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Page 12 of 16 Silk et al. Hepatoma Res 2020;6:73 I http://dx.doi.org/10.20517/2394-5079.2020.61

The onset of cutaneous toxicity with Cabozantinib
The onset of cutaneous toxicity with the use of Cabozantinib to treat HCC has not been described.
[15]
However, the onset has been documented in the treatment of progressive urothelial carcinoma by Zuo et al.
[54]
and in renal clear cell carcinoma by Choueiri et al. About half of the patients in each study treated with
[15]
Cabozantinib developed HFRS with a median onset of 4-5 weeks. Additionally In the study by Zuo et al.
skin changes, including xerosis and scrotal erythema, developed within approximately 5 weeks of
Cabozantinib treatment.

Dose reduction
The starting dose of Cabozantinib is 60 mg daily for the treatment of HCC. Dose reductions for skin
[55]
toxicities are displayed in Tables 1, 2 and 3 .

REGORAFENIB
Regorafenib Cutaneous Toxicity and Toxicity Incidence
Regorafenib is another TKI approved for second-line therapy of HCC. The RESORCE trial showed that in
patients whose HCC progressed on Sorafenib, those subsequently treated with Regorafenib had improved
median OS to 10.6 months (95%CI: 9.1-12.1) compared to 7.8 months (95%CI: 6.3-8.8) in those treated
[5]
with placebo . A follow up study also found that patients sequentially treated with Regorafenib after
Sorafenib had improved OS from the start of Sorafenib treatment to death on study compared to placebo
[56]
control. 26.0 months (95%CI: 22.6-28.1) for Regorafenib and 19.2 months (95%CI: 16.3-22.8) for placebo .

In the RESORCE study, all patients receiving Regorafenib experienced an adverse event. Cutaneous
toxicities related to Regorafenib and their incidences include HFRS (53%, grade 3: 13%) and stomatitis (13%
[5]
grade 3: 1%). Of note, 2% of patients suffering from HFRS discontinued Regorafenib treatment .
The onset of cutaneous toxicity with Regorafenib
Regorafenib induced HFRS occurs early in treatment with one study showing a median time to the
[57]
first occurrence of 15 days . Onset of stomatitis usually occurs between 5 and 14 days after treatment
[58]
initiation .
Monitoring of patients should occur frequently especially early in treatment. Patients should be seen at
least every 1-2 weeks during the first two cycles and every 4-6 weeks thereafter [14,59-61] .

Dose reduction
The recommended starting dose of Regorafenib is 160 mg daily for 21 days followed by 7 days of a dosing
free interval to complete a 28-day cycle. Treatment is continued until disease progression or unacceptable
[62]
toxicity. Dose reductions with Regorafenib are seen in Tables 1, 2, and 3 .
The incidences of the most common cutaneous toxicities and their toxicity grade are summarized for each
tyrosine kinase inhibitor in Table 4.

ADVERSE EVENTS AND EFFICACY OF TKIS
The relationship between patients experiencing adverse events and treatment efficacy has been noted by
multiple investigators. In a study of 65 patients treated with Sorafenib, patients who developed at least
grade 1 skin toxicity had tumor control rates of 48.3% versus 19.4% in patients who did not develop skin
[63]
toxicity . Another study of Sorafenib showed a positive association between higher-grade skin toxicity
(> grade 2) and disease control when compared to patients who developed lower grade toxicity or had no
skin toxicity . An association was also seen with adverse events and overall survival in patients treated
[64]