New Developments in the Management of Hand-Foot Syndrome Associated With Oral Anti-VEGF Tyrosine Kinase Inhibitor–Targeted Anticancer Therapies

Hand-foot skin reaction (HFSR), also known as hand-foot syndrome or palmar-plantar erythrodysesthesia (PPE), is an adverse effect of several chemotherapeutic agents. The syndrome is characterized by redness, swelling, pain, and tingling in the palms of the hands and the soles of the feet. Other symptoms may include sensitivity or intolerance to hot or warm objects or fluids, hyperkeratosis (callus), blistering, and dry skin. Callus-like thickened tender blisters with some surrounding erythema are most typically localized to areas of pressure or friction, such as the heel and forefoot. The National Cancer Institute has classified the clinical manifestations by grades, ranging from 1 to 3. Grade 1 is characterized by minimal skin changes and dermatitis without pain; grade 2 presents with some skin changes and pain; and grade 3 is characterized by pain, severe skin changes such as blistering and/or desquamation, and an inability to undertake adequate self-care activities of daily living (ADL).¹

Along with agents that are known to cause HFSR, such as liposomal doxorubicin and capecitabine, newer molecularly targeted oral anti–vascular endothelial growth factor receptor (VEGFr) tyrosine kinase inhibitor (TKI)-targeted therapies used in several cancers also have been found to cause HFSR. The syndrome begins within the first 2 to 4 weeks of therapy with TKIs, presenting with tender blisters, redness, and swelling, which can progress to thickened and painful lesions that may interfere with ADL such as walking or bathing.^2-4

Although oral VEGFr-TKI agents are convenient to administer and generally well tolerated, with the most common adverse effects being diarrhea, rash, fatigue, and hypertension, the rates of HFSR can be significant. The incidence of HFSR syndrome with sorafenib, sunitinib, pazopanib, axitinib, vandetanib, cabozantinib, and regorafenib, and approved indications for their use, are shown in Table 1.^3-7

The management of HFSR syndrome caused by these agents has only recently been studied. The mechanism of action in HFSR is yet unknown, although some researchers propose that it is distinct from other agents, such as decreased repair mechanisms by endothelial cells to the vasculature after trauma to high-pressure areas such as the palms and soles. Moreover, because most of these agents are multitargeted and affect several receptor TKIs, the HFSR mechanism may be related to other repair functions, such as platelet-derived growth factor receptor. Of note, the intravenous monoclonal antibody inhibitor of VEGF, bevacizumab, does not cause HFSR. HFSR with VEGFr TKIs does not predict drug efficacy, as has been shown with the acne-like skin rash caused by epidermal growth factor receptor inhibitors.^2-4 Interest in the prevention and treatment of HFSR syndrome is on the rise, as these therapies have become standards of care for advanced renal cell carcinoma, hepatocellular carcinoma, and medullary thyroid cancer. Prompt recognition and treatment will minimize the impact on patients’ quality of life and may prevent unnecessary treatment interruptions or dose reductions.

Trials of HFSR Prevention and Treatment

Several recent trials have been published on the topic of HFSR, but with a number of limitations, notably that the majority of current studies explored HFSR caused by capecitabine; VEGFr TKIs were not included in several of these trials.

A study by Zhang and colleagues suggested the use of celecoxib to prevent HFSR in patients receiving capecitabine for colorectal cancer.8 The study concluded that celecoxib was beneficial for preventing HFSR in these patients; however, among other limitations, the recent warnings surrounding celecoxib’s cardiac adverse-event profile limits the generalizability of these results.⁹

Kang and colleagues assessed the benefit of pyridoxine for the prevention of capecitabine-induced HFSR.¹⁰ The patients in this study, who were chemotherapy naive and being treated with a capecitabine-containing regimen, were randomized to receive 200 mg of pyridoxine or placebo daily. Pyridoxine was not found to be an effective prophylactic therapy for HFSR caused by capecitabine.

Wolf and colleagues evaluated a urea/lactic acid–based topical keratolytic agent in capecitabine-induced HFSR.¹¹ This randomized, double-blind, phase 3 trial was conducted with 137 patients who were receiving their first cycle of capecitabine 2000 or 2500 mg/m2 daily for 14 days. Patients received either a urea/lactic acid–based topical keratolytic agent or a placebo cream, applied twice daily for 21 days after the start of capecitabine therapy. The study found no significant difference in the percentage of patients with moderate or severe HFSR between the 2 arms (P = .768); therefore, this cream with lactic acid should not be recommended.

While the previously mentioned studies have investigated prophylactic treatments for capecitabine-induced HFSR, few so far have investigated treatment and prevention in the oral anti–VEGF-TKI population, perhaps owing to the more recent approval dates of these therapies. One such study was conducted using a Chinese herbal extract that is not available from community pharmacies in the United States and did not have statistically significant results; thus, this study was not included in the present review.¹²

A randomized, prospective, open- label trial in Japan plans to enroll 100 patients receiving sorafenib 400 mg twice daily to determine the usefulness of high-slip skin care pads (Remois pads) in controlling pain and preventing skin damage in patients with HFSR. The study is comparing a high-slip skin care pad, changed every 2 to 3 days, with 10% urea cream, used 2 to 3 times a day. Progress will be monitored every 2 to 4 weeks, and the primary end point is the incidence of grade 2 or 3 HFSR during therapy. As of the 2011 abstract publication, 19 patients had been enrolled in the study. No results are currently available.¹³

Table 1

The only other study on the subject of HFSR caused by VEGFr TKIs was presented at the 2012 Annual Meeting of the American Society of Clinical Oncology (ASCO). The large randomized study by Zhenggang and colleagues introduces a promising new treatment using a topical low-cost, over-the-counter (OTC) cream, with a low risk of either systemic adverse effects or possible interactions with any chemotherapy agent.¹⁴ The prospective phase 3 study compared the prophylactic effect of urea-based cream, specifically Eucerin Intensive Repair Extra-Enriched Foot Crème (10% urea; Beiersdorf AG), and best supportive care. The study followed up patients taking sorafenib 800 mg daily for advanced hepatocellular carcinoma; 868 patients with similar baseline characteristics were enrolled. Patients in arm A received urea-based cream twice a day starting on day 1 and continuing for up to 12 weeks, while those in arm B received best supportive care based on the practitioner’s preference, excluding urea-based creams. A significantly lower incidence of HFSRs of all grades was observed in arm A compared with arm B (P <.0001). Furthermore, there was a trend toward a lower incidence of grade ≥2 HFSR in arm A compared with arm B, but it did not reach statistical significance (P = .1638). The findings of this study indicate that urea-based creams may be effective in preventing HFSR caused by sorafenib and could be applicable to other related oral VEGF TKIs. One limitation is that the study results have not yet been published in a peer-reviewed journal.

Figure

 

Table 2

Treatment Guidelines

While the study by Zhenggang and colleagues shows great promise for managing the adverse effects of VEGF-inhibiting TKIs, randomized controlled trials in this area are lacking, and currently there are no ASCO or National Comprehensive Cancer Network guidelines on this topic. However, because these medications are self-administered, patients still need effective education on HFSR management. Mario Lacouture and Eugene Balagula, who research and write extensively on this topic, have published several excellent reviews of the data and evidence as well as consensus panel–based recommendations in journals and in the 2012 edition of The MASCC Textbook of Cancer Supportive Care and Survivorship (chapter 35, Dermatologic Toxicities).¹⁵ The Figure details the treatments recommended in the review by Lacouture and colleagues.¹⁶ The currently available OTC urea-containing creams and lotions are listed in Table 2.

Because HFSR associated with anti-VEGF TKIs is widely considered to be one of the most clinically significant toxicities of these agents, additional research into the prevention and treatment of HFSR is paramount.

References
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