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Silk et al. Hepatoma Res 2020;6:73 I http://dx.doi.org/10.20517/2394-5079.2020.61 Page 3 of 16

is started patients should be advised to avoid tight footwear or gloves. Patients should protect their feet
with insole cushions, shock-absorbing soles, and padded socks and wear gloves to protect their hands.
Emollients can be used liberally.

At night, patients should continue to wear cotton gloves and socks to retain moisture. They should also
avoid extreme temperatures and wash with tepid water [14,15,18,20,22] .

Further recommendations are based upon the grade of HFRS severity. The toxicity grading of HFRS is
characterized according to the National Cancer Institute. Grade 1 toxicity is characterized by minimal skin
changes or dermatitis (i.e., edema, redness, or hyperkeratosis) but without pain. Grade 2 toxicity develops
with skin changes (i.e., peeling, blisters, bleeding, fissures, edema, or hyperkeratosis) with pain and limits
daily activities. Grade 3 toxicity is marked by severe skin changes (i.e., peeling, blisters, bleeding, fissures,
[23]
edema, or hyperkeratosis) with pain that limits self-care .
Grade 1 toxicities can be managed with topical therapy usually with the continuation of the TKI dose [19,20,22] .
Topical treatments are similar to those used for prophylactic care. 20%-40% urea creams should be used on
areas of hyperkeratosis twice a day [15,18,20,22] .

Grade 2 toxicities are managed with topical therapy and dose reductions if necessary. Areas of
[16]
hyperkeratosis should be treated with urea base keratolytic . 0.05% Clobetasol ointment should be applied
to erythematous areas twice daily [15,20,22] . Topical 2% lidocaine cream can be used for analgesia [20,22] .

For Grade 3 toxicities in addition to the above treatments, dose interruption and reduction is required.
Other strategies include the use of pyridoxine with doses of 50-150 mg/day [20,22,24] .

Of note, in one uncontrolled study of 12 patients who developed HFRS when taking Sorafenib, the majority
of patients that were treated twice daily with 40% urea cream in combination with tazarotene 0.1% cream
[25]
or fluorouracil 5% cream saw a ≥ 2-grade improvement in symptoms [Figure 1].

RASH
Symptoms
Rashes observed with TKI treatment vary and can develop as a macule, papule, maculopapular,
erythematous, and/or pruritic. Rashes often develop on the trunk and extremities or scrotum [15,26-28] . Facial
and scalp erythema similar to seborrheic dermatitis has been noted with Sorafenib.

Treatment
The treatment of rashes seen during TKI therapy is once again based upon the toxicity grade. Grade 1
toxicity is described as macules/papules covering < 10% body surface area (BSA) with or without symptoms
(e.g., pruritus, burning, tightness). Grade 2 toxicity is characterized by macules/papules covering 10%-30%
BSA with or without symptoms (e.g., pruritus, burning, tightness); limiting instrumental activities of daily
living (ADL), or a rash covering > 30% BSA with or without mild symptoms. Grade 3 toxicity is defined by
[23]
macules/papules covering > 30% BSA with moderate or severe symptoms; limiting self-care ADL .

In general, patients with rashes should be advised to use perfume-free soaps, apply moisturizers, and
wear loose comfortable clothing [22,29] . Topical corticosteroids and antihistamines may also be useful with
mild rashes [22,30] . Dose reductions and interruptions of the TKI should also occur based on prescribing
information for severe rashes. With proper management, most rashes have been noted to resolve in less
[27]
than 6 weeks . Additionally, some rashes may resolve spontaneously without symptomatic treatment as
can be seen in patients with facial and scalp erythema [26,27] [Figure 2].