ABSTRACT: Hand-foot syndrome is a localized cutaneous side effect associated with the administration of several chemotherapeutic agents, including the oral fluoropyrimidine capecitabine (Xeloda). It is never life-threatening but can develop into a painful and debilitating condition that interferes with patients' normal daily activities and quality of life. Several symptomatic/prophylactic treatments have been used to alleviate hand-foot syndrome, but as yet there is insufficient prospective clinical evidence to support their use. The only proven method of managing hand-foot syndrome is treatment modification (interruption and/or dose reduction), and this strategy is recommended for patients receiving capecitabine. Retrospective analysis of safety data from two large phase III trials investigating capecitabine as first-line therapy in patients with colorectal cancer confirms that this strategy is effective in the management of hand-foot syndrome and does not impair the efficacy of capecitabine. This finding is supported by studies evaluating capecitabine in metastatic breast cancer. Notably, the incidence and management of hand-foot syndrome are similar when capecitabine is administered in the metastatic and adjuvant settings, as monotherapy, or in combination with docetaxel (Taxotere). It is important that patients learn to recognize the symptoms of hand-foot syndrome, so that prompt symptomatic treatment and treatment modification strategies can be implemented.
Hand-foot syndrome, also known as palmar-plantar erythrodysesthesia, palmar-plantar erythema, acral erythema, and the Burgdorf reaction, is a localized, cutaneous side effect associated with a wide range of systemic chemotherapy agents. The condition, probably first described in 1974 in a patient receiving mitotane (Lysodren), was defined in a 1982 case study of a patient receiving a cytarabine-containing chemotherapy regimen.
The development of hand-foot syndrome appears to be predominantly drug and dose dependent, with peak plasma drug concentrations, total cumulative dose, and administration schedule affecting onset and severity.[ 3] Consequently, the time of onset is variable, ranging from 24 hours to 10 months after the start of chemotherapy. Hand-foot syndrome is usually self-limiting and rarely leads to hospitalization or life-threatening manifestations. However, if it is not recognized early and managed effectively, an initially mild, cutaneous reaction can progress to an extremely painful and debilitating condition that can have a considerable impact on a patient's quality of life.
New insights into the management of hand-foot syndrome have been provided by clinical trials evaluating the novel oral fluoropyrimidine capecitabine (Xeloda). Capecitabine was rationally designed to generate fluorouracil (5-FU) preferentially in tumor tissue and offers sustained 5-FU delivery to tumors, thus mimicking continuous-infusion 5-FU. Like continuous-infusion 5-FU, one of the side effects of treatment with capecitabine is hand-foot syndrome.
Capecitabine monotherapy is a highly active oral treatment for patients with metastatic colorectal or breast cancer.[5-13] With favorable safety, capecitabine is also well suited for ad ministration in the adjuvant setting and in combination with other cytotoxic agents. Notably, in anthracycline-pretreated metastatic breast cancer, the combination of capecitabine with docetaxel (Taxotere) conferred a significant survival benefit compared with singleagent docetaxel.
As monotherapy and in combination regimens, capecitabine is well established in the treatment of metastatic breast and colorectal cancer. In this review, data from clinical trials evaluating capecitabine are analyzed with a view to demonstrating the optimal management of hand-foot syndrome in patients receiving the drug. The experience with capecitabine provides a large body of evidence supporting early recognition, prompt treatment interruption, and dose reduction as the optimal strategy for management.
Clinical Manifestation and Diagnosis
The clinical manifestation of handfoot syndrome has been reviewed in detail elsewhere. Its clinical signs and symptoms are distinctive, and diagnosis is usually based on the clinical setting and treatment history.[ 3,16,17] Prior to onset, individuals often experience dysesthesia or paresthesia in the palms and soles, including numbness or tingling. Over the next 3 to 4 days, painful swelling and erythema develop progressively in these areas, particularly on the pads of the distal phalanges, which can disrupt the patient's ability to pursue normal daily activities. If the condition progresses further, the indurated erythematous plaques darken, and over the next few days, develop central areas of pallor. The plaques may subsequently blister and desquamate, and then reepithelialize as part of the healing process.
Blisters tend to develop over pressure areas and remain limited to the palms and, less frequently, the soles. Occasionally, a mild, generalized erythema or morbilliform rash may coincide with the acral reaction. Rarely, deep ischemic necrosis develops at the sites of blister formation. Figure 1 shows the clinical manifestation of hand-foot syndrome, including the characteristic mild erythema developing on the soles of the feet and palms of the hands, as well as a case that has been allowed to progress to severe ulcerating disease.
Histologic studies suggest that the acute erythema of hand-foot syndrome is nonspecific and consistent with a generalized toxicity.[3,18] Because the reaction is usually limited to the palms and soles, features of acral regions such as temperature gradients, vascular anatomy, a relatively rapidly renewing epidermis, and a high concentration of eccrine glands are implicated in its pathogenesis.[3,17] Electron microscopy has shown that the basement membrane remains intact and eccrine sweat gland or duct damage appears to be absent.
Until recently, there was no standard grading system for hand-foot syndrome. However, the Cancer Therapy Evaluation Program Common Terminology Criteria for Adverse Events (CTEP CTCAE) now includes a standard grading scheme for hand-foot syndrome (Table 1). Many of the published clinical trials of agents associated with hand-foot syndrome were initiated prior to the introduction of a standard grading scheme. In capecitabine trials, hand-foot syndrome has been graded 1 to 3, based on functional criteria: Grade 1 was defined as numbness, dysesthesia/paresthesia, tingling, painless swelling, or erythema not disrupting normal activities; grade 2 was defined as painful erythema with swelling that disrupts daily activities; and grade 3 was defined as moist desquamation, ulceration, blistering, severe pain, or any symptoms leading to an inability to perform daily activities.
Drugs Associated With Hand-Foot Syndrome
Although this review focuses on the management of hand-foot syndrome in patients receiving capecitabine, it should be remembered that this syndrome is associated with prolonged administration of a wide range of cytotoxic agents. No feature common to the cytotoxic agents causing the condition has been identified, and the cause of hand-foot syndrome remains unknown. Ethnicity may be implicated but has not been proven, and a recently published Korean study ruled out IVS14+1G→A point mutation as a possible correlate with the severity of hand-foot syndrome.
Anthracyclines are associated with hand-foot syndrome. Although rare with intravenous (IV) bolus anthracycline therapy, it develops more frequently in patients receiving these drugs administered as a continuous infusion. The syndrome was dose-limiting in a phase I study of infused epirubicin (Ellence) and was a major toxicity in a phase II study evaluating infused doxorubicin in patients with metastatic sarcoma. Liposomal daunorubicin (DaunoXome) at high doses has been associated with the condition, and a particularly high incidence of severe hand-foot syndrome (27%) was reported with pegylated liposomal doxorubicin (Doxil). Pegylated liposomal doxorubicin in combination with paclitaxel was associated with an even higher incidence of grade 3 hand-foot syndrome (51%). The condition has also been reported less commonly with the cytotoxic agents hydroxyurea, methotrexate, mercaptopurine (Purinethol), cyclophosphamide (Cytoxan, Neosar), vinorelbine (Navelbine), mitotane, and the taxanes.[3,26-30]
Hand-foot syndrome is a common side effect in patients receiving highdose chemotherapy regimens prior to bone marrow transplants for leukemia. It is important to differentiate between hand-foot syndrome and acute graftvs- host disease (GVHD) in this setting, and both disorders may occur concomitantly.[ 3,31] In particular, hand-foot syndrome is frequently associated with prolonged administration of the nucleoside analog cytarabine,[32,33] and incidences of 39% have been reported in patients receiving cytarabine-based combination therapy regimens. Not surprisingly, hand-foot syndrome is also observed with troxacitabine (Troxatyl), an analog of cytarabine that is investigational in the United States.[35-38]
Hand-Foot Syndrome and the Fluoropyrimidines
Cutaneous reactions in patients receiving 5-FU are dose and schedule dependent. Hand-foot syndrome is rare with IV bolus 5-FU but is doselimiting when 5-FU is administered as a continuous infusion-a pattern first noted by Lokich and Moore in 1984. A meta-analysis of data from randomized trials comparing bolus and continuous-infusion 5-FU in 1,219 patients with advanced colorectal cancer confirmed that handfoot syndrome is significantly more common with continuous-infusion 5-FU (34% vs 13% with bolus 5-FU; P < .0001).
With continuous-infusion 5-FU, the risk of developing hand-foot syndrome is significantly higher in older patients (P = .009), as well as in female patients (P = .04). Although individual data on time to toxicity were not available, survival duration had a significant impact on the risk of developing hand-foot syndrome (P < .0001), suggesting strongly that its incidence is linked to the duration of treatment. The incidence of hand-foot syndrome with continuous infusion 5-FU has not limited the clinical use of infused regimens, which have demonstrated superiority over bolus 5-FU in terms of response rate and overall survival (P < .05).
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