HFSR is typically characterized by redness, marked discomfort, swelling, and tingling in the palms of the hands and/or soles of the feet.32 HFSR can be painful enough to interfere profoundly with activities of daily living (ADLs). In fact, patients may report symptoms after as few as 2 weeks on TKI therapy, at which point they may present to the health-care provider (HCP) wearing slippers, unable to walk, and having difficulty in performing ADLs such as eating, dressing, and bathing.[1] and [33] Although HFSR can lead to TKI dose modification or treatment discontinuation, preventive measures can be taken before TKIs are initiated to reduce the likelihood of HFSR. In addition, early treatment of symptoms may prevent HFSR from progressing to the point at which the patient's ability to receive the full potential benefit of therapy is compromised.[3], [34], [35] and [36]
Signs and symptoms of HFSR may appear concomitantly or sequentially and can affect both hands and both feet. Although symptoms are most prominent on the palms and soles, other areas of the hands and feet may also be involved, including the tips of the fingers and toes, the heels, and metatarsophalangeal skin; areas of flexure; and skin overlying the metacarpophalangeal and interphalangeal joints.3 These “pressure areas” are where the most severe symptoms are typically seen. Common symptoms include dysesthesia and paresthesia, described as “tingling, prickling, or creeping sensations” and/or sensitivity or intolerance to hot or warm objects (which may occur before other symptoms are apparent); erythema; edema; hyperkeratosis; and dry and/or cracked skin.[1] and [34] Actual HFSR lesions are described as tender and scaling, with a peripheral halo of erythema, yellowish and hyperkeratotic plaques, or callous-like blisters (which usually do not contain fluid), typically localized to areas of pressure.[3] and [35] Desquamation, particularly with sunitinib treatment, may also be present.37
Since both sorafenib and sunitinib inhibit the VEGFRs, PDGFRs, c-KIT, and Flt3,38 it is likely that inhibition of one or more of these receptors and/or pathways plays a role in HFSR development.36 Differences in the relative appearance of HFSR symptoms are dependent on whether sorafenib or sunitinib is used. Sunitinib use is more often associated with desquamation, whereas sorafenib is more often associated with areas of hyperkeratosis, particularly formation of thick calluses on the soles of the feet.37 The timing of the first appearance of symptoms may also vary according to the TKI used. HFSR usually develops within the first 2–4 weeks of treatment with a TKI and almost always within the first 6 weeks.35 However, because the severity of HFSR appears to be dose-dependent,3 signs and symptoms may present later rather than sooner in patients treated with sunitinib. This is likely due to the recommended sunitinib dosing schedule, which incorporates a 2-week period during which no drug is administered. Although HFSR frequently decreases in intensity during treatment, even without dose modifications or treatment interruption, prompt treatment of HFSR is recommended to prevent rapid progression. Early symptoms can usually be resolved easily by appropriate treatment, which often allows continuation of full-dose therapy for the prescribed length of time.
It is important to note what HFSR is not. TKI-associated HFSR is not the same clinical entity as the hand–foot syndrome (HFS) traditionally seen with cytotoxic agents such as infusional 5-fluorouracil (5-FU); capecitabine, the oral prodrug of 5-FU; and pegylated liposomal doxorubicin. Although HFSR and HFS share several clinical and pathological aspects—each previously has been called “acral erythema” and “PPE”—they clearly are not the same clinical or pathologic entity. HFSR is neither an allergic reaction to a drug nor an indication that a patient may be intolerant to a drug. Finally, HFSR does not indicate drug efficacy, as may be the case with skin rash in patients with non-small-cell lung cancer treated with erlotinib.[3] and [39]
Grading HFSR
In published reports, the severity of HFSR is usually graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE),32 a three-grade classification system. However, modified criteria are considered by some to be a better fit for routine clinical practice.1 What distinguishes the modified criteria from the NCI criteria (version 4.02) is the inclusion of HFSR-specific clinical characteristics plus certain patient-defined considerations used to categorize severity. The modified criteria expressly define the degree to which HFSR discomfort affects the patient's normal activities, an improvement over version 4.02 used alone. The NCI-CTCAE version 4.02 criteria, the modified criteria, and corresponding patient photographs are presented in Figure 3.[1] and [32]