Management of hand-foot syndrome in patients treated with ...

S34
type of cytotoxic agent used. High rates of severe
HFS have been reported with pegylated liposomal
doxorubicin (D’Agostino et al., 2003), and the
condition appears to be more common and severe
(including infection and septicaemia) than in
patients receiving capecitabine.
Frequency of HFS with capecitabine
HFS (all grades) occurred in approximately 50% of
patients in early phase II studies of capecitabine
single-agent therapy in metastatic breast cancer
(MBC) (Blum et al., 1999) and metastatic colorectal
cancer (MCRC) (Abushullaih et al., 2002; Van
Cutsem et al., 2000), with 10% of patients
experiencing severe (grade 3) HFS. A higher rate
of severe HFS (52%, 12/23 cases) was reported in a
Korean study of capecitabine in combination with
docetaxel (Park et al., 2003), although this may be
related to the ability of docetaxel to cause both
HFS and nail toxicity.
Because HFS is subjectively reported, standardisation
is a challenge and cross-study comparison is
ARTICLE IN PRESS
Table 1 HFS grading according to National Cancer Institute (NCI) (Nagore et al., 2000), World Health
Organisation (WHO) criteria (Nagore et al., 2000), and as used in capecitabine clinical trials (Blum et al., 1999).
NCI grade NCI definition
1 Skin changes or dermatitis without pain, e.g. erythema, peeling
2 Skin changes with pain, not interfering with function
3 Skin changes with pain interfering with function
WHO
grade
WHO definition Clinical lesion Histological findings
1 Dysesthesia/paraesthesia, tingling in
the hands and feet
2 Discomfort in holding objects and upon
walking, painless swelling or erythema
3 Painful erythema and swelling of palms
and soles, periungual erythema and
swelling
4 Desquamation, ulceration, blistering,
severe pain
Clinical
trial
grade *
Clinical domain Functional domain
Erythema Dilated blood vessels of the
superficial dermal plexus
1+oedema
2+fissuration Isolated necrotic keratinocytes in
higher layer of the epidermis
3+blister Complete epidermal necrosis
1 Numbness, dysesthesia/paraesthesia,
tingling, painless swelling or erythema
Discomfort that does not disrupt normal activities
2 Painful erythema, with swelling Discomfort that affects activities of daily living
3 Moist desquamation, ulceration,
Severe discomfort, unable to work or perform
blistering, severe pain
activities of daily living
* Note: Grade to correspond to high intensity on either clinical or functional domain.
Y. Lassere, P. Hoff
difficult. A reliable appraisal of the frequency and
severity of HFS has been obtained in phase III trials
of capecitabine because of the larger numbers of
patients enrolled.
Colorectal cancer
As discussed in the previous two articles in this
Supplement, capecitabine has demonstrated a
superior safety profile compared with 5-FU/LV in
phase III trials of patients with MCRC (Cassidy et al.,
2002); HFS was the only side effect occurring
significantly more frequently on capecitabine (54%
vs. 6%) with grade 3 HFS affecting only 17% of
capecitabine-treated patients (Table 2). In addition,
the lower dose of capecitabine used in
combinations with oxaliplatin (XELOX/CAPOX) or
irinotecan (XELIRI/CAPIRI) appears to result in a
reduced rate of HFS compared with single-agent
therapy (Cassidy et al., 2004a; Patt et al., 2004).
Breast cancer
In a large phase III trial comparing capecitabine in
combination with i.v. docetaxel vs. i.v. docetaxel
alone, the capecitabine/docetaxel combination