Anthracyclines, in particular doxorubicin, are a mainstay of chemotherapeutic regimens for breast cancer (BC). Doxorubicin is often utilized in combination with cyclophosphamide, paclitaxel, or fluorouracil. However, a major limitation of doxorubicin therapy is cardiotoxicity. To mitigate this adverse effect, doxorubicin is available as a pegylated liposomal doxorubicin (PLD) formulation. While associated with fewer cardiac adverse cardiac effects, PLD is commonly associated with hand-foot syndrome (HFS), which is also known as palmar-plantar erythema. Mild HFS is generally painless, but moderate-to-severe HFS (MSHFS) is associated with drug discontinuation or dose reduction, both which can adversely affect patients’ quality of life and survival.
A retrospective analysis was conducted, with findings from this study used to construct a logistic regression prediction model to determine which patients are at greatest risk for developing MSHFS from the administration of PLD.
Inclusion criteria of the study were women with a confirmed pathological diagnosis of BC who were receiving PLD with cyclophosphamide or PLD with cyclophosphamide and docetaxel as adjuvant or neoadjuvant therapy. Patients were excluded if they had metastatic disease; another malignancy other than nonmelanoma skin cancer or cervical carcinoma in situ; had recurrent BC; had incomplete data; or had a history of skin diseases.
HFS was graded using the NCI Common Terminology Criteria for Adverse Events (CTCAE) v4.0 grading criteria. Grade 1 included minimal skin changes or dermatitis (i.e., erythema, edema, hyperkeratosis) without pain; grade 2 included peeling, blistering, bleeding, edema, or hyperkeratosis with pain resulting in limitations in instrumental activities of daily living (ADLs); and grade 3 included severe skin changes including peeling, blistering, bleeding, edema, or hyperkeratosis with pain that limits self-care ADLs. In this paper, MSHFS were defined as having grade HFS >2, which requires PLD dose adjustments. Patients with HFS grade <1 were referred to as NMHFS and did not require an alteration in dosage.
A total of 461 patients were included in the analysis—255 NMHFS and 206 MSHFS. The incidence of MSHFS was 44.7%. The mean age of the study population was 51.1 years, and the mean body mass index (BMI) was 23.83 kg. The mean intensity of PLD was 31.2 mg/m2.
Adverse effects associated with the development of MSHFS included discontinuation of PLD in 12 patients, 89 patients delayed treatment for 5 to 7 days, and 61 patients required a dose reduction to 75% to 80% of the initial dose prescribed. MSHFS was the only adverse drug event that was associated with discontinuation treatment or delaying therapy.
Multivariant logistic regression analysis revealed that higher BMI (odds ratio [OR] = 1.116, P = .002), greater PLD dose intensity (OR = 1.264, P <.001); higher percentage of peripheral blood circulation (estimated by skin temperature checks) (OR = 1.975, P <.05); higher percentage of excessive sweat excretion (determined by the NCI CTCAE v4.0 grading criteria) (OR = 2.925, P <.001); a positive history of gallstones (OR = 3.403, P <.05); and HER2+ status (OR = 1.264, P < 0.001). The authors advise that patients should be asked about sweating as well as whether they have had a history of gallstones to properly assess their risk for developing MSHFS.
This paper provides insight for pharmacists about which patients taking PLD are most at risk for developing MSHFS, which can result in drug discontinuation or dose reduction. Providing patient education on physical cooling, use of antiperspirants, and the application of topical corticosteroids or urea ointment may help alleviate the symptoms of HFS.
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