Treatment of Palmoplantar Keratoderma With Continuous Infusion 5-Fluorouracil
A 49-year-old man electively chose to undergo a trial of intravenous chemotherapy with 5-fluorouracil (5-FU) for his inherited punctate palmoplantar keratoderma (PPK). His father also had this skin disorder, which coincidentally cleared after 2 courses of chemotherapy consisting of 5-FU and cisplatin to treat his lung cancer, prompting the patient to undergo this trial of therapy. After the patient's first course of a 5-day continuous infusion (CI) of 5-FU (1000 mg/m2 per day), the lesions on his hands and feet regressed by approximately 80%. However, after completion of each course, the lesions seemed to reappear to some degree. The patient desired to pursue further therapy; therefore, CI 5-FU at a dose of 250 mg/m2 per day (500 mg/d) was instituted, while pyridoxine was avoided in the hope of causing a hand-foot syndrome that may provide some long-term benefit. After receiving a 12-week course of therapy of CI 5-FU at 250 mg/m2 per day, his lesions were approximately 95% improved, with only a few minute punctate keratoses remaining. At follow-up nearly 4 years later, the lesions remain 90% cleared.
In vivo, the mechanism of 5-FU is quite complex. Depending on whether the tissue type is normal or a tumor, the compound will exert a different action.17 Cells proliferating at a rapid rate, especially solid tumors, are more of a target for the toxic effects from 5-FU than are nonproliferating cells.15 Systemic therapy with 5-FU can cause a variety of dermatologic manifestations, such as maculopapular eruption, hyperpigmentation, nail changes, lupuslike butterfly rash, inflammation of actinic keratoses, and palmar-plantar erythrodysesthesia syndrome (PPES), also known as hand-foot syndrome.18 Clinically, these changes can be categorized into 3 subsets: rashes and eruptions, cytotoxic changes, and alterations in pigmentation.18,19
Hand-foot syndrome is characterized by a "tingling sensation" of the palms and soles. It starts out as dysesthesia, and after a few days, there is a burning pain associated with swollen palms and soles that are erythematous, cracked, and eruptive. In severe cases, ulceration and blistering can occur followed by desquamation.18-20 Treatment with pyridoxine (100–150 mg/d) has been proven to be effective in preventing PPES or in making the symptoms less severe without having to discontinue 5-FU therapy.18,21 Therefore, pyridoxine should be avoided if hand-foot syndrome is a desired outcome, such as in our case.
The specific mechanism by which 5-FU causes PPES remains unknown, and the specific distribution on the palms and soles also is poorly understood. However, it has been hypothesized that PPES is a "direct toxic effect of the chemotherapeutic drug against epidermal cells" and, thus, PPES is the result of a cytotoxic reaction that mainly affects keratinocytes.22 The epidermis of the palms and soles are highly proliferative, making it a target for 5-FU to induce changes within the epidermis—making it more susceptible to PPES.15 Histologic findings in the basal cell layer of the skin include a variable degree of epidermal necrosis and poor cell infiltrate. Changes in the epidermis consist of vasodilation of the blood vessels and papillary edema from the mechanical and thermal trauma.22,23
Two meta-analyses of frontline trials for advanced colorectal cancer compared and evaluated the efficacy and toxicities of intravenous CI 5-FU versus bolus administration. With the exception of hand-foot syndrome, the meta-analysis revealed that CI 5-FU was associated with a significant reduction in grade 3 or 4 hematologic and nonhematologic toxicities (4% vs 31%), but there was an increased incidence of hand-foot syndrome with CI 5-FU compared with bolus administration (34% vs 13%).24,25
There is little, if any, data to support or guide therapy duration; therefore, the basis for treatment length was determined by oncologist and dermatologist observations of drug effect, lack of adverse effect, and willingness of the patient to continue therapy. Treatment was discontinued when it appeared that it had been fully successful, which was approximately 12 weeks for our patient.
Although our patient experienced only mild side effects, 5-FU has the potential to cause serious adverse effects. The earliest of milder untoward effects include anorexia and nausea followed by stomatitis and diarrhea. Mucosal ulcerations may occur throughout the gastrointestinal tract, particularly in patients receiving continuous infusions of 5-FU; these ulcerations can lead to fulminant diarrhea and hypovolemic shock.26 Myelosuppressive effects are more common with bolus administration of 5-FU than with CI and include leukopenia, thrombocytopenia, and anemia.26 Neurologic manifestations, including acute cerebellar syndrome, have been reported, as have reports of cardiac toxicity, particularly acute chest pain with ischemia.26
Cisplatin was ruled out as being a contributory factor in the clearing of the patient's father's keratoses. Other than alopecia, cisplatin is known to have minimal dermatologic effects. However, Lee et al27 reported a case of cisplatin-induced severe allergic exfoliative dermatitis associated with ischemia and necrosis of the hands. The adverse effects and toxicities associated with cisplatin are well recognized and include immunosuppression, neurotoxicity, nausea and vomiting, ototoxicity, and hypomagnesemia.27
Conclusion
An objective assessment of our patient suggested that systemic 5-FU was the most likely reason for the apparent clearing of this patient's keratoses. However, a randomized controlled trial is needed to determine if systemic 5-FU is applicable in the treatment of PPK. This case brings new light to a disease for which treatment options are limited and no cure exists.
