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Page 2 of 16 Silk et al. Hepatoma Res 2020;6:73 I http://dx.doi.org/10.20517/2394-5079.2020.61

2 curative strategies in HCC: resection and transplant. Unfortunately, 50% of patients who undergo
resection will relapse in 2 years and many patients on transplant lists become ineligible for transplant due
to disease progression. The majority of patients still require systemic therapies. In 2008, the FDA approved
the tyrosine kinase inhibitor (TKI) Sorafenib as the first systemic therapy for patients with inoperable
hepatocellular cancer. Its approval was based on the overall survival (OS) benefit of Sorafenib compared
[4]
to placebo in the first-line setting 10.7 months vs. 7.9 months, respectively . Since Sorafenib’s approval,
several other tyrosine kinase inhibitors have been added to the armamentarium against late-stage HCC.
[5-7]
These new TKIs include Lenvatinib, Cabozantinib, and Regorafenib . Cutaneous toxicities are frequently
observed during targeted treatment of cancer, as many targeted therapies, including TKIs, inhibit growth
[8]
factors found in the skin .
In this review, we will focus on the adverse skin reactions seen during the treatment of hepatocellular
carcinoma by various tyrosine kinase inhibitors. The focus will be on symptomatology and management of
these reactions. Additionally, this review will discuss whether the development of cutaneous toxicities can
be prognostic.

Symptomatology and treatment for particular cutaneous toxicities are discussed with each major toxicity.
The cutaneous toxicities of particular TKIs will be discussed within each TKI’s section along with the
toxicity’s onset and suggested dose modifications of the TKI.

HAND FOOT REACTION SYNDROME
Risk factors and incidence
The incidence of hand foot reaction syndrome (HFRS) in the treatment of HCC varies depending on the
[9]
TKI . Predisposing factors to HFRS seen in TKI treatments include female gender, ECOG status 2 or
lower, two or more organs involved, baseline lung/liver metastases, a baseline white blood count above
9
[10]
5.5 × 10 cells/L, and the duration of the TKI therapy . Frequency is also higher in Asian populations [11,12] .
Whereas incidences of HFRS are varied, symptomatology of HFRS is shared between TKIs.
Symptoms
Patients affected by HFRS experience a prodromal tingling sensation on their palms or soles which
progresses to burning pain. Hand and foot erythema and edema develops with tense blistering and peeling
with lesions evolving into areas of callus-like hyperkeratosis with surrounding erythema [13-16] .

Lesions tend to develop over pressure-bearing surfaces, which may be related to the pathophysiology of
their development.

Pathophysiology
Although competing hypotheses exist [9,17,18] , the TKI dual inhibition of different receptors, such as VEGF
and PDGFR, may be required to trigger dermatological symptoms. Damage occurs when TKIs block
signaling pathways resulting in the alteration of repair mechanisms or distortion to microvascular structure
in areas where there is frequent trauma or friction like the palms and soles [12,14,18] .

Toxicity grading and treatment
Management of HFRS is based on expert knowledge from oncologists and dermatologists. Before TKI
treatment begins, proper consultation with podiatry and dermatology should be made. A full-body skin
examination with special attention paid to the hands and feet should be performed. Evidence of abnormal
weight bearing can be corrected with mechanical support. Areas of baseline hyperkeratotic skin can be
removed with manicures and pedicures [19,20] . During treatment, twice daily prophylactic application of a
20% urea-based cream has also been suggested by some experts to prevent HFRS [20,21] . When treatment