Single agent sorafenib therapy at standard doses of 400 mg twice daily has been shown to be well-tolerated, with a total incidence of HFSR in approximately 25–30% of patients (7
); the use of bevacizumab alone has not been associated with development of HFSR. The approval of sorafenib for renal cell carcinoma and hepatocellular carcinoma and its use in combination therapies for other cancers, make it important to identify the mechanisms and predictors of the development of sorafenib-associated HFSR. We hypothesized that combination therapy targeting the VEGF pathway might result in augmentation of sorafenib HFSR. Comparison of patients receiving single agent sorafenib versus reduced dose sorafenib in combination with bevacizumab confirmed that hypothesis. Expected potential risk factors such as prior taxane exposure, pre-existing peripheral neuropathy, or development of rash were not associated with HFSR. However, an increase in the incidence and severity of HFSR was demonstrated with combination sorafenib/bevacizumab therapy compared to single agent sorafenib at any given cumulative dose of sorafenib (), suggesting that bevacizumab’s anti-VEGF effects potentiates sorafenib-related HFSR symptoms.
Sorafenib is associated with a variety of different dermatologic side effects, including facial/scalp erythema and dysesthesias, alopecia, splinter hemorrhages, keratoacanthomas (5
), leukocytoclastic vasculitis (6
), and epidermal inclusion cysts. HFSR is the sorafenib dermatologic toxicity with the greatest frequency and the greatest morbidity. HFSR associated with sorafenib therapy affects friction and weight-bearing acral surfaces more focally than the classic hand-foot syndrome that has been reported with traditional chemotherapeutic agents such as cytarabine, fluorouracil, and methotrexate () (18
Previous studies have reported a dose-dependent relationship between the starting dose of sorafenib and the incidence of HFSR. Our study adds to this data by demonstrating the increased incidence of HFSR with increasing cumulative sorafenib dose. This was observed both in our single agent sorafenib studies, as well as in the combination sorafenib/bevacizumab study. The association with cumulative dose cautions providers to maintain a high index of suspicion for HFSR the longer patients receive sorafenib. The impact of dose on the development of HFSR is not welldelineated, but based on clinical experience, dose-reduction and discontinuation of sorafenib reduces the severity of HFSR. Although no other association was found between risk of HFSR and number and type of prior therapies including exposure to pegylated liposomal doxorubicin, previous toxicities, baseline neuropathy, or dermatologic toxicity from prior treatment, an additional confounder that was not evaluated may have contributed to our findings. Development of HFSR was not demonstrated to be a harbinger of clinical benefit as suggested by rash in response to EGFR inhibitors (2
There are no data to date addressing the role of the VEGF pathway in the pathophysiology of HFSR. However, several findings in this study suggest that the VEGF pathway is important in the causation of HFSR: 1) the frequency and severity of HFSR was increased when sorafenib is paired with bevacizumab; 2) the predilection of HFSR for traumatic foci suggests that VEGF inhibition may retard tissue repair from minor trauma; 3) the increased incidence of HFSR in patients randomized to initiate treatment with one cycle of single agent bevacizumab prior to combination therapy illustrates the potentiating effects of bevacizumab on sorafenib-related HFSR; 4) the association of HFSR and the development of or worsened pre-existing hypertension suggests a vascular effect; and 5) the cumulative bevacizumab dose was also directly associated with incidence of HFSR (P<0.0001), further illustrating the impact of the antiVEGF property of bevacizumab on this sorafenib-associated toxicity. Apart from this study, it is known that bevacizumab treatment results in poor wound healing (20
Sorafenib causes an array of non-HFSR dermatologic toxicities (21
). Approximately half of the patients in the three studies developed skin rash, with no variance between the studies. Why this incidence was higher than previously reported (18–40%) is unclear; our patients had a high frequency of dermatologic consultations, and thus had a higher number of recognized rashes (7
). Several of the dermatologic findings (de novo
keratosis pilaris, epidermal inclusion cysts, and keratoacanthomas) are characterized by keratinocyte proliferation and focal apoptosis histologically. The MAPK, MSK1, and VEGF pathways play important role in normal keratinocyte function and inhibition of these pathways by sorafenib may result in the toxicity observed (23
). This hypothesis should be explored in future studies.
Development of non-HFSR skin toxicities was associated with circulating sorafenib concentration. This suggests that rash may herald higher circulating concentration and thus higher sorafenib concentration in skin. Preclinical sorafenib organ distribution studies demonstrated that the half-life of sorafenib in skin is longer (72.8 hrs) than in other organs (20–36 hrs).7
Other hypotheses regarding the etiology of sorafenib-associated HFSR have been posited. These include 1) accumulation of potentially toxic local concentrations in eccrine sweat glands that present in greatest number or density in the palms and soles; 2) damaged vascular integrity due to sorafenib’s dual VEGFR-2 and PDGF-β inhibition; and 3) keratinocyte injury from sorafenib inhibition of c-kit or RAF-kinase (24
). The histology of skin biopsies of early sorafenib-related HFSR lesions demonstrated focal epithelial damage with dyskeratotic keratinocytes, reactive epithelial changes in the basal layer of the epidermis and in eccrine sweat ducts, and lack of obvious vascular damage ().
In summary, sorafenib-related dermatologic manifestations are varied. HFSR and rash are the most common dermatologic toxicities associated with sorafenib, and their etiology remains uncertain. We report a direct association between cumulative sorafenib and bevacizumab doses and incidence of HFSR as well as increased HFSR in patients treated with combination anti-VEGF/VEGFR therapy. Our results suggest that sorafenib’s inhibition of the VEGF pathway may be an important factor in HFSR pathogenesis.