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European Journal <strong>of</strong> Oncology Nurs<strong>in</strong>g (2004) 8, S31–S40<br />

<strong>Management</strong> <strong>of</strong> <strong>hand</strong>-<strong>foot</strong> <strong>syndrome</strong> <strong>in</strong> <strong>patients</strong><br />

<strong>treated</strong> <strong>with</strong> capecitab<strong>in</strong>e (Xeloda s )<br />

Yvonne Lassere , Paulo H<strong>of</strong>f<br />

Cl<strong>in</strong>ical Protocol Adm<strong>in</strong>istration, MD Anderson Cancer Center, 1515 Holcombe Unit 426,<br />

Houston TX 77030, USA<br />

KEYWORDS:<br />

Capecitab<strong>in</strong>e;<br />

Xeloda s ;<br />

Hand-<strong>foot</strong> <strong>syndrome</strong><br />

ARTICLE IN PRESS<br />

Correspond<strong>in</strong>g author. Tel.: +1-713-792-6512; fax: +1-713-745-2845.<br />

E-mail address: ylassere@mdanderson.org (Y. Lassere).<br />

1462-3889/$ - see front matter r 2004 Elsevier Ltd. All rights reserved.<br />

doi:10.1016/j.ejon.2004.06.007<br />

www.elsevier.com/locate/ejon<br />

Summary Comparative trials <strong>of</strong> capecitab<strong>in</strong>e (Xeloda s ) versus 5-FU/LV <strong>in</strong><br />

metastatic colorectal cancer have shown that <strong>hand</strong>-<strong>foot</strong> <strong>syndrome</strong> (HFS) was the<br />

only cl<strong>in</strong>ical adverse event occurr<strong>in</strong>g more frequently <strong>with</strong> capecitab<strong>in</strong>e. Most<br />

<strong>patients</strong> <strong>with</strong> HFS present <strong>with</strong> dysesthesia, usually <strong>with</strong> a t<strong>in</strong>gl<strong>in</strong>g sensation <strong>in</strong> the<br />

palms and soles <strong>of</strong> the <strong>hand</strong>s and feet. This can progress <strong>in</strong> 3–4 days to burn<strong>in</strong>g pa<strong>in</strong><br />

plus well-def<strong>in</strong>ed symmetric swell<strong>in</strong>g and erythema. The <strong>hand</strong>s tend to be more<br />

commonly affected than the feet, and might even be the only area affected <strong>in</strong> some<br />

<strong>patients</strong>. HFS can <strong>in</strong>terfere <strong>with</strong> the general activities <strong>of</strong> daily liv<strong>in</strong>g, especially<br />

when blister<strong>in</strong>g, moist desquamation, severe pa<strong>in</strong> or ulceration occurs. While HFS is<br />

manageable, if ignored it can progress rapidly. However, dose <strong>in</strong>terruption and<br />

reduction <strong>of</strong> capecitab<strong>in</strong>e usually leads to a rapid reversal <strong>of</strong> signs and symptoms<br />

<strong>with</strong>out long-term consequences. Nurses play a key role <strong>in</strong> educat<strong>in</strong>g <strong>patients</strong> how to<br />

recognise HFS, when to <strong>in</strong>terrupt treatment and how to adjust the dose to ma<strong>in</strong>ta<strong>in</strong><br />

effective therapy <strong>with</strong> capecitab<strong>in</strong>e over the long term. It is particularly important<br />

that <strong>patients</strong> and nurses are aware that dose <strong>in</strong>terruption/reduction does not affect<br />

the overall antitumour efficacy <strong>of</strong> capecitab<strong>in</strong>e.<br />

r 2004 Elsevier Ltd. All rights reserved.<br />

Zusammenfassung Vergleichende Versuche mit Capecitab<strong>in</strong>e (Xeloda s ) im Vergleich<br />

zu 5-FU/LV bei metastasierendem kolorektalem Karz<strong>in</strong>om haben gezeigt,<br />

dassdas Hand-FuX-Syndrom (HFS) die e<strong>in</strong>zige Nebenwirkung ist, die mit Capecitab<strong>in</strong>e<br />

häufiger auftritt. Bei den meisten Patienten mit HFS tritt Dysästhesie auf,<br />

normalerweise mit e<strong>in</strong>em Prickeln auf den Handflächen und FuXsohlen. Dies kann<br />

<strong>in</strong>nerhalb von 3 bis 4 Tagen zu e<strong>in</strong>em brennenden Schmerz und klar def<strong>in</strong>ierten<br />

symmetrischen Schwellungen und Erythem fortschreiten. Die Hände s<strong>in</strong>d im<br />

allgeme<strong>in</strong>en öfter befallen als die FüXe und können bei e<strong>in</strong>igen Patienten sogar<br />

die e<strong>in</strong>zigen befallenen Bereiche se<strong>in</strong>. HFS kann die normalen Verrichtungen<br />

des tǎglichen Lebens bee<strong>in</strong>trächtigen, besonders, wenn Blasenbildung, feuchte


S32<br />

Introduction<br />

Capecitab<strong>in</strong>e (Xeloda s ) was specifically designed<br />

for oral adm<strong>in</strong>istration, to deliver 5-FU to the<br />

tumour site and to avoid systemic 5-FU exposure<br />

(Ishikawa et al., 1998; Miwa et al., 1998). As<br />

discussed <strong>in</strong> article 1 <strong>in</strong> this Supplement (Sternberg<br />

et al., 2004), the unique tumour-selective conversion<br />

<strong>of</strong> capecitab<strong>in</strong>e to active 5-FU is achieved by a<br />

3-step enzymatic process. The f<strong>in</strong>al step <strong>of</strong> the<br />

conversion is mediated by the enzyme thymid<strong>in</strong>e<br />

phosphorylase, which is found at higher levels <strong>in</strong><br />

cancer cells compared <strong>with</strong> normal tissues. As a<br />

result, more <strong>of</strong> the active anticancer agent 5-FU is<br />

produced where it is needed (i.e. <strong>with</strong><strong>in</strong> cancer<br />

cells rather than <strong>in</strong> healthy tissues).<br />

Oral capecitab<strong>in</strong>e is be<strong>in</strong>g <strong>in</strong>creas<strong>in</strong>gly accepted<br />

<strong>in</strong>to cl<strong>in</strong>ical practice as it permits convenient<br />

adm<strong>in</strong>istration <strong>in</strong> a home-based sett<strong>in</strong>g. Capecitab<strong>in</strong>e<br />

tablets are taken orally twice daily approximately<br />

12 h apart (after breakfast and after d<strong>in</strong>ner)<br />

for 2 weeks followed by a 1-week, treatment-free<br />

period. After this 1-week ‘rest’ period, the patient<br />

starts the next cycle. The normal recommended<br />

dosage is 1250 mg/m 2 twice daily, unless dose<br />

reduction is <strong>in</strong>dicated because <strong>of</strong> adverse events.<br />

At this dosage, capecitab<strong>in</strong>e is generally well<br />

tolerated, <strong>with</strong> a low <strong>in</strong>cidence <strong>of</strong> grade 3/4<br />

adverse events (see article 2 <strong>in</strong> this supplement).<br />

One <strong>of</strong> the most common adverse events associated<br />

<strong>with</strong> its use <strong>in</strong> cl<strong>in</strong>ical trials and <strong>in</strong> cl<strong>in</strong>ical practice<br />

is <strong>hand</strong>-<strong>foot</strong> <strong>syndrome</strong> (HFS), which is rarely serious<br />

and never life-threaten<strong>in</strong>g (Cassidy et al., 2002).<br />

However, HFS can significantly <strong>in</strong>terfere <strong>with</strong> the<br />

activities <strong>of</strong> normal daily liv<strong>in</strong>g.<br />

The aim <strong>of</strong> the current paper is to describe the<br />

occurrence <strong>of</strong> HFS <strong>in</strong> capecitab<strong>in</strong>e-<strong>treated</strong> <strong>patients</strong>,<br />

its nature, recognition, and severity, and<br />

the role <strong>of</strong> the oncology nurse <strong>in</strong> manag<strong>in</strong>g HFS<br />

optimally.<br />

ARTICLE IN PRESS<br />

Abschuppung, starke Schmerzen oder Geschwürbildung auftreten. Obwohl man HFS<br />

be<strong>hand</strong>eln kann, entwickelt es sich rapide, wenn man es ignoriert. Zeitweiliges<br />

Absetzen oder e<strong>in</strong>e Verm<strong>in</strong>derung der Dosierung von Capecitab<strong>in</strong>e führt jedoch<br />

normalerweise zu e<strong>in</strong>em raschen Abkl<strong>in</strong>gen der Anzeichen und Symptome ohne<br />

langfristige Folgen. Das Pflegepersonal spielt e<strong>in</strong>e führende Rolle dabei, die<br />

Patienten dar<strong>in</strong> zu unterweisen wie man HFS erkennt, wann man die Benandlung<br />

unterbrechen sollte und wie man die Dosierung verändert, um e<strong>in</strong>e wirksame<br />

Be<strong>hand</strong>lung mit Capecitab<strong>in</strong>e langfristig aufrecht zu erhalten. Besonders wichtig ist<br />

dabei, dass Patienten und Pflegepersonal wissen, dass die Unterbrechung oder<br />

M<strong>in</strong>derung der Dosierung die langfristige turnorbekämpfende Wirksamkeit von<br />

Capecitab<strong>in</strong>e nicht bee<strong>in</strong>trǎchtigt.<br />

r 2004 Elsevier Ltd. All rights reserved.<br />

Hand-<strong>foot</strong> <strong>syndrome</strong><br />

HFS, which is also known as palmar-plantar<br />

erythrodysesthesia (or PPE), was first described <strong>in</strong><br />

the literature <strong>in</strong> 1974 <strong>in</strong> <strong>patients</strong> receiv<strong>in</strong>g mitotane<br />

therapy for hypernephroma (Burgdorf et al.,<br />

1982; Baack and Burgdorf, 1991; Nagore et al.,<br />

2000). In the early 1980s, it was referred to as<br />

chemotherapy-<strong>in</strong>duced acral erythema, and appeared<br />

to be associated <strong>with</strong> cont<strong>in</strong>uous exposure<br />

to various chemotherapy drugs (Baack and Burgdorf,<br />

1991).<br />

Description/classification<br />

Y. Lassere, P. H<strong>of</strong>f<br />

In early reports, acral erythema was characterised<br />

by erythema, numbness, t<strong>in</strong>gl<strong>in</strong>g, dysesthesia,<br />

and/or paraesthesia on the palms or soles; the<br />

condition can also rarely affect the trunk, neck,<br />

chest, scalp, and extremities (Baack and Burgdorf,<br />

1991). In advanced cases, <strong>patients</strong> experience pa<strong>in</strong><br />

<strong>with</strong> swell<strong>in</strong>g <strong>of</strong> the sk<strong>in</strong>, and even desquamation,<br />

ulceration or blister<strong>in</strong>g.<br />

HFS has been def<strong>in</strong>ed more recently as a dist<strong>in</strong>ct<br />

and specific presentation (Nagore et al., 2000).<br />

Most <strong>patients</strong> present <strong>with</strong> dysesthesia, usually<br />

<strong>with</strong> a t<strong>in</strong>gl<strong>in</strong>g sensation <strong>of</strong> the palms and soles,<br />

which can progress <strong>in</strong> 3–4 days to burn<strong>in</strong>g pa<strong>in</strong> plus<br />

well-def<strong>in</strong>ed symmetric swell<strong>in</strong>g and erythema<br />

(Fig. 1a). The <strong>hand</strong>s tend to be more commonly<br />

affected than the feet, and might even be the only<br />

area affected <strong>in</strong> some <strong>patients</strong>. Erythema is<br />

uncommon outside these areas, although occasionally<br />

a mild erythema or morbiliform eruption on the<br />

trunk, neck, chest and extremities can accompany<br />

the acral response (Baack and Burgdorf, 1991; Kroll<br />

et al., 1989). Blister<strong>in</strong>g and desquamation (shedd<strong>in</strong>g<br />

<strong>of</strong> scales or small sheets <strong>of</strong> sk<strong>in</strong>) may also


develop, particularly when the causative agent is<br />

not promptly discont<strong>in</strong>ued.<br />

Dose reduction or discont<strong>in</strong>uation <strong>of</strong> the causative<br />

agent usually leads to a rapid reversal <strong>of</strong> signs<br />

and symptoms <strong>with</strong>out long-term consequences.<br />

Nevertheless, HFS can <strong>in</strong>terfere <strong>with</strong> the general<br />

activities <strong>of</strong> daily liv<strong>in</strong>g, especially when blister<strong>in</strong>g,<br />

moist desquamation, severe pa<strong>in</strong> or ulceration<br />

occurs (Jucgla and Sais, 1997). Without prompt<br />

management, HFS can progress to an extremely<br />

pa<strong>in</strong>ful and debilitat<strong>in</strong>g condition (Fig. 1b).<br />

Although HFS is not life threaten<strong>in</strong>g, as a cutaneous<br />

condition affect<strong>in</strong>g the <strong>hand</strong>s and feet, it can cause<br />

significant discomfort and impairment <strong>of</strong> function,<br />

potentially lead<strong>in</strong>g to worsened quality <strong>of</strong> life <strong>in</strong><br />

<strong>patients</strong> receiv<strong>in</strong>g cytotoxic chemotherapy.<br />

Different systems have been used for the<br />

classification <strong>of</strong> HFS. The National Cancer Institute<br />

(NCI) has a general 3-grade classification system<br />

(Table 1). There are no grade 4 events <strong>in</strong> this HFS<br />

classification. There is also a World Health Organisation<br />

(WHO) classification system based on 4<br />

grades (Table 1). In cl<strong>in</strong>ical trials <strong>of</strong> capecitab<strong>in</strong>e<br />

ARTICLE IN PRESS<br />

<strong>Management</strong> <strong>of</strong> <strong>hand</strong>-<strong>foot</strong> <strong>syndrome</strong> S33<br />

Figure 1 Appearance <strong>of</strong> HFS. (a) Characteristic erythema<br />

associated <strong>with</strong> moderate HFS. (b) Without appropriate<br />

management, HFS can progress to an extremely pa<strong>in</strong>ful<br />

and debilitat<strong>in</strong>g condition<br />

a protocol-specific, 3-grade system has generally<br />

been applied (Blum et al., 1999), which is a<br />

practical guide <strong>in</strong> cl<strong>in</strong>ical practice for dose reduction/<strong>in</strong>terruption<br />

<strong>of</strong> capecitab<strong>in</strong>e (Table 1).<br />

Mechanism <strong>of</strong> HFS<br />

5-FU was the first agent to be consistently<br />

identified as a causative agent for HFS (Lokich<br />

and Moore, 1984) and, until the 1990s, was the<br />

agent most frequently associated <strong>with</strong> HFS, particularly<br />

when adm<strong>in</strong>istered by cont<strong>in</strong>uous <strong>in</strong>fusion<br />

(Bellmunt et al., 1988; Fabian et al., 1990; Leo et<br />

al., 1994; Ng et al., 1994). More recently, HFS has<br />

become recognised as one <strong>of</strong> the most common<br />

adverse events <strong>with</strong> capecitab<strong>in</strong>e.<br />

The mechanism <strong>of</strong> HFS is unclear. In <strong>patients</strong><br />

receiv<strong>in</strong>g 5-FU, HFS is dose-dependent and probably<br />

related to drug accumulation <strong>in</strong> the sk<strong>in</strong><br />

(Bellmunt et al., 1988; Leo et al., 1994), possibly<br />

<strong>of</strong> 5-FU metabolites (Diasio, 1998). Interest<strong>in</strong>gly,<br />

HFS <strong>in</strong>duced by 5-FU appears to be more common <strong>in</strong><br />

elderly female <strong>patients</strong> (Meta-Analysis Group <strong>in</strong><br />

Cancer, 1998), although no such age or gender<br />

association has been observed <strong>with</strong> capecitab<strong>in</strong>e<br />

(Abushullaih et al., 2002; Cassidy et al., 2002).<br />

Neither the frequency nor severity <strong>of</strong> HFS appears<br />

to correlate <strong>with</strong> plasma concentrations <strong>of</strong> various<br />

capecitab<strong>in</strong>e metabolites (Cassidy et al., 2002;<br />

Gieschke et al., 2002, 2003).<br />

One theory relat<strong>in</strong>g to capecitab<strong>in</strong>e-associated<br />

HFS is that specialised sk<strong>in</strong> cells (kerat<strong>in</strong>ocytes)<br />

might have upgraded levels <strong>of</strong> the enzyme thymid<strong>in</strong>e<br />

phosphorylase (Asgari et al., 1999), which<br />

could be a cause <strong>of</strong> capecitab<strong>in</strong>e metabolite<br />

accumulation, and hence result <strong>in</strong> an <strong>in</strong>creased<br />

likelihood <strong>of</strong> develop<strong>in</strong>g HFS. Another theory is that<br />

capecitab<strong>in</strong>e may be elim<strong>in</strong>ated by the eccr<strong>in</strong>e<br />

system (sweat secretion), result<strong>in</strong>g <strong>in</strong> HFS caused<br />

by an unknown mechanism relat<strong>in</strong>g to the <strong>in</strong>creased<br />

number <strong>of</strong> eccr<strong>in</strong>e glands on the <strong>hand</strong>s and feet<br />

(Mrozek-Orlowski et al., 1999). HFS may also result<br />

from <strong>in</strong>creased vascularisation and <strong>in</strong>creased pressure<br />

and temperature <strong>in</strong> the <strong>hand</strong>s and feet. In<br />

addition, long-term alcohol <strong>in</strong>take and strenuous<br />

physical activity may <strong>in</strong>crease the likelihood <strong>of</strong><br />

develop<strong>in</strong>g HFS.<br />

When exam<strong>in</strong>ed under the microscope, tissues<br />

affected by HFS show general <strong>in</strong>flammatory<br />

changes, dilated blood vessels, oedema and white<br />

blood cell <strong>in</strong>filtration, although noth<strong>in</strong>g really<br />

stands out as a clear marker for the condition<br />

(Abushullaih et al., 2002; Nagore et al., 2000).<br />

Consequently, there is no ideal diagnosis for HFS. In<br />

addition, HFS appears to differ accord<strong>in</strong>g to the


S34<br />

type <strong>of</strong> cytotoxic agent used. High rates <strong>of</strong> severe<br />

HFS have been reported <strong>with</strong> pegylated liposomal<br />

doxorubic<strong>in</strong> (D’Agost<strong>in</strong>o et al., 2003), and the<br />

condition appears to be more common and severe<br />

(<strong>in</strong>clud<strong>in</strong>g <strong>in</strong>fection and septicaemia) than <strong>in</strong><br />

<strong>patients</strong> receiv<strong>in</strong>g capecitab<strong>in</strong>e.<br />

Frequency <strong>of</strong> HFS <strong>with</strong> capecitab<strong>in</strong>e<br />

HFS (all grades) occurred <strong>in</strong> approximately 50% <strong>of</strong><br />

<strong>patients</strong> <strong>in</strong> early phase II studies <strong>of</strong> capecitab<strong>in</strong>e<br />

s<strong>in</strong>gle-agent therapy <strong>in</strong> metastatic breast cancer<br />

(MBC) (Blum et al., 1999) and metastatic colorectal<br />

cancer (MCRC) (Abushullaih et al., 2002; Van<br />

Cutsem et al., 2000), <strong>with</strong> 10% <strong>of</strong> <strong>patients</strong><br />

experienc<strong>in</strong>g severe (grade 3) HFS. A higher rate<br />

<strong>of</strong> severe HFS (52%, 12/23 cases) was reported <strong>in</strong> a<br />

Korean study <strong>of</strong> capecitab<strong>in</strong>e <strong>in</strong> comb<strong>in</strong>ation <strong>with</strong><br />

docetaxel (Park et al., 2003), although this may be<br />

related to the ability <strong>of</strong> docetaxel to cause both<br />

HFS and nail toxicity.<br />

Because HFS is subjectively reported, standardisation<br />

is a challenge and cross-study comparison is<br />

ARTICLE IN PRESS<br />

Table 1 HFS grad<strong>in</strong>g accord<strong>in</strong>g to National Cancer Institute (NCI) (Nagore et al., 2000), World Health<br />

Organisation (WHO) criteria (Nagore et al., 2000), and as used <strong>in</strong> capecitab<strong>in</strong>e cl<strong>in</strong>ical trials (Blum et al., 1999).<br />

NCI grade NCI def<strong>in</strong>ition<br />

1 Sk<strong>in</strong> changes or dermatitis <strong>with</strong>out pa<strong>in</strong>, e.g. erythema, peel<strong>in</strong>g<br />

2 Sk<strong>in</strong> changes <strong>with</strong> pa<strong>in</strong>, not <strong>in</strong>terfer<strong>in</strong>g <strong>with</strong> function<br />

3 Sk<strong>in</strong> changes <strong>with</strong> pa<strong>in</strong> <strong>in</strong>terfer<strong>in</strong>g <strong>with</strong> function<br />

WHO<br />

grade<br />

WHO def<strong>in</strong>ition Cl<strong>in</strong>ical lesion Histological f<strong>in</strong>d<strong>in</strong>gs<br />

1 Dysesthesia/paraesthesia, t<strong>in</strong>gl<strong>in</strong>g <strong>in</strong><br />

the <strong>hand</strong>s and feet<br />

2 Discomfort <strong>in</strong> hold<strong>in</strong>g objects and upon<br />

walk<strong>in</strong>g, pa<strong>in</strong>less swell<strong>in</strong>g or erythema<br />

3 Pa<strong>in</strong>ful erythema and swell<strong>in</strong>g <strong>of</strong> palms<br />

and soles, periungual erythema and<br />

swell<strong>in</strong>g<br />

4 Desquamation, ulceration, blister<strong>in</strong>g,<br />

severe pa<strong>in</strong><br />

Cl<strong>in</strong>ical<br />

trial<br />

grade *<br />

Cl<strong>in</strong>ical doma<strong>in</strong> Functional doma<strong>in</strong><br />

Erythema Dilated blood vessels <strong>of</strong> the<br />

superficial dermal plexus<br />

1+oedema<br />

2+fissuration Isolated necrotic kerat<strong>in</strong>ocytes <strong>in</strong><br />

higher layer <strong>of</strong> the epidermis<br />

3+blister Complete epidermal necrosis<br />

1 Numbness, dysesthesia/paraesthesia,<br />

t<strong>in</strong>gl<strong>in</strong>g, pa<strong>in</strong>less swell<strong>in</strong>g or erythema<br />

Discomfort that does not disrupt normal activities<br />

2 Pa<strong>in</strong>ful erythema, <strong>with</strong> swell<strong>in</strong>g Discomfort that affects activities <strong>of</strong> daily liv<strong>in</strong>g<br />

3 Moist desquamation, ulceration,<br />

Severe discomfort, unable to work or perform<br />

blister<strong>in</strong>g, severe pa<strong>in</strong><br />

activities <strong>of</strong> daily liv<strong>in</strong>g<br />

* Note: Grade to correspond to high <strong>in</strong>tensity on either cl<strong>in</strong>ical or functional doma<strong>in</strong>.<br />

Y. Lassere, P. H<strong>of</strong>f<br />

difficult. A reliable appraisal <strong>of</strong> the frequency and<br />

severity <strong>of</strong> HFS has been obta<strong>in</strong>ed <strong>in</strong> phase III trials<br />

<strong>of</strong> capecitab<strong>in</strong>e because <strong>of</strong> the larger numbers <strong>of</strong><br />

<strong>patients</strong> enrolled.<br />

Colorectal cancer<br />

As discussed <strong>in</strong> the previous two articles <strong>in</strong> this<br />

Supplement, capecitab<strong>in</strong>e has demonstrated a<br />

superior safety pr<strong>of</strong>ile compared <strong>with</strong> 5-FU/LV <strong>in</strong><br />

phase III trials <strong>of</strong> <strong>patients</strong> <strong>with</strong> MCRC (Cassidy et al.,<br />

2002); HFS was the only side effect occurr<strong>in</strong>g<br />

significantly more frequently on capecitab<strong>in</strong>e (54%<br />

vs. 6%) <strong>with</strong> grade 3 HFS affect<strong>in</strong>g only 17% <strong>of</strong><br />

capecitab<strong>in</strong>e-<strong>treated</strong> <strong>patients</strong> (Table 2). In addition,<br />

the lower dose <strong>of</strong> capecitab<strong>in</strong>e used <strong>in</strong><br />

comb<strong>in</strong>ations <strong>with</strong> oxaliplat<strong>in</strong> (XELOX/CAPOX) or<br />

ir<strong>in</strong>otecan (XELIRI/CAPIRI) appears to result <strong>in</strong> a<br />

reduced rate <strong>of</strong> HFS compared <strong>with</strong> s<strong>in</strong>gle-agent<br />

therapy (Cassidy et al., 2004a; Patt et al., 2004).<br />

Breast cancer<br />

In a large phase III trial compar<strong>in</strong>g capecitab<strong>in</strong>e <strong>in</strong><br />

comb<strong>in</strong>ation <strong>with</strong> i.v. docetaxel vs. i.v. docetaxel<br />

alone, the capecitab<strong>in</strong>e/docetaxel comb<strong>in</strong>ation


was generally as well tolerated as docetaxel s<strong>in</strong>gleagent<br />

therapy, <strong>with</strong> HFS be<strong>in</strong>g the only notable<br />

exception (O’Shaughnessy et al., 2002). The overall<br />

rate <strong>of</strong> HFS was 64% <strong>in</strong> <strong>patients</strong> receiv<strong>in</strong>g capecitab<strong>in</strong>e/docetaxel,<br />

<strong>with</strong> 24% <strong>of</strong> <strong>patients</strong> experienc<strong>in</strong>g<br />

grade 3 HFS (Table 2). These rates <strong>of</strong> HFS are<br />

similar to those previously noted dur<strong>in</strong>g capecitab<strong>in</strong>e<br />

s<strong>in</strong>gle-agent therapy <strong>in</strong> <strong>patients</strong> <strong>with</strong> other<br />

solid tumour types.<br />

Therefore, although the overall tolerability <strong>of</strong><br />

oral capecitab<strong>in</strong>e was good, the majority <strong>of</strong><br />

<strong>patients</strong> developed HFS, which was severe <strong>in</strong><br />

17–24% <strong>of</strong> <strong>patients</strong>. It is important that the<br />

<strong>syndrome</strong> is well managed to prevent progression<br />

to a more severe grade <strong>of</strong> HFS, to avoid capecitab<strong>in</strong>e<br />

dose reductions and to limit the need for<br />

discont<strong>in</strong>uation <strong>of</strong> capecitab<strong>in</strong>e therapy.<br />

<strong>Management</strong> <strong>of</strong> HFS<br />

Dose <strong>in</strong>terruption followed, if necessary, by dose<br />

reduction should be the ma<strong>in</strong>stay <strong>of</strong> HFS management.<br />

Reduc<strong>in</strong>g the capecitab<strong>in</strong>e dose <strong>with</strong>out<br />

<strong>in</strong>terruption at the first signs <strong>of</strong> HFS is likely to<br />

result <strong>in</strong> progression <strong>of</strong> the <strong>syndrome</strong>. To deliver<br />

capecitab<strong>in</strong>e therapy as effectively as possible<br />

requires that <strong>patients</strong> become active, educated<br />

participants <strong>in</strong> their own treatment, and that side<br />

effects be prevented, recognised and managed<br />

adeptly (Gerbrecht, 2003). An example <strong>of</strong> manag<strong>in</strong>g<br />

a patient <strong>with</strong> MCRC who develops HFS while<br />

receiv<strong>in</strong>g capecitab<strong>in</strong>e is shown <strong>in</strong> Fig. 2.<br />

Patients should, therefore, be made aware <strong>of</strong> the<br />

first signs and symptoms <strong>of</strong> HFS and <strong>in</strong>structed,<br />

upon development <strong>of</strong> grade 2 or 3 symptoms, to<br />

ARTICLE IN PRESS<br />

<strong>Management</strong> <strong>of</strong> <strong>hand</strong>-<strong>foot</strong> <strong>syndrome</strong> S35<br />

Table 2 Frequency <strong>of</strong> HFS (all grades and grade 3) <strong>with</strong> oral capecitab<strong>in</strong>e vs. i.v. comparators <strong>in</strong> large phase II/<br />

phase III trials.<br />

Capecitab<strong>in</strong>e Comparator<br />

HFS (%) All grade Grade 3 All grade Grade 3<br />

Colorectal cancer<br />

Capecitab<strong>in</strong>e s<strong>in</strong>gle-agent vs. 5-FU/LV (Cassidy et al., 2002) 54 17 6 1<br />

XELOX (Cassidy et al., 2004a) vs. FOLFOX-4 (de Gramont et al., 2000) 36 3 29 0<br />

XELIRI (Patt et al., 2004) vs. FOLFIRI (Douillard et al., 2000) 41 6 17 0<br />

CAPOX vs. FUFOX (Arkenau et al., 2004) 30 1 27 0<br />

Breast cancer<br />

Capecitab<strong>in</strong>e+docetaxel vs. docetaxel (O’Shaughnessy et al., 2002) 64 24 8 1<br />

CAPOX=oxaliplat<strong>in</strong> on days 1&8+capecitab<strong>in</strong>e on days 1–14, every 3 weeks; FOLFIRI=ir<strong>in</strong>otecan on day 1+bolus 5-FU/LV, followed<br />

by 5-FU (22-hour <strong>in</strong>fusions) on days 1&2, every 2 weeks; FOLFOX=oxaliplat<strong>in</strong> on day 1+bolus 5-FU/LV, followed by 5-FU (22-hour<br />

<strong>in</strong>fusions) on days 1&2, every 2 weeks; FUFOX=oxaliplat<strong>in</strong>+bolus 5-FU/LV on days 1, 8, 15 and 22, every 5 weeks;<br />

XELIRI=ir<strong>in</strong>otecan on day 1+capecitab<strong>in</strong>e on days 1–14, every 3 weeks; XELOX=oxaliplat<strong>in</strong> on day 1+capecitab<strong>in</strong>e on days 1–14,<br />

every 3 weeks.<br />

<strong>in</strong>terrupt treatment until improved to grade 0 or 1.<br />

Treatment can be re-<strong>in</strong>itiated at that time, provid<strong>in</strong>g<br />

that the patient is not beyond day 14 <strong>of</strong> the<br />

cycle, <strong>in</strong> which case dos<strong>in</strong>g would resume after the<br />

scheduled 7-day rest period. If the symptoms<br />

persist or appear dur<strong>in</strong>g the rest period, dos<strong>in</strong>g<br />

for the next cycle is delayed until symptoms have<br />

resolved to grade 0 or 1. Doses are adjusted as<br />

directed <strong>in</strong> the capecitab<strong>in</strong>e package <strong>in</strong>sert.<br />

While HFS is manageable, if left un<strong>treated</strong> it can<br />

progress rapidly. React<strong>in</strong>g quickly to the signs and<br />

symptoms <strong>of</strong> HFS should prevent development <strong>of</strong><br />

grade 2/3 symptoms and, therefore, reduce the<br />

impact on dose <strong>in</strong>tensity. Nurses play a key role <strong>in</strong><br />

educat<strong>in</strong>g the patient how to recognise HFS, when<br />

to <strong>in</strong>terrupt treatment and giv<strong>in</strong>g <strong>in</strong>structions on<br />

adjust<strong>in</strong>g the dose to ma<strong>in</strong>ta<strong>in</strong> effective therapy<br />

<strong>with</strong> capecitab<strong>in</strong>e over the long term. It is<br />

particularly important that <strong>patients</strong> and nurses<br />

are fully aware that dose <strong>in</strong>terruption/reduction<br />

does not affect the overall antitumour efficacy <strong>of</strong><br />

capecitab<strong>in</strong>e (Cassidy and Twelves, 2000; Cassidy et<br />

al., 2002).<br />

Dose reduction after <strong>in</strong>terruption <strong>of</strong> therapy<br />

Discont<strong>in</strong>uation <strong>of</strong> capecitab<strong>in</strong>e usually leads to<br />

recovery over several days/weeks, depend<strong>in</strong>g on<br />

severity (Abushullaih et al., 2002). Follow<strong>in</strong>g<br />

discont<strong>in</strong>uation, the guidel<strong>in</strong>es for dose reduction<br />

should be the same as those applied to the general<br />

management <strong>of</strong> any adverse events occurr<strong>in</strong>g<br />

dur<strong>in</strong>g capecitab<strong>in</strong>e therapy (Table 3) and provided<br />

<strong>in</strong> the package <strong>in</strong>sert. HFS tends to resolve rapidly,<br />

<strong>of</strong>ten <strong>with</strong>out recurrence, but if it does recur and<br />

the patient is still benefit<strong>in</strong>g from therapy, the<br />

physician may decide to change the treatment


S36<br />

cycle. An example would be <strong>in</strong>creas<strong>in</strong>g the <strong>in</strong>terval<br />

between cycles to 2 weeks or chang<strong>in</strong>g the cycle<br />

length (e.g. 10 days on, 11 days <strong>of</strong>f).<br />

ARTICLE IN PRESS<br />

Table 3 Capecitab<strong>in</strong>e dose-modification scheme for all adverse events.<br />

NCI-CTC toxicity<br />

grade<br />

Ma<strong>in</strong>ta<strong>in</strong><br />

<strong>in</strong>terruption<br />

Appearance <strong>of</strong><br />

toxicity<br />

Adjustment dur<strong>in</strong>g therapy Adjustment for<br />

next cycle<br />

(relative to<br />

<strong>in</strong>itial dose)<br />

2 1st Interrupt until resolved to grade 0/1 100%<br />

2nd Interrupt until resolved to grade 0/1 75%<br />

3rd Interrupt until resolved to grade 0/1 50%<br />

4th Discont<strong>in</strong>ue drug permanently<br />

3 1st Interrupt until resolved to grade 0/1 75%<br />

2nd Interrupt until resolved to grade 0/1 50%<br />

3rd Discont<strong>in</strong>ue drug permanently<br />

4 a<br />

1st Discont<strong>in</strong>ue drug permanently or <strong>in</strong>terrupt until<br />

resolved to grade 0/1 b<br />

50%<br />

NCI-CTC, National Cancer Institute Common Toxicity Criteria.<br />

a<br />

Not applicable to HFS.<br />

b<br />

At discretion <strong>of</strong> the cl<strong>in</strong>ician.<br />

NO<br />

55-year old woman <strong>with</strong> MCRC<br />

Initiate treatment <strong>with</strong> oral capecitab<strong>in</strong>e<br />

(1250 mg/m 2 twice daily on days 1–14, every 3 weeks)<br />

1st episode <strong>of</strong> grade 2 HFS<br />

Interrupt capecitab<strong>in</strong>e treatment<br />

Does HFS resolve to grade 0/1?<br />

YES<br />

Re<strong>in</strong>troduce capecitab<strong>in</strong>e<br />

at 1250 mg/m twice daily<br />

Discont<strong>in</strong>ue drug permanently<br />

OR<br />

Interrupt until resolved to grade 0/1<br />

(at the discretion <strong>of</strong> the cl<strong>in</strong>ician)<br />

1st episode <strong>of</strong> grade 4 HFS OR<br />

3rd episode <strong>of</strong> grade 3 HFS<br />

Ma<strong>in</strong>ta<strong>in</strong><br />

<strong>in</strong>terruption<br />

Ma<strong>in</strong>ta<strong>in</strong><br />

<strong>in</strong>terruption<br />

1st episode <strong>of</strong> grade 3 HFS OR<br />

2nd episode <strong>of</strong> grade 2 HFS<br />

NO<br />

Interrupt capecitab<strong>in</strong>e treatment<br />

Does HFS resolve to grade 0/1?<br />

YES<br />

Re<strong>in</strong>troduce capecitab<strong>in</strong>e<br />

at 1000 mg/m twice daily<br />

2nd episode <strong>of</strong> grade 3 HFS<br />

OR 3rd episode <strong>of</strong> grade 2 HFS<br />

NO<br />

Interrupt capecitab<strong>in</strong>e treatment<br />

Does HFS resolve to grade 0/1?<br />

YES<br />

Re<strong>in</strong>troduce capecitab<strong>in</strong>e<br />

at 625 mg/m twice daily<br />

Y. Lassere, P. H<strong>of</strong>f<br />

Figure 2 Example <strong>of</strong> manag<strong>in</strong>g a patient <strong>with</strong> MCRC who develops HFS dur<strong>in</strong>g treatment <strong>with</strong> capecitab<strong>in</strong>e s<strong>in</strong>gle-agent<br />

therapy.<br />

When the guidel<strong>in</strong>es for dose <strong>in</strong>terruption and<br />

dose reduction are followed, hospitalisations are<br />

rare. In a recently presented study <strong>of</strong> capecitab<strong>in</strong>e


vs. 5-FU/LV (Mayo Regimen) as adjuvant therapy for<br />

<strong>patients</strong> <strong>with</strong> Dukes’ C colon cancer, only two<br />

capecitab<strong>in</strong>e-<strong>treated</strong> <strong>patients</strong> required hospitalisation<br />

(for 1 day) (Cassidy et al., 2004b;<br />

Scheithauer et al., 2003).<br />

Supportive measures<br />

There are few supportive measures that have<br />

proven effectiveness <strong>in</strong> controll<strong>in</strong>g symptoms. Use<br />

<strong>of</strong> topical emollients and creams would appear to<br />

be a prudent prophylactic and symptomatic treatment<br />

at the first signs <strong>of</strong> grade 1 HFS (Gerbrecht,<br />

2003). Regular use <strong>of</strong> a topical petroleum-lanol<strong>in</strong><br />

based o<strong>in</strong>tment <strong>with</strong> antiseptic hydroxyqu<strong>in</strong>ol<strong>in</strong>e<br />

sulphate applied 3-times daily has been reported to<br />

alleviate the symptoms <strong>of</strong> HFS <strong>in</strong>duced by various<br />

chemotherapeutic agents (<strong>in</strong>clud<strong>in</strong>g capecitab<strong>in</strong>e)<br />

(Ch<strong>in</strong> et al., 2001). It should be noted that,<br />

anecdotally, some people are allergic to lanol<strong>in</strong>based<br />

products. Nevertheless, dose <strong>in</strong>terruption<br />

and, if necessary, dose reduction should rema<strong>in</strong> the<br />

primary tool <strong>in</strong> HFS management.<br />

As a general recommendation, symptoms can<br />

<strong>of</strong>ten be relieved by:<br />

immers<strong>in</strong>g the <strong>hand</strong>s and feet <strong>in</strong> cool water<br />

avoid<strong>in</strong>g extremes <strong>of</strong> temperature, pressure, and<br />

friction on the sk<strong>in</strong><br />

cushion<strong>in</strong>g sore sk<strong>in</strong> <strong>with</strong> s<strong>of</strong>t pads<br />

topical wound care and consultation <strong>with</strong> a<br />

dermatologist for any blister<strong>in</strong>g or ulceration<br />

(Gerbrecht, 2003).<br />

Topical (Esteve et al., 1995; Gordon et al., 1995;<br />

Komamura et al., 1995; Vakalis et al., 1998; Vukelja<br />

et al., 1989) or systemic (Brown et al., 1991; Esteve<br />

et al., 1995; Hellier et al., 1996; H<strong>of</strong>f et al., 1998;<br />

Titgan, 1997) corticosteroids have been reported to<br />

be useful for prophylaxis and treatment <strong>of</strong> HFS<br />

<strong>in</strong>duced by a range <strong>of</strong> different drugs, although<br />

their use <strong>in</strong> capecitab<strong>in</strong>e-associated HFS is unproven.<br />

While steroids are capable <strong>of</strong> reduc<strong>in</strong>g<br />

<strong>in</strong>flammation, their long-term use can lead to<br />

th<strong>in</strong>n<strong>in</strong>g <strong>of</strong> the sk<strong>in</strong>, which is likely to cause<br />

more symptoms. Diemethysulfoxide 99% 4-times<br />

daily has been reported to be <strong>of</strong> benefit <strong>in</strong><br />

<strong>patients</strong> receiv<strong>in</strong>g liposomal doxorubic<strong>in</strong> (Lopez et<br />

al., 1999) but is aga<strong>in</strong> unproven <strong>with</strong> capecitab<strong>in</strong>e<strong>in</strong>duced<br />

HFS.<br />

The use <strong>of</strong> pyridox<strong>in</strong>e (vitam<strong>in</strong> B6), at a highly<br />

variable dose, has been anecdotally reported to be<br />

useful for prophylaxis and treatment <strong>of</strong> HFS<br />

<strong>in</strong>duced by various agents, e.g. capecitab<strong>in</strong>e, 5-<br />

FU, docetaxel (Andres et al., 2003; Beveridge et<br />

al., 1990; Fabian et al., 1990; Lauman and<br />

Mortimer, 2001; Van Cutsem et al., 2000; Vukelja<br />

ARTICLE IN PRESS<br />

<strong>Management</strong> <strong>of</strong> <strong>hand</strong>-<strong>foot</strong> <strong>syndrome</strong> S37<br />

et al., 1989, 1993). One study <strong>in</strong> dogs showed that<br />

prophylactic pyridox<strong>in</strong>e significantly delayed the<br />

onset and severity <strong>of</strong> HFS <strong>in</strong>duced by liposomal<br />

pegylated doxorubic<strong>in</strong>, allow<strong>in</strong>g a higher cumulative<br />

dose to be delivered (Vail et al., 1998). As<br />

pyridox<strong>in</strong>e is a safe nutritional supplement, its<br />

prophylactic use might appear appeal<strong>in</strong>g, although<br />

efficacy needs to be proven prospectively <strong>in</strong><br />

controlled trials before rout<strong>in</strong>e treatment can be<br />

recommended. Such studies need to confirm no<br />

effect on capecitab<strong>in</strong>e efficacy and whether effective<br />

prophylaxis might permit adm<strong>in</strong>istration <strong>of</strong> a<br />

higher cumulative dose <strong>of</strong> capecitab<strong>in</strong>e.<br />

An <strong>in</strong>terest<strong>in</strong>g adjunctive treatment <strong>with</strong> capecitab<strong>in</strong>e<br />

might be concurrent use <strong>of</strong> celecoxib, a<br />

COX-2 antagonist used <strong>in</strong>cidentally for control <strong>of</strong><br />

pa<strong>in</strong> and arthritis. In a retrospective series <strong>of</strong> 67<br />

<strong>patients</strong> receiv<strong>in</strong>g capecitab<strong>in</strong>e, the addition <strong>of</strong><br />

celecoxib appeared to reduce the rate <strong>of</strong><br />

HFS4grade 1 (from 34% <strong>with</strong> capecitab<strong>in</strong>e alone<br />

to 13% <strong>with</strong> capecitab<strong>in</strong>e plus celecoxib), as<br />

well as diarrhoea4grade 2 (from 29% to 3%) (L<strong>in</strong><br />

et al., 2002). However, <strong>in</strong> this series, most <strong>patients</strong><br />

required dose reductions. This retrospective<br />

study has generated a hypothesis that needs to<br />

be tested <strong>in</strong> a prospective randomised sett<strong>in</strong>g.<br />

Until then, there is <strong>in</strong>sufficient evidence to<br />

recommend the use <strong>of</strong> celecoxib <strong>in</strong> the prophylaxis<br />

<strong>of</strong> HFS.<br />

Conclusions<br />

While HFS is a common and <strong>in</strong>convenient side effect<br />

<strong>with</strong> capecitab<strong>in</strong>e, the condition is easily managed<br />

<strong>with</strong> dose <strong>in</strong>terruption and, if necessary, dose<br />

reductions. Prompt <strong>in</strong>tervention means that <strong>patients</strong><br />

do not need to <strong>in</strong>terrupt treatment for long<br />

periods and can, therefore, cont<strong>in</strong>ue to benefit<br />

from capecitab<strong>in</strong>e therapy.<br />

Oncology nurses, through patient education and<br />

close cl<strong>in</strong>ical assessment, play a crucial role <strong>in</strong> the<br />

early identification and prevention <strong>of</strong> progressive<br />

pa<strong>in</strong>, loss <strong>of</strong> the sk<strong>in</strong>’s <strong>in</strong>tegrity, and disability. In<br />

addition, once HFS is identified, the nurses’ role <strong>in</strong><br />

patient education, support, and symptom management<br />

is essential to ma<strong>in</strong>ta<strong>in</strong> effective patient care<br />

and, <strong>in</strong> some cases, the patient’s will<strong>in</strong>gness to<br />

cont<strong>in</strong>ue therapy. Table 4 summarises some <strong>of</strong> the<br />

key preventative and management techniques<br />

for HFS.<br />

Patient education needs to highlight the need for<br />

report<strong>in</strong>g side effects and <strong>in</strong>terrupt<strong>in</strong>g therapy<br />

when required. Written materials should be provided<br />

for the patient to re<strong>in</strong>force the teach<strong>in</strong>g


S38<br />

completed at cl<strong>in</strong>ic visits. These materials should<br />

<strong>in</strong>corporate:<br />

1. Instructions on dos<strong>in</strong>g, <strong>in</strong>clud<strong>in</strong>g how many<br />

tablets to take <strong>with</strong> each dose and <strong>in</strong>formation<br />

on the tim<strong>in</strong>g and importance <strong>of</strong> fluid <strong>in</strong>take<br />

<strong>with</strong> medication.<br />

2. A diary or calendar to track dos<strong>in</strong>g and side<br />

effects.<br />

3. Rem<strong>in</strong>ders stress<strong>in</strong>g the importance <strong>of</strong> call<strong>in</strong>g<br />

promptly and <strong>in</strong>terrupt<strong>in</strong>g treatment at the first<br />

signs <strong>of</strong> grade 2 toxicity.<br />

4. Contact numbers for oncology nurses and physicians.<br />

These materials should be accompanied by<br />

weekly follow-up phone calls for the first few<br />

weeks <strong>of</strong> therapy to ensure that <strong>patients</strong> fully<br />

understand their role <strong>in</strong> report<strong>in</strong>g side effects and<br />

<strong>with</strong>hold<strong>in</strong>g therapy, as <strong>in</strong>structed.<br />

In conclusion, the nurses’ role <strong>in</strong> manag<strong>in</strong>g HFS <strong>in</strong><br />

capecitab<strong>in</strong>e-<strong>treated</strong> <strong>patients</strong> is pivotal for both its<br />

prevention and palliation.<br />

References<br />

Abushullaih, S., Saad, E.D., Munsell, M., H<strong>of</strong>f, P.M., 2002.<br />

Incidence and severity <strong>of</strong> HFS <strong>in</strong> colorectal cancer <strong>patients</strong><br />

<strong>treated</strong> <strong>with</strong> capecitab<strong>in</strong>e: a s<strong>in</strong>gle-<strong>in</strong>stitution experience.<br />

Cancer Investigation 20 (1), 3–10.<br />

ARTICLE IN PRESS<br />

Table 4 Summary <strong>of</strong> preventative and management techniques for HFS.<br />

Y. Lassere, P. H<strong>of</strong>f<br />

1 Ensure patient is able to recognise HFS (and other adverse events) by education and use <strong>of</strong> written<br />

<strong>in</strong>formation available from the manufacturer or otherwise.<br />

2 Recommend preventative emollient use (e.g. <strong>hand</strong> cream).<br />

3 Ensure that the patient follows dose <strong>in</strong>terruption/reduction guidel<strong>in</strong>es carefully, which apply to all<br />

adverse events. Make sure the patient understands the importance <strong>of</strong> this prior to start<strong>in</strong>g treatment<br />

and has written <strong>in</strong>formation available from the manufacturer or otherwise.<br />

4 Ensure the patient has telephone access to a key person, e.g. oncology nurse, dur<strong>in</strong>g <strong>of</strong>fice hours <strong>in</strong> the<br />

event <strong>of</strong> need to answer questions or concerns.<br />

5 Follow up <strong>with</strong> the patient (by phone) to determ<strong>in</strong>e the outcome <strong>of</strong> HFS and provide other supportive<br />

advice.<br />

6 Reassure the patient that there are no permanent complications once adverse events have resolved.<br />

7 Advise <strong>patients</strong> to use topical emollients and creams to keep the sk<strong>in</strong> moist.<br />

8 Recommend <strong>patients</strong> to avoid extremes <strong>in</strong> temperature, pressure, and friction <strong>of</strong> sk<strong>in</strong>.<br />

9 Mention that relief can be achieved by submerg<strong>in</strong>g <strong>hand</strong>s and feet <strong>in</strong> cool water.<br />

10 Suggest cushion<strong>in</strong>g sore sk<strong>in</strong> <strong>with</strong> s<strong>of</strong>t pads or socks and keep<strong>in</strong>g the sk<strong>in</strong> exposed to air whenever<br />

possible to prevent excess sweat<strong>in</strong>g.<br />

11 Refer <strong>patients</strong> to a dermatologist if blister<strong>in</strong>g or ulceration occurs.<br />

12 As a last resort, if treatment is <strong>of</strong> benefit, change the dos<strong>in</strong>g regimen.<br />

13 Discont<strong>in</strong>ue treatment if HFS is severe and unresolved by dose <strong>in</strong>terruption/reduction.<br />

Andres, R., Mayordomo, J.I., Isla, D., Yubero, A., Saenz, A.,<br />

Alvarez, I., Polo, E., Lara, R., Escudero, P., Tres, A., 2003.<br />

Capecitab<strong>in</strong>e plus gemcitab<strong>in</strong>e is an active comb<strong>in</strong>ation for<br />

<strong>patients</strong> <strong>with</strong> metastatic breast cancer refractory to anthracycl<strong>in</strong>es<br />

and taxanes. Proceed<strong>in</strong>gs <strong>of</strong> the American Society <strong>of</strong><br />

Cl<strong>in</strong>ical Oncology 22, 89 (abstract 356).<br />

Arkenau, H.-T., Schmoll, H., Kubicka, S., Seufferle<strong>in</strong>, T., Reichardt,<br />

P., Freier, W., Graeven, U., Grothey, A., Porschen, R.,<br />

2004. Phase III trial <strong>of</strong> <strong>in</strong>fusional 5-fluorouracil/fol<strong>in</strong>ic acid<br />

plus oxaliplat<strong>in</strong> (FUFOX) versus capecitab<strong>in</strong>e plus oxaliplat<strong>in</strong><br />

(CAPOX) as first l<strong>in</strong>e treatment <strong>in</strong> advanced colorectal<br />

carc<strong>in</strong>oma (ACRC): results <strong>of</strong> an <strong>in</strong>terim safety analysis.<br />

Proceed<strong>in</strong>gs <strong>of</strong> the American Society <strong>of</strong> Cl<strong>in</strong>ical Oncology 23,<br />

257 (abstract 3546).<br />

Asgari, M.M., Haggerty, J.G., McNiff, J.M., Milstone, L.M.,<br />

Schwartz, P.M., 1999. Expression and localization <strong>of</strong> thymid<strong>in</strong>e<br />

phosphorylase/platelet-derived endothelial cell growth<br />

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