Palmar plantar erythrodysesthesia (PPE) is a toxicity that can occur to the palms of hands and soles of feet with specific chemotherapy treatments. The National Cancer Institute (2010) describes PPE (also known as hand- foot syndrome) as a condition marked by pain, swelling, numbness, tingling, or redness of the hands or feet. In the literature, PPE has been more descriptively defined as a cutaneous toxicity that manifests with palmar and plantar erythema, edema, and dysesthesia with varying degrees of pain, scaling, and vesiculation (Lipworth, Robert, and Zhu, 2009). The incidence of PPE depends on the drug therapy, dosage, and the manner in which the drug is administered. Examples of drug administration include the duration of an infusion and time off therapy in between doses.
The most common chemotherapy drugs known to cause PPE include: capecitabine (occurring in 28-74% of patients), 5-fluorouracil (in 34% of patients receiving a continuous infusion and 13% of patients receiving bolus injection), and liposomal doxorubicin (in up to 48% of patients) (Lipworth et al, 2009)). Less often, continuous infusion doxorubicin, high-dose interleuken-2, liposomal daunorubicin, cytarabine, idarubicin, cyclophosphamide, hydroxyurea, methotrexate, docetaxel, mercaptopurine, mitozantrone, paclitaxel, vinorelbine, floxuridine, and tegafur have caused PPE. Targeted therapies, including sorafenib, sunitinib, and lapatinib, are also known to cause PPE.
PPE can affect quality of life and is often a dose-limiting side effect when symptoms become unmanageable. PPE typically presents with dysesthesia and tingling in the hands and feet, which usually appear 2-12 days after administration of chemotherapy (Lorusso et al, 2007). These symptoms may progress, 3-4 days later, into mild symmetrical edema and erythema of the palms and soles, or other high-pressure areas, and typically resolve in 1-2 weeks. However, PPE may evolve into blistering desquamation, crusting, ulceration, and epidermal necrosis if the next chemotherapy cycle is not delayed or dose reduced (Lorusso et al). Therefore, it is important for health care providers to monitor patients at risk for the condition and assess the severity of PPE in those who are affected.
PPE can be distressing and have a detrimental effect on quality of life when patients are not able to work or carry out their normal activities (Webster-Gandy, How, and Harrold, 2007). Early identification and intervention can prevent increasing complications as well as increase the chance of tolerating further cancer therapy. Logically, the longer treatment is tolerated, the greater likelihood of treatment benefit or reaching the goals of completing therapy.
There actually have been some reports of PPE being correlated with improved survival, suggesting that greater exposure to the therapeutic drug, as represented by the PPE, also results in improved outcomes. This theory could explain a phase I trial with sorafenib therapy which found a statistically significant increase in the length of time to progression among patients who developed PPE, from 1.5 months in unaffected patients to 5 months in patients with PPE (Lipworth et al, 2009).
The exact mechanism of PPE is unknown. One practical theory is that there is a direct (accumulative) toxicity of the drug in the epidermis and dermal vasculature (Yarbro, Frogge, and Goodman, 2004). Additionally, it has been assumed that palms and soles might achieve higher concentrations of chemotherapeutic agents as a result of the rich capillary network at the thickened papillary dermis and increased blood flow (Lotem et al, 2000). The contribution of local pressure or trauma to the skin has also been observed as a risk factor for PPE, given that areas such as the axillae, groin, sacrum, and others can be affected by PPE (Lorusso et al, 2007).
Another theory suggests both inflammatory processes and increased vascularization exist, which results in the substances penetrating through the extended capillaries (Martschick et al, 2009). The high turnover rate of keratinocytes (predominant cell in the epidermis) may also make hands and feet more susceptible to damage (Martschick et al). One theory for capecitabine induced PPE is that keratinocytes in the skin have increased levels of thymidine phosphorylase (TP) (the enzyme responsible for generating 5-fluorouracil), which leads to the accumulation of capecitabine metabolites in the hands and feet (Milano et al, 2008). Milano et al discovered that TP and dihydropyrimidine dehydrogenase (DPD) (the enzyme responsible for catabolizing 5-fluorouracil into dihydrofluorouracil) are expressed significantly higher in palms versus the back. However, the mechanism of higher concentrations of dihydrofluorouracil causing PPE has not been explained. A cell proliferation marker (Ki67) was also significantly higher in epidermal basal cells of the palm compared to the back. This suggests that the high proliferation rate of the epidermal basal cells in the palm could make them more sensitive to the local action of cytotoxic drugs (Milano et al).
Another theory is that the drug accumulates in the high density of eccrine glands of the palms and soles and that the drug can actually be excreted in sweat (Lorusso et al, 2007). Other associations to anatomic differences in the hands and feet include a thick stratum corneum and wide dermal papillae, as well as the absence of folliculo-sebaceous units (Martschick et al, 2009). Martschick et al studied the pathomechanism of anthracycline-induced PPE by using laser scanning microscopy to detect liposomal doxorobicin versus epirubicin and their metabolites in and on the skin of patients subsequent to systemic administration. They detected that both substances arrived "at the skin through the sweat glands and then spread[ing] out laterally on the surface before penetrating back into the stratum corneum, as if applied topically". While the substances where also detected in other areas of sweat glands such as the forehead, the forehead has a thin stratum corneum. This could indicate that a thick stratum corneum, which represents a large reservoir for penetrating substances, is another factor in the development of PPE. The stored substance can induce oxidative processes and formation of free radicals in the skin, which may lead to development of skin lesions.
In one analysis, the incidence of PPE in patients who received liposomal doxorubicin was 67% compared to 0% in patients receiving epirubicin (Martschick et al, 2009). This indicates that the characteristics of the liposome play a role in PPE development, including its ability to disintegrate in the stratum corneum. Additionally, liposomal doxorubicin has a longer half-life and higher concentrations can be found in the skin.
Risk factors for developing PPE include the type, dose and duration of chemo or biotherapy being used. The risk for PPE increases with each dose of potential PPE inducing chemotherapy. One study found that only patients who had hyperhidrosis (excessive sweating) of the palms and plantae developed PPE after receiving liposomal doxorubicin (Lorusso et al, 2007). A systematic review of 4,883 patients patients receiving sorafenib, those with renal cell carcinoma had a relative risk of 1.52 for PPE compared to other malignancies (Lipworth et al, 2009). Other risk factors include advanced age, female sex, performance status, and exposure to total body irradiation (Lipworth et al).
As previously described, PPE presents with prodromal tingling and dysesthesia with erythema in the palms of the hands, fingers, and soles of the feet which may progress to burning pain with dryness, cracking, desquamation, papules, ulceration, edema, and rash. Sensory impairment, paresthesia, and pruritis have also been reported (Webster-Gandy et al, 2007). The pain can become so severe that it feels as if one is walking on glass (Yarbro et al, 2004).
The severity of PPE can be described based on a grading system. The National Cancer Institute (NCI) created a simple definition grading system. Grade 1 is skin changes or dermatitis without pain (erythema, peeling). Grade 2 is skin changes with pain, not interfering with function. Grade 3 is skin changes with pain, interfering with function. In comparison, the World Health Organization (WHO) developed a more descriptive grading system and can be viewed in the Appendix.
Other names for PPE include acral erythema, palmoplantar erythema, hand-foot syndrome, and Burgdorf reaction. Acral erythema is one condition that is described as another name for PPE in some literature and in other sources has a completely separate definition. However, there is not enough distinction between the two conditions to label them as separate conditions. The presenting symptoms of PPE can overlap with other dermatological conditions. The most important differentiating factor is the patient's risk based on previous treatments and medical history. Some differential diagnoses for PPE are further described.
Neutrophilic eccrine hidradenitis is a rare inflammatory skin disorder characterized by erythematous and edematous papules, plaques or nodules located on the trunk, extremities and face that may be pruritic or tender. The condition occurs most often in patients undergoing chemotherapy for AML and has a distinctive histopathologic feature of a neutrophilic infiltrate around eccrine glands and coils. It can also occur in patients with Hodgkin's lymphoma or solid tumors.
Palmoplantar eccrine hidradenitis is another skin disorder with painful erythematous papules and nodules of abrupt onset on the soles and, less frequently, on the palms. While it appears almost exclusively in otherwise healthy children, histopathologic findings are similar to those seen in neutrophilic eccrine hidradenitis.
Osler nodes are painful, red, raised lesions that are usually found on the pads of fingers or toes. They are a skin manifestation of infective endocarditis. The exact pathogenesis in unclear,but they may be caused by immune complex deposition or septic microemboli.
Erythema multiforme is an acute, self-limited skin disease with lesions that usually appear symmetrically on the dorsal surfaces of the hands and extensor aspects of the extremities. They may also appear on the palms or soles. The erythematous macules or papules evolve into classic iris or target lesions, with a central dusky or darker red area and a peripheral paler pink or edematous zone. A burning sensation may be felt in affected areas.
Palmar erythema is nontender reddening of the palms of the hands at the thenar and hypothenar eminences (fleshy pads on either side of the palm). It may also involve the fingers and soles of the feet (plantar erythema). This disorder is associated with various physiologic or pathologic changes, including liver disease, pregnancy, thyrotoxicosis and rheumatoid arthritis. Palmar erythema in liver disease and pregnancy may be due to high levels of estrogen.
Primary treatment for PPE, especially when the toxicity reaches grade 2 or 3 on the NCI grading system, is stopping treatment until symptoms improve to grade 1 or completely resolve and/or continuing therapy at a reduced dose. Further dose adjustment depends on the chemotherapy given and the overall goal of treatment. For example, the package insert for capecitabine recommends if PPE initial toxicity is severe at grade 3 it is advised to adjust the next dose to 75% of the initial dose (Gresset, Stanford, and Hardwicke, 2006). If grade 2 or grade 3 toxicity occurs a second time, the suggested adjustment for the next cycle is 75% of the initial dose for grade 2 and 50% for grade 3. If grade 3 toxicity occurs a third time it would be advised to discontinue the drug permanently, whereas grade 2 would require a dose adjustment to 50% of initial dose. If grade 2 toxicity occurred a fourth time, the drug would be discontinued permanently (Gresset et al).
Pyridoxine, or vitamin B6, has been studied as a treatment for PPE induced by chemotherapeutic agents. Case reports and retrospective cohort studies found significant symptom improvement with doses of 50 to 300 mg of vitamin B6 daily (Lipworth et al, 2009). Beveridge et al (1990) performed a randomized clinical trial in which 50 mg pyridoxine was given twice daily versus nothing to patients receiving continuous 5-fluorouracil. The patients receiving pyridoxine with PPE had a higher rate of symptom improvement (38% vs. 0%) and a lower rate of deterioration (46% vs. 92%). However, the pyridoxine had no effect on the extent to which the chemotherapy had to be held or could be escalated.
Cyclo-oxygenase-2 inhibitors are thought to mediate the inflammation seen in PPE and have been studied as prophylactic therapy. Retrospective studies have found a reduced incidence of PPE in patients taking celecoxib with capecitabine (Lipworth et al, 2009). An ongoing randomized placebo-controlled phase III trial is assessing the role of celecoxib in preventing PPE caused by capecitabine (ClinicalTrials.gov NCT00305643).
Very few effective treatments for PPE have been verified with randomized clinical trials. Some case reports have reported promising outcomes for treatment with Vitamin E. Kara, Sahin, and Erkisi (2005) found that Vitamin E therapy at 300 mg/day by mouth allowed 4 patients who developed grade 2-3 PPE to continue therapy with docetaxel and capecitabine without dose reduction. After one week of treatment PPE began to disappear.
Data for all other therapies for PPE are limited to case reports and series, which must be evaluated with careful consideration of publication bias. Steroids, both systemic and topical, used as prophylaxis or as treatment, have shown varying success. Several uncontrolled series have observed decreased rates of PPE from liposomal doxorubicin, cytarabine, and docetaxel in conjunction with steroid therapy, while others show no benefit (Lipworth et al, 2009).
Other therapies identified in case series as having some benefit include: topical henna, urea 12.5%, topical dimethyl sulfoxide, and the cytoprotective agent amifostine (Lipworth et al, 2009). Emollients, specifically Udderly Smooth udder cream when used in conjuction with pyridoxine and petroleum/lanolin-based ointment containing the antiseptic hydroxyquinolone, have both been documented to provide symptomatic relief (Lipworth et al).
Vasoconstrictive therapy has been studied under the premise that by vasoconstricting the acral surfaces, the drug delivery is decreased to the skin in these areas. Both localized cooling for treatment and prophylaxis and application of a nicotine patch during treatment have shown benefit in reducing PPE (Lipworth et al, 2009). Mangili et al (2007) observed that the use of ice packs around wrists and ankles prevented PPE onset in a group of women treated with liposomal doxorubicin for gynecological cancers. Only 7.1% of women in the ice pack group developed mild PPE versus 36% in the premedication (pyridoxine and dexamethasone) only group, with PPE ranging from mild to severe. One woman in the ice pack group who did develop PPE had a severe hydiopathic vasculitis of the lower extremities that presented before starting chemotherapy, which could have made her less responsive to the ice treatment. The other woman developed cutaneous toxicity after performing warm wax hair removal. However, there are no controlled randomized trials proving the use of ice packs reduces the incidence of PPE, and there is concern that preventing the drug from reaching certain areas may allow some cancer cells to escape treatment.
Lifestyle modifications, like avoiding high-temperatures, excessive exercise, or ill-fitting clothing and shoes can be of benefit (Lipworth et al, 2009). The most important aspect of PPE treatment is teaching at-risk patients the signs and symptoms to watch for and report to their health care provider. The sooner PPE is identified, the sooner interventions can be implemented with the hope of reducing PPE severity and optimizing chemotherapy treatment.
PPE is a known toxicity and possible side effect of certain chemotherapy agents, most often with capecitabine, 5-fluoruracil, liposomal doxorubicin, and sorafenib, and less often with other therapies, as previously mentioned. The clinical presentation of PPE can vary from person to person, but most often occurs within 2 weeks after a dose administration and can progress from dysesthesia, tingling, erythema, and edema to desquamation, blistering, ulceration, and necrosis. Mild or moderate symptoms usually spontaneously resolve over a couple of weeks as the causative therapy is further metabolized and cutaneous healing begins. While very few treatment regimens have shown definitive efficacy, it is important to recognize PPE symptoms early on in order to monitor for progression of symptoms and stop therapy and/or dose reduce therapy when necessary. Interventions can be tried early upon identification of PPE development, hence creating the greatest possibility of stabilizing or reducing PPE severity. It has been shown that being able to obtain a full course of therapy creates better patient outcomes, and therefore it is important to minimize side effects and optimize therapy. Furthermore, identifying PPE early allows symptoms to be managed in an effective manner, preventing them from getting to a point when functionality is disturbed and quality of life is decreased.
|NCI grade||NCI definition|
|1||Skin changes or dermatitis without pain, e.g., erythema, peeling|
|2||Skin changes with pain, not interfering with function|
|3||Skin changes with pain interfering with function|
|WHO grade||WHO definition||Clinical lesion||Histological findings|
|1||Dysesthesia/parathesia, tingling in the hands and feet||Erythema||Dilated bloodvessels of superficial and dermal plexus|
|2||Discomfort in holding objects and upon walking, painless swelling or erythema||1+edema|
|3||Painful erythema and swelling of palms and soles, periungual erythema and swelling||2+fissuration||Isolated necrotic keratinocytes in higher layer of the epidermis|
|4||Desquamation, ulceration||3+blister||Complete epidermal necrosis|
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