Peripheral neuropathy exacerbation associated with topical 5-fluorouracil

Abstract

Peripheral neuropathy secondary to 5-flourouracil and capecitabine (Xeloda) has been reported. We report the first case of exacerbation of peripheral neuropathy related to topical 5-flourouracil (Efudex). A 70-year-old Caucasian male with a history of actinic keratosis for 15 years was treated intermittently with topical application of 5-flourouracil. He also developed sensory peripheral neuropathy around the same time, but extensive work-up disclosed no clear etiology. In early 2005, he developed an exacerbation of his peripheral neuropathy following a 21-day course of topical 5-flourouracil for actinic keratosis, especially pain and parasthesias. Dihydropyrimidine dehydrogenase activity was evaluated in the peripheral mononuclear cells both by radioassay and by [2-C] uracil breath test. Dihydropyrimidine dehydrogenase activity was within the normal range by both methods. Stopping topical 5-flourouracil resolved the symptoms to baseline. Instead of topical 5-flourouracil, topical imiquimod was used which did not exacerbate his neuropathy. He was not re-challenged with topical 5-flourouracil. Topical 5-flourouracil has been known to cause mainly dermatological adverse effects, but systemic effects because of absorption are possible, especially in dihydropyrimidine dehydrogenase-deficient patients. As our patient had no other cause responsible for his neuropathy, the onset of symptoms coincided historically with topical application of 5-flourouracil and the 5-flourouracil usage preceded an exacerbation of sensory symptoms, we conclude that this drug was responsible for his polyneuropathy.

A sleeping phantom leg awakened following hemicolectomy, thrombosis, and chemotherapy: a case report

“…Degeneration of the peripheral nerves, particularly in patients with pre-existing neuropathy, may cause irreversible changes in pain gating through the dorsal and ventral horns, leading to altered central pain processing. While 5-FU, with which our patient was treated, is not typically identified as causing CIPN, there are at least two prior case reports of 5-FU-induced neuropathy [13,14]. Our patient presented with general diminished protection at all peripheral regions, possibly due to age-related degenerative processes or to the rare occurrence of 5-FU-induced sensorimotor axonal neuropathy.…”

Risk of Toxicity From Topical 5‐Fluorouracil Treatment in Patients Carrying DPYD Variant Alleles

“…Another patient who experienced similar systemic topical 5‐FU toxicity tested negative for a null activity (i.e., AS = 0) DPYD variant, and no further testing was conducted 6 . Other systemic toxicities, such as neutropenia, angioedema, neurological conditions, and taste abnormalities, have been reported in patients treated with topical 5‐FU, most of whom were not tested 7 or did not carry a DPYD variant or had normal DPD activity 8,9 . This is the first study, to our knowledge, investigating the risk of topical 5‐FU toxicity in a cohort of patients with known DPYD genotype or DPD activity.…”

“…6 Other systemic toxicities, such as neutropenia, angioedema, neurological conditions, and taste abnormalities, have been reported in patients treated with topical 5-FU, most of whom were not tested 7 or did not carry a DPYD variant or had normal DPD activity. 8,9 This is the first study, to our knowledge, investigating the risk of topical 5-FU toxicity in a cohort of patients with known DPYD genotype or DPD activity. Our results indicate the risk of severe toxicity from topical 5-FU treatment is extremely low, even in patients with partial DPD deficiency.…”

“…5‐fluorouracil (5‐FU) cream (5%) is administered as a topical treatment for dermatologic conditions, including actinic keratosis 1,2 . Use of topical 5‐FU causes minor local toxicity (e.g., erythema, crusting, and ulceration) in 60%–80% of patients 3,4 and there are case reports of rare, severe systemic toxicity 5–9 . Intravenous 5‐FU and the oral pro‐drug capecitabine are systemically administered fluoropyrimidine chemotherapy used to treat colorectal and other solid tumors 10 that cause severe (> 30%), and, in some cases, fatal (< 1%) toxicity 11 …”

“…1,2 Use of topical 5-FU causes minor local toxicity (e.g., erythema, crusting, and ulceration) in 60%-80% of patients 3,4 and there are case reports of rare, severe systemic toxicity. [5][6][7][8][9] Intravenous 5-FU and the oral pro-drug capecitabine are systemically administered fluoropyrimidine chemotherapy used to treat colorectal and other solid tumors 10 that cause severe (> 30%), and, in some cases, fatal (< 1%) toxicity. 11 Risk of severe toxicity from fluoropyrimidine chemotherapy is ~ 2-4 times greater in the 5%-7% of patients who carry a polymorphism in the DPYD gene that reduces activity of the dihydropyrimidine dehydrogenase (DPD) enzyme responsible for 5-FU catabolism.…”