OBSERVATION Capecitabine-Induced Hand-Foot Syndrome Complicated by Pseudomonal Superinfection Resulting in Bacterial Sepsis and Death Case Report and Review of the Literature Fridolin J. Hoesly, MD; Sarah G. Baker, MD; Nilanthi D. Gunawardane, MD; Jonathan A. Cotliar, MD Background: Hand-foot syndrome (HFS) is a rela- over both hands and feet, consistent with HFS. Pseudo- tively common dermatologic toxic reaction to certain monal superinfection leading to bacterial sepsis and death anticancer therapies. Although not life-threatening, this rapidly ensued. complication can reduce patient quality of life. Dose modi- fication of the inciting agent serves as the most effective Conclusions: Although HFS is widely regarded as a non– management of HFS, although a variety of anecdotal re- life-threatening toxic reaction to cancer treatment, our ports suggest that other agents may also be efficacious. case demonstrates that infectious complications of this We present the first reported case of fatal HFS (to our condition can prove fatal. Prevention, early recogni- knowledge) and provide a comprehensive review of this tion, and implementation of various management strat- condition. egies for HFS and its infectious complications are im- portant in optimizing patient quality of life and minimizing Observations: A 61-year-old woman with metastatic unfavorable outcomes. breast cancer who was undergoing treatment with ca- pecitabine developed erythema, fissuring, and erosions Arch Dermatol. 2011;147(12):1418-1423 AND-FOOT SYNDROME REPORT OF A CASE (HFS), also known as pal- moplantar erythrodyses- thesia or acral erythema, A 61-year-old woman with metastatic breast is a localized skin erup- cancer who had been treated with oral lapa- tion associated with the initiation of tinib (1250 mg/d) and capecitabine (1250 H 2 therapy with certain chemotherapeutic mg/m twice daily) over the previous 4 years agents.1,2 It is considered a subtype of toxic presented with a 3-week history of painful erythema of chemotherapy, a term that en- erosions and ulcerations of her hands and compasses a broad spectrum of antican- feet along with bilateral lower extremity cer medication–induced cutaneous reac- swelling. She denied any other symptoms, and her medical history was otherwise tions.3 The clinical presentation of HFS is unremarkable. Her other medications in- characterized by a prodrome of dysesthe- cluded fulvestrant and pamidronate. Dur- sia followed by the development of pain- ing the previous 3 years, she had experi- ful, symmetrical edema and erythema of enced intermittent flares of grades 1 and 2 the palms, digits, and soles that may evolve 4,5 HFS due to capecitabine use. Her symp- into blisters and erosions. Although HFS toms were successfully treated with fluoci- has the potential to substantially affect nonide cream, 0.05%, and ammonium lac- quality of life, it is not recognized as a life- tate cream, 12%, although she had not been 6 threatening condition and rarely leads to treating her skin with topical agents before hospitalization.7 We report a case of HFS her appointment. Physical examination re- that was complicated by pseudomonal su- vealed erythema and fissuring over both perinfection resulting in bacterial sepsis Author Affiliations: palms and circumferential erosions involv- Department of Dermatology, and death and provide a review of the HFS ing her right thumb and left middle finger Northwestern University literature focusing on the management of (Figure 1A). She had bilateral lower ex- Feinberg School of Medicine, this condition. To our knowledge, this is tremity edema as well as erythema and ero- Chicago, Illinois. the first reported case of fatal HFS. sions over both soles and the web spaces of ARCH DERMATOL/ VOL 147 (NO. 12), DEC 2011 WWW.ARCHDERMATOL.COM 1418 ©2011 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/30/2021 A B Figure 1. Diffuse erythema and fissuring of the palms with focal erosions on the fingers (A) and the right foot (B). her feet (Figure 1B). A diagnosis of grade 3 HFS was made of a subungual abscess that formed after onycholysis; how- according to the National Cancer Institute (NCI) Com- ever, HFS was not identified as a contributing factor.10 mon Terminology Criteria for Adverse Events version 4.0, Our case demonstrates the life-threatening potential of and capecitabine therapy was discontinued. Treatment with HFS and highlights the importance of its prevention, mupirocin ointment, econazole cream, and oral ciprofloxa- prompt recognition, and appropriate management. cin was initiated because of a clinical suspicion of cutane- The NCI grading scale is commonly used to rate HFS ous superinfection and the patient’s history of Pseudomo- (categorized as palmar-plantar erythrodysesthesia syn- nas aeruginosa paronychia of her left great toe 7 months drome and described as redness, marked discomfort, earlier. Wound cultures obtained from both the hands and swelling, and tingling of the palms and/or soles) sever- the feet during the initial evaluation yielded pansensitive ity on a scale of 1 to 3 (Table 1).11 Almost 80% of pa- P aeruginosa. The patient was contacted to discuss the cul- tients with HFS present with NCI grade 1 toxicity.4 ture results, and at that time she reported the onset of mal- The most common causes of HFS include aise and scleral icterus. She was instructed to go to the emer- capecitabine, cytosine arabinoside (cytarabine), doxoru- gency department, and on arrival she was found to be in bicin, 5-fluorouracil, and the taxanes.3,4 Our patient septic shock, with acute kidney injury and hepatic dys- developed HFS as a result of capecitabine therapy, function, resulting in coagulopathy. Pseudomonal super- which causes this condition in 28% to 74% of treated infection of the patient’s HFS was considered the most likely patients.12 Capecitabine is a prodrug that is enzymati- source of sepsis, although the results of blood cultures re- cally converted to 5-fluorouracil within tumor cells. mained negative. Despite broad-spectrum intravenous an- The onset of HFS can range from within 24 hours to 10 tibiotic therapy and aggressive resuscitative measures, she months of the initiation of chemotherapy, with shorter died less than 24 hours later. time to onset and greater severity being associated with higher peak plasma levels and total cumulative COMMENT dose.2,4,12 Capecitabine-related HFS usually appears within the first 3 cycles of treatment13 and commonly It is well known that HFS can have a dramatic impact worsens in subsequent cycles,1 as occurred in this case. on quality of life and can necessitate dose modification Our patient was also taking lapatinib, a dual inhibitor of or discontinuation of cancer therapy; however, it is not epidermal growth factor receptor and human epidermal considered a dangerous condition in and of itself. There growth factor receptor 2; however, this drug is most have been a few reports of HFS leading to tissue necro- commonly associated with the development of skin sis and requiring amputation,8,9 but we report the first eruptions that are localized to the trunk.14 In one death (to our knowledge) due to complications of HFS. review, fewer than 1% of the 926 patients who were In a study evaluating weekly docetaxel plus ca- receiving lapatinib monotherapy developed HFS.14 Of pecitabine therapy for advanced non–small cell lung can- interest, multikinase inhibitors such as sorafenib and cer, there was 1 reported death due to sepsis as a result sunitinib also cause a similar cutaneous toxic reaction ARCH DERMATOL/ VOL 147 (NO. 12), DEC 2011 WWW.ARCHDERMATOL.COM 1419 ©2011 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/30/2021 Table 1. National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 Grading of Hand-Foot Syndromea Grade Adverse Event Term 123 Palmar-plantar erythrodysesthesia Minimal skin changes (erythema, Skin changes (peeling, blisters, Severe skin changes (peeling, syndrome (hand-foot syndrome) edema, or hyperkeratosis) bleeding, edema, or blisters, bleeding, edema, or without pain hyperkeratosis) with pain, limiting hyperkeratosis) with pain, limiting instrumental ADLa self-care ADL Abbreviation: ADL, activities of daily living. a Data from the National Cancer Institute.11 Table 2. Comparison of Hand-Foot Syndrome and Hand-Foot-Skin Reaction Variable Hand-Foot Syndrome Hand-Foot-Skin Reaction Frequently implicated drugs Capecitabine, cytarabine, doxorubicin, 5-fluorouracil, Sorafenib, sunitinib (multikinase inhibitors)6 taxanes4 Histopathologic findings Hyperkeratosis, parakeratosis Hyperkeratosis, parakeratosis Spongiosis Well-defined horizontal zone of keratinocyte necrosis Focal vacuolization and pyknosis in basal cell layer and discohesion (distinct from basal vacuolization or Dermis with ectatic blood vessels, mild perivascular scattered pyknotic cells often seen in hand-foot lymphohistiocytic infiltrate4,15,16 syndrome) Dermis with ectatic blood vessels, mild perivascular lymphohistiocytic infiltrate with or without eosinophils in dermis15,17 Clinical appearance Edema, erythema, and scale with or without blisters and Scale with surrounding erythema progressing to erosions4,5 hyperkeratosis with or without blisters and erosions6,18 Distribution Symmetrical and diffuse over the palms, soles, and Localized to pressure-bearing or flexural areas on palms digits4,5 and soles6 Onset 24 h to 10 mo after initiation of therapy2,4 (median,