall from a spoon in

Figure 2. Henna is a dye extracted from the dried leaves and skin ofbranches of Lawsonia inermis.

Figure 1. Lawsonia inermis (Henna).

2 S. Ilyas et al. Cutan Ocul Toxicol, Early Online: 1–3

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a solid stream. If it comes down in globs, it may be too thick.

The paste should be the consistency of stirred yogurt. Henna

paste generally lasts for about 48 h total at room temperature.

HFS manifests as acral erythema with swelling and

dysesthesis of the palms and soles, progressing to burning

pain4. Although its pathobiological mechanism remains

unclear; it is dose-dependent and is probably related to

accumulation of drug metabolites in the skin8. No age or

gender association has been observed with capecitabine

related HFS. Neither frequency nor severity of HFS appears

to correlate with plasma concentrations of various capecita-

bine metabolites. There are three possible pathogenetic

mechanisms postulated so far: (1) high levels of thymidine

phosphorylase (TP) and dihydropyrimidine dehydrogenase

(DPD) in skin keratinocytes result in capecitabine’s metab-

olite accumulation. Moreover, high proliferation rate of

epidermal basal cells in the palm could make them more

sensitive to local action of capecitabine, (2) the elimination of

capecitabine by the eccrine system and an increased number

of eccrine glands in hand and foot skin, and (3) the increased

blood flow and temperature in hands and feet.

Generally, the reduction of dosage should be recommended

the basis of HFS management as untreated HFS can lead to

interference in one’s daily life activities. HFS cannot be

prevented and currently the treatments aimed at controlling

syndrome are not very effective. Such treatment includes

topical emollients, antibiotics to prevent secondary infection,

topical steroids, Vitamin B6, cyclooxygenase COX2 inhibi-

tors and discontinuation of the offending drug in severe

cases10,11. In case of relapse on withdrawal, the offending

drug maybe cautiously re-introduced in a lower dose, which

may affect the efficacy. Our patient did not require any dose

reduction or discontinuation of treatment during her following

six cycles.

Henna has very low allergenicity. However, people often

mix henna with other coloring substances such as para-

phenylenediamine in order to darken the color and create a

permanent tattoo effect. Para-phenylenediamine is known to

have a high allergenicity potential and may result in serious

allergic reactions. Such anecdotal reports have been

reported15–17. We suggest to perform a patch test specially

if someone has not used henna previously and more

importantly if the constituents indicate inclusion of para-

phenylenediamine, a known potent contact allergen.

Our coincidental observation about henna use to manage

HFS made us to search the medical literature. We found a

case series of 10 patients from Turkey in which henna dye was

found beneficial for the treatment of HFS18. Our case and the

data from the case series underline the basis to further

evaluate the anti-inflammatory, antipyretic and analgesic

effects of henna. We encourage other investigators to publish

any similar cases or any other herbal or non-drug therapies.

Our department of Experimental Therapeutics is planning to

conduct a pilot study in patients with gastrointestinal and

breast cancer patients. In addition, we intend to assess the

pharmacokinetics of henna, hoping this may lead to the

development of a more patient friendly use form, such as a

cream or lotion.

Declaration of interest

The authors report no conflicts of interest. The authors alone

are responsible for the content and writing of this article.

References

1. Saif MW, Eloubeidi MA, Russo S, et al. A phase I study ofcapecitabine with concomitant radiotherapy for patients withlocally advanced pancreatic cancer: expression analysis of endo-scopic genes related to outcome. J Clin Oncol 2005;23:8679–8687.

2. Saif MW, Katirtzoglou NA, Syrigos KN. Capecitabine: anoverview of the side effects and their management. AnticancerDrugs 2008;19:447–464.

3. Saif MW. Capecitabine versus continuous-infusion 5-Fluorouracilfor colorectal cancer: a retrospective efficacy and safety compari-son. Clin Colorectal Cancer 2005;5:89–100.

4. Saif MW. Capecitabine and hand-foot syndrome. ExpertOpinionin Drug Safety 2011;10:159–169.

5. Comandone A, Bretti S, La Grotta G, et al. Palmar-plantarerythrodysestasia syndrome associated with 5-fluorouracil treat-ment. Anticancer Res 1993;13:1781–1783.

6. Gordone KB, Tajuddin A, Guitart J, et al. Hand-foot syndromeassociated with liposome-encapsulated doxorubicin therapy.Cancer 1995;75:2169–2173.

7. Saif MW, Diasio R. Is capecitabine safe in patients withgastrointestinal cancer and dihydropyrimidine dehydrogenasedeficiency? Clin Colorectal Cancer 2006;5:359–362

8. Shahrokni A, Rajebi MR, Saif MW. Toxicity and efficacy of 5-fluorouracil and capecitabine in a patient with TYMS genepolymorphism: a challenge or a dilemma? Clin Colorectal Cancer2009;8:231–234

9. Saif MW, Elfiky A. Identifying and treating fluoropyrimidine-associated cutaneous toxicity in white and non-white patients.J Supp Oncol 2007;5:337–343.

10. Saif MW, Sandoval A. Atypical hand-and-foot syndrome in anAfrican American patient treated with capecitabine with normalDPD activity: is there an ethnic disparity? Cutan Ocul Toxicol2007;27:311–315

11. Kandil HH, al-Ghanem MM, Sarwat MA, al-Thallab FS. Henna(Lawsonia intermis Linn.) inducing haemolysis among G6PD-deficient newborns. A new clinical observation. Ann Trop Paediatr1996;16:287–291.

12. Rahmoun N, Boucherit-Otmani Z, Boucherit K, et al. Antifungalactivity of the Algerian Lawsonia inermis (henna). Pharm Biol2013;51:131–135.

13. Mikhaeil BR, Badria FA, Maatooq GT, Amer MM. Antioxidantand immunomodulatory constituents of henna leaves. ZNaturforsch 2004;59:468–476.

14. Uddin N, Siddiqui BS, Begum S, et al. Bioassay-guided isolationof urease and a-chymotrypsin inhibitory constituents from thestems of Lawsonia alba Lam. (Henna). Fitoterapia 2013;84:202–207.

15. Turan H, Okur M, Kaya E, et al. Allergic contact dermatitis topara-phenylenediamine in a tattoo: a case report. Cutan OculToxicol 2013;32:185–187.

16. Belhadjali H, Akkari H, Youssef M, et al. Bullous allergic contactdermatitis to pure henna in a 3-year-old girl. Pediatr Dermatol2011;28:580–581.

17. Kazandjieva J, Balabanova M, Kircheva K, Tsankov N. Contactdermatitis due to temporary henna tattoos. Skin Med 2010;8:191–192.

18. Yucel I, Guzin G. Topical henna for capecitabine induced hand-foot syndrome. Invest New Drugs 2008;26:189–192.

DOI: 10.3109/15569527.2013.832280 Topical henna ameliorated HFS 3

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