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`Antineoplastic therapy-induced palmar plantar
`erythrodysesthesia ('hand-foot') syndrome:
`Incidence, recognition and...
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`Article in American Journal of Clinical Dermatology · July 2000
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`Eduardo Nagore
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`
`REVIEW ARTICLE
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`Am J Clin Dermatol 2000 Jul-Aug; 1 (4): 225-234
`1175-0561/00/0007-0225/$20.00/0
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`© Adis International Limited. All rights reserved.
`
`Antineoplastic Therapy–Induced
`Palmar Plantar Erythrodysesthesia
`(‘Hand-Foot’) Syndrome
`Incidence, Recognition and Management
`
`Eduardo Nagore,1 Amelia Insa2 and Onofre Sanmartín1
`1 Instituto Valenciano de Oncología, Valencia, Spain
`2 Hospital Universitario Dr Peset Aleixandre, Valencia, Spain
`
`Contents
` . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 225
`Abstract
`1.
`Incidence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 226
`2. Clinical Presentation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 226
`3. Pathology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 227
`4. Pathogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 228
`5. Differential Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 228
`6. Specific Comments on Relevant Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 228
`6.1 Fluorouracil . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 229
`6.2 Fluorouracil Analogues . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 229
`6.2.1 Capecitabine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 229
`6.2.2 Tegafur
` . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 230
`6.3 Cytarabine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 230
`6.4 Doxorubicin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 230
`6.4.1 Liposome-Encapsulated Doxorubicin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 231
`6.5 Docetaxel
` . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 231
`6.6 Other Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 231
`7. Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 231
`8. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 232
`
`Abstract
`
`Palmar plantar erythrodysesthesia (PPE) is a distinctive and relatively frequent toxic reaction related to some
`chemotherapeutic agents. Doxorubicin, cytarabine, docetaxel, and fluorouracil are the most frequently implicated
`agents. PPE seems to be dose dependent and both peak drug concentration and total cumulative dose determine
`its occurrence.
`PPE presents as a painful erythema, often preceded by paresthesia, located on the palms and soles in the
`context of treatment with chemotherapy. Histologically, PPE shows few specific findings. Mild spongiosis,
`scattered necrotic and dyskeratotic keratinocytes and vacuolar degeneration of the basal layer is seen. Dermal
`changes in most cases include dilated blood vessels, papillary edema, and a sparse superficial perivascular
`lymphohistiocytic infiltrate can be found in varying degrees in the epidermis.
`Withdrawal or dose reduction of the implicated drug usually gives rise to amelioration of the symptoms.
`Supportive treatments such as topical wound care, elevation, and cold compresses may help to relieve the pain.
`Use of systemic corticosteroids, pyridoxine (vitamin B6), blood flow reduction, and, recently, topical 99%
`dimethyl-sulfoxide have been used with variable outcomes. It could be of interest to consider them as preventive
`measures when drugs with a strong association with PPE are going to be administered.
`
`

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`226
`
`Nagore et al.
`
`Table I. Agents that have been associated with palmar plantar erythro-
`dysesthesia
`
`Most frequently associated
`Cytarabine
`Docetaxel
`Doxorubicin and liposome-encapsulated doxorubicin
`Fluorouracil
`
`Less frequently associated
`Capecitabine
`Cisplatin
`Cyclophosphamide
`Daunorubicin
`Doxifluridine
`Etoposide
`Floxuridine
`Hydroxyurea (hydroxycarbamide)
`Mercaptopurine
`Methotrexate
`Mitotane
`Paclitaxel
`Tegafur
`Vinorelbine
`
`1. Incidence
`
`Palmar plantar erythrodysesthesia (PPE) is a cutaneous drug
`reaction that is most often induced by chemotherapeutic agents.
`It is important to be aware of this reaction since it can be a dose-
`limiting toxicity.
`PPE was firstly described by Zuehlke in 1974 associated with
`mitotane therapy for hypernephroma.[1] Subsequently, many re-
`ports, using different terms for the condition (acral erythema,
`hand-foot syndrome, palmar-plantar erythema, Burgdorf’s reac-
`tion, and toxic erythema of the palms and soles), have appeared
`in the literature.[2]
`Many drugs have been implicated as causing PPE. Cytarab-
`ine, doxorubicin, fluorouracil, and docetaxel are the most com-
`monly involved drugs, although many others have also been re-
`ported to cause this condition (table I).[1-89] Nevertheless, it is
`very difficult to assess the real relationship between PPE and
`some agents since most cases are described in the context of dif-
`ferent multidrug regimens.
`The actual incidence of PPE is very difficult to determine
`because most reports in literature are isolated case reports or short
`case series, and when a drug is evaluated by oncologists in large
`series, its cutaneous reactions are usually mentioned with few
`details. However, an estimation can be made by considering some
`case series in which PPE has been found to occurs in 6 to 64% of
`patients treated with different chemotherapy regimens.[34,89] In
`
`most cases (nearly 80%), patients present with less severe grades
`of PPE [1 and 2 of WHO criteria and 1 of the National Cancer
`Institute (NCI) criteria (these criteria are described in section
`2)],[18,62] although the severity is very variable depending on the
`chemotherapy regimen, and some series have reported more fre-
`quent severe toxicity.[57]
`We review herein some of the major aspects of PPE and
`detailed information in those drugs which are more frequently
`associated with this reaction. To this end, we have systematically
`reviewed articles obtained from MEDLINE published between
`1966 and March 2000 using all the synonymous for PPE men-
`tioned earlier as key words.
`
`2. Clinical Presentation
`
`Whatever the causative agent, the clinical presentation of
`PPE is very similar and is distinct from other adverse skin reac-
`tions.[8,19,23,26,27,34,38,55,59,65,66,73,88-91]
`Most patients present with a prodrome of dysesthesia, usually
`a tingling sensation of the palms and soles. In a few days, it pro-
`gresses to a burning pain in conjunction with well-defined swell-
`ing and erythema. The erythema is symmetric, and sometimes
`more marked over the pads of the distal phalanges. Some patients
`may develop alternating bands of erythema over joint surfaces or
`have periungual skin involvement. The hands are usually more
`severely affected than the feet, and may be the only area involved
`(figs 1 and 2). Rarely, erythema may also be noted outside the
`palmar and plantar regions.[29,47] Some patients may only present
`with fine desquamation with or without erythema. A bullous vari-
`ant has also been described, specifically associated with cytarab-
`
`Fig. 1. Palmar edema and erythema, with fine desquamation (palmar plantar
`erythrodysesthesia WHO grade 2).
`
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`Palmar Plantar Erythrodysesthesia
`
`227
`
`from WHO and NCI (table II). These classifications are of interest
`because, according to some protocols, a high degree of severity
`may necessitate a dose reduction for some drugs. When WHO
`grade 3 or 4 or NCI grade 3 toxicity first appears, or WHO grade
`2 toxicity appears repeatedly, the dosage should be decreased to
`50 or 75% of the initial dosage, or the drug discontinued. Drug
`withdrawal is preferable if toxicity of these grades recurs even
`after the dosage is decreased.
`
`3. Pathology
`
`There are no studies with a large series which describe his-
`tologic findings. However, some case reports include histologic
`evaluation (table III).[8,15,19,23,24,26,27,34,38,50,59,63,65,66,73,79,87-90,92]
`PPE is a clinical variant of a cytotoxic reaction that primarily
`affects keratinocytes, and the histopathologic findings are similar
`to those seen with direct toxic reactions, such as radiation recall
`dermatitis, localized epidermal necrolysis or generalized epider-
`mal necrolysis. All these adverse skin reactions demonstrate the
`same basic histologic pattern of an interface dermatitis with a
`cell-poor infiltrate and a variable degree of epidermal necrosis.[92]
`Early or mild cytotoxic reactions (PPE WHO grades 1 and
`2) show isolated necrotic basal keratinocytes (fig. 4). In severe
`cytotoxic reactions (WHO grades 3 and 4) the entire basal layer
`is destroyed, and a blister may form together with complete epi-
`dermal necrosis (fig. 5).[15]
`Dermal changes in most cases include dilated blood vessels,
`papillary edema, and a sparse superficial perivascular lympho-
`histiocytic infiltrate. Eccrine glands may also be involved in some
`
`Fig. 3. Palmar edema, erythema, and blisters in the lateral aspects of the digits
`(palmar plantar erythrodysesthesia WHO grade 4).
`
`Fig. 2. Palmar erythema, with fissuration (palmar plantar erythrodysesthesia WHO
`grade 3).
`
`ine or methotrexate.[39,76] However, in our experience, bullous PPE
`may appear with other agents such as fluorouracil or doxorubicin
`(fig. 3). Bullous PPE is merely a severe form of this entity. The
`lesions tend to worsen if therapy is continued, and tenderness and
`associated edema may cause restriction of the fine movements of
`the fingers.[37] The erythema becomes darker or violaceous, and
`spreads to involve the entire surface of the palms and soles. The
`pain may be so severe that daily activities are limited. If the drug
`responsible is stopped within a few days of the reactions appear-
`ing a gradual clearing of symptoms will occur over a period of 2
`weeks. Areas of pallor with blisters develop, and eventually des-
`quamate with extensive, but superficial, exfoliation. In some pa-
`tients, when treatment is continued despite the appearance of the
`PPE, lesions may evolve into a palmoplantar keratoderma.[44,65]
`In rare instances, long term sequelae may occur despite cessation
`of chemotherapy, with persistence of abnormal sensation and ap-
`pearance of the affected digits.[7]
`PPE seems to be dose dependent. Both peak drug concentra-
`tion and total cumulative dose determine its occurrence because
`regimens with either bolus (short term) infusions or continuous
`low dosage administration can induce the reaction in a dose-de-
`pendent manner.[6,40,47,51] In general, the reaction happens sooner
`(from 24 hours to 2 or 3 weeks) and more severely with bolus or
`short term chemotherapy than with low-dose continuous infu-
`sions (up to 2 to 10 months). Rechallenge of patients with the
`causative chemotherapeutic agents using similar dosage sched-
`ules has lead to recurrence of the reaction in most but not all
`patients.[25,29,52,61]
`There are a number of different classifications for grading the
`degree of severity of PPE, but the two most often used are those
`
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`228
`
`Nagore et al.
`
`Table II. Classification of palmar plantar erythrodysesthesia severity according to WHO and National Cancer Institute (NCI) criteria
`
`WHO criteria
`grade
`1
`
`2
`
`3
`
`4
`
`definition
`Dysesthesia/paresthesia, tingling in the hands and feet
`
`NCI criteria
`grade
`1
`
`definition
`Skin changes or dermatitis without pain (e.g., erythema,
`peeling)
`
`Discomfort in holding objects and upon walking, painless
`swelling or erythema
`Painful erythema and swelling of palms and soles,
`periungual erythema and swelling
`Desquamation, ulceration, blistering, severe pain
`
`2
`
`3
`
`Skin changes with pain, not interfering with function
`
`Skin changes with pain interfering with function
`
`cases. Eccrine squamous syringometaplasia may also be seen in
`some cases of severe PPE (WHO grades 3 and 4) (fig. 6).[66,90]
`
`4. Pathogenesis
`
`The cause of PPE is currently unknown. Formerly, as there are
`some clinical and histologic similarities between PPE and acute
`graft-versus-host disease (AGVHD) it has been suggested that
`chemotherapeutic drug-induced changes in cell surface receptors
`might be able to induce host-versus-altered host changes.[9] How-
`ever, currently, the most likely and accepted hypothesis is a direct
`toxic effect of the chemotherapeutic drug against epidermal cells
`because of the dose-relationship and the common histopathologic
`findings with other entities produced by direct toxicity.[92,93] It is
`of interest that PPE is a dose-limiting factor in some treatment
`regimens, when other toxicities can be modulated. Nevertheless,
`there is not a clear explanation for its particular distribution. Spe-
`cific features of the hands and feet could play a role in its location.
`The thick stratum corneum, the temperature gradient, the vascular
`anatomy, the rapidly dividing epidermis, the absence of seba-
`ceous glands and hairs follicles, the high concentration of eccrine
`glands, and wide dermal papillae may all be important in the
`pathogenesis.[88,89] Other traits must be involved since there is no
`direct relationship between drug, dosage, and severity in all pa-
`tients. Concomitant drug therapy, transfusions, blood transfu-
`sions, and the metabolic status of the patient may contribute as
`well.[24,89]
`
`5. Differential Diagnosis
`
`Although the diagnosis is usually evident, it may be difficult
`to differentiate PPE from AGVHD when the reaction occurs in a
`patient who has received a bone marrow transplant.[89-90] More-
`over, both disorders may occur simultaneously. Other signs of the
`disease may provide clues in the case of AGVHD, such as gas-
`trointestinal abnormalities (including diarrhea and abdominal
`pain), elevated liver enzymes levels, and a rapid decline in the T
`helper cell/suppressor cell ratio.[90] However, in the absence of
`extracutaneous involvement, AGVHD can appear identical to
`PPE.[89] The involvement of the palms and soles in AGVHD is
`usually a diffuse macular erythema which may form papules, in
`contrast to the areas of well-defined intense erythema and edema
`that are seen in PPE.[90] Histologically, both PPE and AGVHD
`are indistinguishable in their early stages. Serial biopsies may
`sometimes be needed to differentiate between them.[24] The pre-
`sence of degenerate keratinocytes, at all levels of the epidermis
`and associated with adjacent lymphocytes (satellite cell necrosis),
`are characteristic of AGVHD.[94] In contrast, the finding of squa-
`mous syringometaplasia suggests PPE.[90]
`It is important to distinguish between these 2 entities because
`they require different treatment. Moreover, cyclosporine infu-
`sion, which is one of the most important treatments for AGVHD,
`is reported to worsen the pain of PPE possibly due the alcohol
`present in the infusion.[45]
`
`6. Specific Comments on Relevant Drugs
`
`In this section we describe the more relevant and specific
`characteristics displayed by the drugs associated with a high in-
`
`Table III. Histologic grades with their corresponding clinical expression (related to WHO criteria)
`
`Grade
`1
`2
`3
`4
`
`Clinical lesion
`Erythema
`1 + edema
`2 + fissuration
`3 + blister
`
`Histologic findings
`Dilated blood vessels of the superficial dermal plexus
`
`Isolated necrotic keratinocytes in higher layer of the epidermis
`Complete epidermal necrosis
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`Palmar Plantar Erythrodysesthesia
`
`229
`
`of PPE was almost doubled when fluorouracil was given by CI.
`Interestingly, female patients and older patients had a signifi-
`cantly higher risk of PPE.[54] Popescu et al.[62] also reported an
`overall higher incidence of PPE in women, however, they did not
`observe any difference in age-related toxicity for PPE.
`The mechanism by which fluorouracil causes PPE is un-
`known. A strong correlation between this toxicity and high doses
`of fluorouracil has been postulated by some authors, on the basis
`of the incidence of PPE observed in high dose, short term, con-
`tinuous fluorouracil infusion studies.[30,77] It has also been sug-
`gested that fluorouracil has a cumulative effect on the skin, since
`some authors have described PPE appearing after a median num-
`ber of 9 treatment courses, corresponding to a median fluorouracil
`cumulative dosage of 18500 mg/m2.[18]
`Development of PPE usually leads to discontinuation of flu-
`orouracil, dosage reduction or delay of planned chemotherapy,
`with resolution of the skin manifestations.[18,25,81] In fact, since
`myelosuppresion can be modulated using CI regimen and
`leucovorin, PPE is the dose-limiting toxicity. Sometimes PPE
`occurring as a complication of fluorouracil therapy may result in
`symptoms and signs that continue for many months after with-
`drawal of the causative agent.[7]
`
`6.2 Fluorouracil Analogues
`
`6.2.1 Capecitabine
`Capecitabine is a rationally designed oral fluoropyrimidine
`carbonate that is activated by tumor cells into fluorouracil. It has
`been approved for the treatment of breast cancer that progresses
`after standard chemotherapy with paclitaxel and an anthracy-
`
`Fig. 5. Histopathologic findings in severe palmar plantar erythrodysesthesia (WHO
`grades 3 and 4): interface dermatitis, complete epidermal necrosis, blister formation, and
`reticular desquamation of the dermis can be seen.
`
`Fig. 4. Histopathologic findings in mild palmar plantar erythrodysesthesia (WHO grades
`1 and 2): interface dermatitis, isolated necrotic keratinocytes, vascular dilatation, and
`dermal edema can be seen.
`
`cidence of PPE. Tegafur, which has a relatively low incidence of
`PPE, has also been included to emphasize its different clinical
`behaviour to that of fluorouracil despite being one of its deriva-
`tives.
`
`6.1 Fluorouracil
`
`Fluorouracil is a fluoropyrimidine antimetabolite that under-
`goes complex intracellular metabolic activation to fluorodeoxy-
`uridine monophosphate (FdUMP), which inhibits thymidylate
`synthetase, and to fluoridine triphosphate (FTUP), which is in-
`corporated into RNA as a false base. The cytotoxicity of fluoro-
`uracil is relatively specific to the S-phase and the agent has been
`found to be effective in treating numerous types of solid tu-
`mors.[80]
`Dermatitis has been reported during treatment with fluoro-
`uracil and leucovorin (calcium folinate) in 10 to 24% of pa-
`tients,[11,18,41] but the incidence of PPE is variable and may range
`from 6 to 67%.[20,33,49,51,62] PPE occurs more often with pro-
`tracted infusion schedules of fluorouracil than when the agent is
`given as a bolus infusion.[51] However, it may also be seen in
`patients receiving a high dose leucovorin-modulated fluorouracil
`bolus.[56]
`A recent meta-analysis of all randomized trials that compared
`fluorouracil bolus with fluorouracil continuous infusion (CI),
`based on individual data from 1219 patients, was conducted to
`compare the toxicity of the 2 schedules of fluorouracil adminis-
`tration and to identify predictive factors for toxicity.[54] The over-
`all proportion of PPE was 34% for patients assigned to fluoroura-
`cil CI and 13% for patients assigned to fluorouracil bolus. The
`adjusted PPE relative risk was 1.87, which indicates that the risk
`
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`Nagore et al.
`
`6.3 Cytarabine
`
`Cytarabine is an analogue of deoxycytidine that is phosphor-
`ylated to an active metabolite, ara-C triphosphate. Ara-C triphos-
`phate inhibits DNA polymerase and is incorporated into DNA,
`resulting in strand breaks. Cytarabine is most active in hemato-
`logic malignancies in combination with other drugs.[80]
`PPE associated with cytarabine was first described by
`Burgdorf et al.[14] The incidence of this palmar-plantar reaction
`has varied from 14 to 33% in patients treated with cytarabine at
`dosages of 1000 mg/m2 or more,[40,61,78] especially if 8 or more
`doses at this level have been administered. Some patients treated
`with conventional cytarabine dosages of 100 mg/m2 have also
`developed PPE.[22,50,70] The incidence at this lower drug dosage
`level is not defined, but it is much lower than at high doses.
`Dysesthesias often herald the onset of the erythema, and the
`edema may be marked enough to limit finger motion. Some pa-
`tients also have fever, facial edema and erythema, and erythem-
`atous maculopapular rashes characteristic of a type I hypersensi-
`tivity reaction.[22,40,50] In most cases, only the hands are involved,
`but this reaction has also been described as involving only the
`ears.[48] The skin usually heals without scarring, and patients have
`been treated with cytarabine again without recurrence of this tox-
`icity.[70]
`
`6.4 Doxorubicin
`
`Doxorubicin is an anthracycline antibiotic that induces for-
`mation of covalent topoisomerase-DNA complexes, and prevents
`the enzyme from completing the relegation portion of the liga-
`tion-relegation reaction. Doxorubicin can also intercalate in be-
`tween base pairs of DNA and generate toxic oxygen free radicals.
`It is effective in a large variety of tumors. Numerous solid tumors
`are responsive, including neuroblastoma, soft tissue and bone sar-
`comas, breast cancer, ovarian cancer, bladder cancer, thyroid can-
`cer, small cell lung cancer, and gastric cancer. A large number of
`hematologic malignancies also respond to doxorubicin.[80]
`Doxorubicin is usually given in combination therapy, and
`mainly with drugs that also have been associated with the devel-
`opment of PPE, therefore is quite difficult to assess the exact
`incidence of PPE after doxorubicin administration. Some authors
`have reported an incidence of PPE as high as 29% associated with
`doxorubicin given as a monotherapy CI regimen.[67,69] PPE ap-
`peared in 22% of patients treated with doxorubicin 30 mg/m2/day
`by intravenous bolus on days 1 to 3 administered at 14-day inter-
`vals.[5] A regimen of weekly doxorubicin and fluorouracil CI re-
`sulted in 89% of patients developing PPE (WHO grade 1 to 3).[36]
`This incidence is higher than that reported for either doxorubicin
`
`Fig. 6. Squamous syringometaplasia in palmar plantar erythrodysesthesia.
`
`cline-containing regimen[80] and for the treatment of advanced
`colon cancer.[95]
`The dose-limiting toxicity of this agent using a chronic divided
`daily administration schedule is similar to long term fluorouracil
`infusions with mucositis, diarrhea, and PPE.[12,13,17,75] WHO
`grade 3 to 4 PPE has been reported in 10% of patients treated with
`capecitabine at 2510 mg/m2/day given for 2 weeks followed by a
`week rest period and repeated in 3-week cycles.[10]
`
`6.2.2 Tegafur
`Tegafur is a fluoropyrimidine analogue of fluorouracil (1-2-
`tetrahydrofluoril-5-fluorouracil), It is a fluorouracil prodrug
`which is metabolized in liver to fluorouracil by cytochrome P450
`and enzymatic hydrolysis. It is used in the treatment of advanced
`gastrointestinal neoplasms. It is considered as an alternative oral
`therapy to intravenous fluorouracil.[65]
`Cutaneous adverse effects of tegafur are frequent events.
`However, only isolated cases of chemotherapy-induced PPE have
`been reported to be associated with tegafur, and therefore the
`exact incidence is not currently known. Most cases presented at
`dosages of about 500 to 1600 mg/day.[8,16,44,65]
`It has been suggested that PPE in patients treated with tegafur
`could be a fluorouracil dependent reaction as it results at serum
`fluorouracil concentrations equivalent to very low dose fluoro-
`uracil CI.[44] Another possible explanation for this cutaneous re-
`action is that tegafur is metabolized not only to fluorouracil, but
`also to dehydro-tegafur another hydroxilated metabolite, which
`may be pharmacologically active and may be responsible for this
`reaction.[8]
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`or fluorouracil alone. The combination of these 2 drugs might
`explain this high incidence.
`
`6.4.1 Liposome-Encapsulated Doxorubicin
`Liposome-encapsulated doxorubicin is a preparation of
`doxorubicin encapsulated in a liposome formulation containing
`polyethylene glycol. The liposome prevents binding of the drug
`to plasma proteins and also inhibits its excretion. Therefore, these
`preparations have a theoretical advantage when compared with
`the free drug in tumor treatment because they have a significantly
`longer circulation time and may provide an alternative for pro-
`longed infusions.[35] Liposomal doxorubicin has been used in the
`treatment of breast cancer, ovarian cancer, Kaposi’s sarcoma,
`melanoma, and small cell lung cancer.
`PPE is a significant adverse effect of therapy with liposomal
`doxorubicin and may limit its use in some cases. In fact, patients
`who experience PPE should have the drug discontinued until the
`symptoms clear. PPE incidence has been reported in 3.4 to 40%
`of patients treated with liposomal doxorubicin.[32,37,46,57,83] Pa-
`tients are more likely to develop PPE after higher doses of lipo-
`somal doxorubicin,[37,57] after higher dosage intensity,[3] and after
`multiple cycles.[57,72] However, lengthening the interval between
`treatments and dosage reductions decrease the incidence of
`PPE.[57,72] PPE associated with liposomal doxorubicin is similar
`to observations made in patients receiving protracted infusions of
`doxorubicin.[67]
`Although the mechanism of skin damage in the PPE has not
`been studied in detail, it has been suggested that it is a cumulative
`but reversible effect of liposomal doxorubicin, depending on dos-
`age and schedule. Given the prolonged circulation time of lipo-
`somal doxorubicin, it is conceivable that a slow release of
`doxorubicin takes place in the intravascular compartment, mim-
`icking a continuous drug infusion. An alternative possibility is
`that liposomes localize in mucous membranes and skin and
`slowly release the drug in situ.[72] The skin elements most suscep-
`tible to the toxic effect of a DNA replication inhibitor such as
`doxorubicin would be the rapidly dividing keratinocytes of the
`basal layer of the epidermis. A physical factor precipitating the
`PPE is clearly involved, because palmar, plantar, and sacral skin
`areas are the most commonly affected.[57,72]
`
`6.5 Docetaxel
`
`Docetaxel is a semisynthetic derivative from the leaf extracts
`of Taxus baccata. It has a similar mechanism of action as
`paclitaxel, and actually is more potent in enhancing microtubule
`assembly. It also promotes apoptosis. Clinical responses have
`been observed in breast and ovarian cancer, non-small cell lung
`cancer, pancreatic, and gastric carcinomas.[80]
`
`Skin toxicity may occur in 50 to 75% of patients receiving
`docetaxel. Docetaxel also induces PPE although its incidence has
`not been defined in the different studies published.[80] PPE asso-
`ciated with docetaxel appears to be a more generalized form of
`chemotherapy-induced PPE and it is seen in a significant percent-
`age of patients receiving this drug; Zimmerman et al.[79] reported
`PPE developing in 58% of patients treated with docetaxel at 100
`mg/m2/day as either a 2- or a 3-hour infusion every 21 days. The
`average time that elapsed between treatment and the development
`of an eruption was from 2 to 4 days. Increased peak plasma con-
`centrations did not correlate with severity of reaction, thus sug-
`gesting that these reactions are either idiosyncratic or more prob-
`ably related to tissue concentration via local blood flow or
`sweat.[79] Docetaxel administered on a weekly basis might be
`associated with a lowers incidence of PPE as less dermatologic
`events have been described with this schedule.[96]
`Paradoxically, only one case of paclitaxel-induced PPE has
`been reported in the literature.[26]
`
`6.6 Other Drugs
`
`PPE has occasionally been related to other drugs (table I).
`Most reports consisted of one or a few cases and large series show
`that it is a low frequency secondary effect.
`However, it is interesting to note the case of vinorelbine. PPE
`has not been reported with vinorelbine given as a bolus. Recently,
`a 7% incidence of PPE has been observed in a new treatment
`schedule for metastatic breast cancer in which continuous 96 hour
`infusions of high dosages of vinorelbine were used.[42] PPE will
`be seen with greater frequency in the future because this modality
`may be used more widely.
`
`7. Treatment
`
`Other than dose reduction, lengthening of the drug adminis-
`tration interval and ultimately, drug withdrawal, there is no ther-
`apy for PPE that has been proven to be effective in large-scale
`clinical trials.
`Some treatments have been proposed in small series or as
`isolated cases although they need to be corroborated in large se-
`ries (table IV). Symptomatic relief may be obtained with wound
`care to prevent infection, elevation to reduce edema, cold com-
`presses, and pain medications.[88,89] Cooling the hands and feet
`during treatment to decrease blood flow to these areas may atten-
`uate the severity of the reaction.[87]
`Potent topical corticosteroids have been used with variable
`success, and a better outcome is obtained if the affected areas are
`cooled or emollients are also applied.[2,37,73,81,91] Systemic ther-
`apy with corticosteroids may help in some cases.[39,42,82,83,91] In-
`
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`232
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`Nagore et al.
`
`Table IV. Treatment recommendations for palmar plantar erythrodysesthesia
`
`General measures
`Dose reduction, drug withdrawal or lengthening
`administration interval (all drugs)
`Wound care
`Elevation of the extremity
`Cold compresses
`Pain medication
`Emollients
`
`Specific treatments
`Pyridoxine (vitamin B6) [fluorouracil, liposome encapsulated doxorubicin, doxorubicin,
`docetaxel, etoposide]
`Cooling the hands (docetaxel)
`Oral corticos