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Silk et al. Hepatoma Res 2020;6:73 I http://dx.doi.org/10.20517/2394-5079.2020.61 Page 9 of 16

SORAFENIB
Sorafenib cutaneous toxicities and toxicity incidence
Sorafenib was FDA approved for the treatment of HCC in 2008 after a phase three randomized placebo-
controlled trial showed that it extended patient survival. Safety results of that study reported that 80% of
patients taking Sorafenib experienced an adverse event with the majority of patients experiencing grade 1
or 2 dermatological events. These events and the percentage of patients reporting them included: alopecia
(14%, grade 3: 0%), dry skin (8%, grade 3: 0%), HFRS (24%, grade 3: 8%), pruritus (8%, grade 3: 0%), rash
[4]
and/or desquamation (16%, grade 3: 1%) . Similar adverse events were also seen in another study that
[11]
investigated Sorafenib therapy in an Asian-Pacific population . Other cutaneous toxicities reported with
Sorafenib include sublingual splinter hemorrhage which occurs in as many as 60%-70% of patients as well
as case reports of scrotal eczema [32,52] .

The onset of cutaneous toxicity with Sorafenib
HFRS occurs within days or months after starting Sorafenib, but most commonly manifests during
the first 6 weeks of therapy [22,26,27] . Rashes usually present on the extremities and/or the trunk within
[22]
the first to the second month of treatment . Scrotal rashes have been seen between the 2nd and 12th
weeks of therapy [22,27] . Alopecia observed in patients treated with Sorafenib occurs within four months of
treatment [26,27] . The subungual splinter hemorrhages appear within the first 2 months of treatment [26,27] .

It is recommended that physicians see their patients in 2-week intervals for the first 2 months of Sorafenib
treatment to manage skin toxicities [20,22] .

Dose reductions
[38]
The starting dose of Sorafenib is 800 mg daily. Dose reductions for skin toxicity are seen in Tables 1, 2, and 3 .

LENVATINIB
Lenvatinib cutaneous toxicity and toxicity incidence
In a phase 3 trial, Lenvatinib was shown to be non-inferior to Sorafenib for OS in the first-line treatment
[13]
of HCC that was not amenable to curative or local therapy . Cutaneous toxicities seen with Lenvatinib
include: HFRS (27%, grade 3: 3%), alopecia (3% grade 3: 0%) and rash (10%, grade 3: 0%) .
[7]
The onset of cutaneous toxicity with Lenvatinib
The onset of Lenvatinib’s cutaneous toxicities for the treatment of HCC has not been described. However,
their onset has been documented during the use of Lenvatinib for thyroid cancer . The median time to
[28]
the first onset of HFSR was 5.9 weeks and 7.3 weeks for rash. Most rashes occurred during the first cycle of
therapy. Whereas HFRS could occur throughout therapy.

Dose reductions
Lenvatinib for HCC is dosed depending on body weight with patients 60 kg or greater started at 12 mg
daily whereas those less than 60 kg starting at 8 mg daily. Dose reductions for skin toxicities are displayed
[53]
in Tables 1, 2 and 3 .

CABOZANTINIB
Cabozantinib cutaneous toxicity and toxicity incidence
Cabozantinib has been approved as second-line therapy for patients with HCC who have progressed
on Sorafenib. In phase 3 CELESTIAL trial, Cabozantinib treated patients’ median OS was 10.2 months
(95%CI: 9.1-12.0) compared to 8.0 months (95%CI: 6.8-9.4) in patients treated with placebo. Cabozantinib
cutaneous toxicities and incidences include: HFRS (46%, grade 3: 17%), stomatitis (13%, grade 3: 2%), and
[6]
rash (12%, grade 3 < 1%) .