Balanitis associated with FOLFIRI chemotherapy

Introduction

Here we describe a case of systemic FOLFIRI-associated balanitis successfully treated by topical steroids, without discontinuation of chemotherapy treatment. FOLFIRI consists of the pyrimidine analog antimetabolite, 5-fluorouracil (5-FU), the topoisomerase inhibitor, irinotecan, and folinic acid. FOLFIRI is commonly used in the treatment of various solid malignancies, including cancers of the gastrointestinal tract. Several local and diffuse cutaneous changes have been described in association with systemic 5-FU treatment, including serpentine supravenous hyperpigmentation,1, 2 melanonychia,³ mucosal dyspigmentation, periungual ulceration, palmar keratoderma, acral erythema,⁴ and others. Acral erythema is the most common manifestation, estimated to occur in 34% of patients with continuous 5-FU infusion.⁵ Clinically, it is also known as hand-foot syndrome, palmar-plantar dysesthesia, toxic erythema of the palms and soles, Burgdorf reaction, and, more recently, is included within the umbrella term toxic erythema of chemotherapy (TEC).⁶ Irinotecan has also been associated with alopecia, hyperpigmentation, and hand-foot syndrome. However, balanitis is a relatively unrecognized and underreported side effect that could significantly impact patient quality of life and may require chemotherapy dose modification or reduction. With this case description, we aim to aid in the early recognition and management of FOLFIRI-associated balanitis, as early treatment may avoid interruption of chemotherapy.

Case report

A man in his 50s with esophageal cancer was admitted to the hospital for intractable diarrhea. His chemotherapy regimen had recently been switched to FOLFIRI for esophageal cancer. During admission, he complained of a pruritic rash on his hands and a painful rash on his penis associated with dysuria. These symptoms started with the second cycle of chemotherapy. He self-treated the rash with emollients but had limited relief. He was afebrile. On the circumcised glans penis extending over the corona and onto the distal penile shaft, there was a circumferential confluent red plaque with serous crust and scale (Fig 1). On his palmar hands, bilaterally overlying joints, there were moderate pink plaques with scaling (Fig 2, A). There was notable xerosis of the palms and fissuring at finger bases (Fig 2, B). There was no melanonychia, serpentine skin hyperpigmentation, stomatitis, or mucosal dyspigmentation. He had no history of asthma or atopic dermatitis and did not take any over-the-counter medications or herbal supplements. Urine testing found negative leukocyte esterase and nitrites, and urine chemistry values were within normal limits. A superficial wound culture of the penis found normal flora, with no Pseudomonas aeruginosa, β-hemolytic Streptococci, or Staphylococcus aureus, and no leukocytes detectable by staining. Testing for Chlamydia trachomatis and Neisseria gonorrhoeae was negative, venereal disease research laboratory findings were nonreactive, and thrombocyte count was within normal limits. The patient never received hematopoietic cell transplantation or blood products. Skin biopsy was not performed. Possible diagnoses considered included irritant contact dermatitis, psoriasis, nummular eczema, erosive lichen planus, extramammary Paget disease, and human papilloma virus infection. In light of the characteristic clinical appearance and temporal relationship to FOLFIRI treatment as well as lack of evidence for infectious etiologies or graft-versus-host disease, a diagnosis of toxic erythema of chemotherapy with balanitis and grade 2 acral erythema was established. Topical steroid (clobetasol 0.05% twice a day) ointment for 14 days for the hands and 7 days for the glans penis was recommended. After 3 days of topical therapy, pruritus and pain improved. Seven days after initiation of therapy, the patient was seen in the oncology clinic, and balanitis had resolved. There was no dose modification made to the chemotherapy regimen because of these dermatologic side effects. The patient received 2 additional cycles of chemotherapy during weeks 3 and 5 after the initial reaction with no report of symptom recurrence during follow-up appointments.

Fig 1.

Balanitis. Representative clinical image coronal (A) and sagittal (B).

Fig 2.

Toxic erythema of chemotherapy. Representative images of hands (A) and palm/base of thumb (B).

Discussion

A rare case of chemotherapy-associated balanitis and TEC responding to topical steroid treatment is described. Review of literature identified a single report of balanitis in the setting of 5-FU treatment.⁷ However, that report described erosive balanitis in a patient with stomatitis in the setting of mucositis, which commonly occurs with 5-FU treatment. In contrast, our report describes a patient with no erosions or stomatitis and an eruption extending beyond the glans penis. Individual cases of balanitis have also been reported in association with other chemotherapies, including bicalutamide, doxorubicin, methyl GAG (Methylglyoxal bis[guanylhydrazone], mitoguazone), cetuximab,⁸ and capecitibine,² which are not applicable in this case. TEC in association with 5-FU is well recognized to occur in approximately 15% to 34% of patients treated with continuous infusion of 5-FU. A summary of dermatologic entities described in association with systemic 5-FU therapy is shown in Table 1. The pathogenesis of balanitis in this setting remains unclear but is likely related to the pathogenesis of acral erythema. Acral erythema is thought to occur from direct toxic effect of chemotherapeutic agent on eccrine glands.¹³ In this case, balanitis occurred 7 days after cycle 2 of FOLFIRI therapy. It is important to recognize and manage balanitis in a timely manner to minimize impact on quality of life and determine whether dose modification of chemotherapy is indicated. Chemotherapy-associated balanitis requiring chemotherapy discontinuation and treated with pyridoxine was previously reported.¹⁴

Table 1.

Dermatologic side effects of systemic 5-FU treatment

Side effect	Frequency	Management	Study
Oral mucositis	40%	Supportive with transdermal fentanyl, morphine mouthwash	Lalla et al9
Serpentine supravenous hyperpigmentation	N/A	Self-limited	Chan and Lin10
Radiation recall	∼15%	Drug discontinuation	Burris and Hurtig11
Hair thinning	10%-30%	Supportive	Miller et al4
Nail discoloration	10%-30%	No specific management	Sapp and DeSimone2
Palmar-plantar syndrome	13%-34%	Supportive with high-potency topical steroids	Nagore et al12

This case shows that after excluding infectious etiologies and graft-versus-host disease, FOLFIRI-associated balanitis may be effectively treated with potent topical corticosteroids. Application of topical corticosteroids to the face and genitalia requires proper application instruction, patient understanding, and a high level of caution. Skin atrophy, striae, dermatitis, acne, purpura, hypertrichosis, delayed wound healing, and dyspigmentation may develop, and exacerbation of infections are seen less frequently.¹⁵ In our case, a daily skin examination was performed by the dermatology team while the patient was on the inpatient medical floor. Other treatment options described in the literature include topical tacrolimus, testosterone propionate ointment, carbenoxolone gel, saline soaks, and intralesional corticosteroids. Although not present in this patient, the individual contribution of foreskin presence to chemotherapy-associated balanitis has not been reported in the literature but is an important question that should be explored in additional studies.