|Presented by: Elizabeth Lynn, BSN, RN, MSN Candidate|
|The Abramson Cancer Center of the University of Pennsylvania|
Continuing Education Information
This continuing education activity is designed to enable nurses and nurse practitioners in clinical practice to understand the pathophysiology of palmar-plantar erythrodysesthia, identify symptoms and describe the management of this complication of chemotherapy.
This activity has been approved for 1.0 contact hour by the Hospital of the University of Pennsylvania, Department of Nursing Development and Education, an approved provider of continuing nursing education by the PA State Nurses Association, an accredited approver by the American Nurses Credentialing Center's Commission on Accreditation.
To receive continuing education credits for this activity:
The presenters and planning committee report no conflicts of interest.
This activity expires June 1, 2015.
The educational objectives of this activity are:
Overview and Clinical Significance
Palmar-Plantar Erythrodysesthesia (PPE), also known as Palmar-Plantar Erythema, Acral Erythema, Hand-Foot Syndrome (HFS), and Burgdorf's Reaction, is a common adverse reaction to many cytotoxic chemotherapies and multikinase inhibitors (MKI) (Degen et al., 2010). PPE is characterized by symmetric palmar and/or plantar erythema and desquamation with pain, parasthesia (abnormal sensation), and temperature intolerance (particularly to heat) (Bos, Nijsten, de Jonge, & Hamberg, 2012). PPE is considered a common adverse effect in many frequently used cancer therapies, including Pegylated Liposomal Doxorubicin, 5-FU, capecitabine, sorafenib, and sunitinib (Degen et al., 2010). PPE is a less common adverse effect in many other therapies, including Methotrexate, Cisplatin, and Paclitaxel. Table 1 demonstrates the breadth of therapeutic agents that are associated with PPE.
While PPE is not a life threatening condition, it can have a serious effect on a patient's quality of life, requiring dose reduction and/or interruption of treatment, and presents a risk that the patient will become noncompliant with their treatment plan (Anderson et al., 2009). Patients receiving capecitabine experience a 10-17% incidence rate of grade 3 PPE, and PPE is considered the most common dose-limiting adverse reaction when treating with capecitabine (Azuma et al., 2012). In patients treated with Multikinase Inhibitors (MKIs), the incidence of PPE results in dose reductions in 40-44% of patients, brief treatment interruptions for 29-30% of patients, and discontinuation of treatment in 17-19% of patients (Choi, 2011).
The incidence and severity of PPE is both dose and schedule dependent. Schedule dependence is demonstrated in the use of 5-FU, where continuous infusion is associated with higher incidence of PPE (median 35%) than bolus (median 6.2%). Capecitabine has an even higher incidence rate of PPE (median 53.5%) (Yen-Revollo, 2008). Dose dependence is demonstrated in the incidence and severity of PPE for patients receiving Sorafenib, with infrequent incidence of PPE occurring in doses under 300 mg BID, and increased incidence and severity for doses 300-600 mg BID, and a dose limiting toxicity at 600 mg BID.
The precise etiology of PPE is unclear. The clinical and microscopic cellular changes seen in PPE are similar to other types of toxic damage to the skin, including reaction that is dose dependent, increased incidence with prolonged exposure, and increased frequency and severity when multiple substances which cause PPE are combined (Degen et al., 2010). Yet without understanding the underlying mechanism that is causing the damage, treatment has been generally limited to attempting to prevent injury and treating symptoms. It is therefore critical when caring for a patient at risk for PPE to educate the patient about the condition and its symptoms, protective measures the patient can use to reduce the occurrence of PPE, and methods for treating the condition should it occur. And, while the mechanism underlying the skin damage associated with PPE is not fully understood, the relationship between the incidence and severity of PPE and the efficacy of cancer treatment has been positively correlated (Azuma et al., 2012). Research has demonstrated a positive relationship between capecitabine associated PPE and efficacy of treatment of colorectal cancer in terms of disease control rate and progression free survival (Azuma et al., 2012). Therefore management of PPE symptoms and progression to enable patients to continue with their treatment regimen uninterrupted provides the best hope for positive treatment outcomes.
While the exact cause of Palmar-Plantar Erythrodysesthesia is unknown, there are a number of theories as to the cause, from excretion of substances directly causing damage, to vascular micro trauma causing leakage of substances into tissue resulting in damage. There has also been research focused on the variation in incidence of PPE within populations, and the potential for pharmacogenetic involvement in the incidence and level of severity.
Table 2 presents the National Cancer Institute Common Terminology Criteria for Adverse Events (V4.02) for Palmar-Plantar Erythrodysesthesia regardless or precipitating agent.
PPE associated with chemotherapy presents slightly differently than PPE associated with MKIs. Because of the increased use of combination therapies, it is important for clinicians to be able to differentiate the features of chemotherapy associated PPE and MKI associated PPE in order to adjust the dose of specific agent causing the PPE and to maintain dose intensity of the remaining agent (Gomez & Lacouture, 2011).
PPE associated with chemotherapy begins with dysesthesia (unpleasant, abnormal sensation), followed within a few days by burning pain and sharply outlined erythema with swelling that may develop into blisters (Degen et al., 2010). Generally PPE begins early in therapy, although it can occur one or more months after beginning treatment (Degen et al., 2010). There can be desquamation of the stratum corneum layer of skin, followed by ulceration or erosions (Degen et al., 2010). The lesions are found mainly on the palms of the hands and soles of the feet, with plantar symptoms more severe. In severe cases patients can experience the same symptoms on the dorsum of the hands and feet, intertriginous areas, and areas covered by tight fitting clothing (Degen et al., 2010). PPE associated with chemotherapy can occur 1-21 days after initiating therapy, and up to several months later with continued low-dose therapies (Choi, 2011). Permanent damage is rare in PPE, and significant improvement is experienced within weeks of discontinuing treatment (Degen et al., 2010).
The early symptoms of PPE associated with the MKIs sorafenib and sunitinib are the same as chemotherapy, with dysesthesia, burning pain, and erythema with swelling (Degen et al., 2010). Patients receiving sorafenib have a median onset of symptoms of 18.4 days (range 3-56 days), and sunitinib has a later onset with a median of 32.4 days (range 5-82 days) (Degen et al., 2010). Unlike the symptoms associated with chemotherapy, PPE associated with MKIs does not affect the dorsum of the hands and feet or intertriginous areas (Degen et al., 2010). The symptoms are most pronounced on the pressure points of the palms and soles of feet, even affecting the margins of the feet and skin between the toes and fingers (Degen et al., 2010). PPE associated with MKIs can also affect areas of the body under mechanical stress, including sites of amputation, fingertips, and on skin overlying joints (Almeida da Cruz et al., 2012). It can also cause callus-like thickening of the stratum corneum, formation of large, tense blisters, and can worsen quickly within days (Gomez & Lacouture, 2011). Table 3 summarizes the differentiating symptoms associated with specific agents.
The incidence and severity of PPE is based in part on the type of agent, schedule, and dose. Appendix 1 lists common agents, dosing regimens and incidence of PPE. Combination therapies that involve two PPE causing agents have the highest incidence of PPE as well as the highest occurrence of severe (grade 3) PPE. Severe cases of PPE, regardless of the agent(s) involved, can result in ulcerative dermatitis or skin thickening with severe pain that has a significant impact on a patient's ability to walk, manipulate objects with their hands, and to perform self care (Choi, 2011).
There are a number of skin conditions that affect the palmar and/or plantar surfaces. The following is a list of common differential diagnosis and distinguishing factors.
The management strategy for PPE consists of measures to prevent occurrence of the condition, as well as interventions to treat an occurrence. Very little of the management techniques are evidence based, but are rather based on experiences in clinical practice and/or based on one or more of the theories regarding the condition's pathophysiology.
Management of PPE starts with patient education and communication. It is critical that the patient be engaged prior to treatment in a discussion regarding the early signs and symptoms of PPE (Gomez & Lacouture, 2011), and that there are ongoing reassessment of PPE symptoms and the impact on the patient using a tested quality of life measure (Dermatology Quality of Life / DLQI, Skindex-16, or PPE specific HFS-14) (Sibaud et al., 2011). Patient education should include prophylactic measures which have been shown in clinical practice to reduce the incidence and/or severity of PPE, including:
(Choi, 2011; Degen et al., 2010; Almeida da Cruz et al., 2012; Yen-Revollo, 2008; Gomez & Lacouture, 2011)
Prior to initiating treatment, a comprehensive skin exam of the entire body should be conducted to identify predisposing factors for PPE (hyperkeratosis, eczema, fungal disease, or misalignment) (Gomez & Lacouture, 2011). If indicated, a pedicure by a podiatrist and/or an evaluation by orthotist should be ordered (Gomez & Lacouture, 2011). To the extent possible, pre-existing skin conditions and risk factors should be addressed prior to initiating treatment.
Research has identified a limited number of pharmacological treatments that have been used successfully to reduce the frequency and severity of PPE under specific circumstances. A single clinical study found that inhibitors of dihydropyrimidine dehydrogenase (DPYD), such as Gimeracil, reduced the incidence of PPE in patients receiving fluoropyrimidines (5-FU and capecitabine) (Yen-Revollo, 2008). The mechanism of action of DPYD inhibitors in reducing the incidence of PPE is supported by research by Almeida da Cruz et al. (2012), which found that individuals with DPYD deficiency have decreased incidence in PPE. Other research has found the incidence and severity of PPE in patients receiving capecitabine alone or capecitabine + oxaliplatin is reduced with the use of cyclooxygenase 2 inhibitors such as Celecoxib (Degen et al., 2010; Zhang, 2012). The researchers have theorized that Celecoxib impairs circulation to the hands and feet, thereby reducing exposure to the cytotoxic agent. A similar mechanism of action has been proposed in retrospective studies of the use of nicotine patches during and after administration of capecitabine. A retrospective study has found nicotine patches to reduce the incidence and severity of PPE in patients receiving capecitabine, and the efficacy of nicotine patches is currently being further studied by the National Cancer Institute in a clinical trial (Degan, 2010; Almeida da Cruz et al., 2012).
A number of treatments have been found to relieve the symptoms and limit the severity of PPE. In cases of severe, debilitating grade 3 PPE, discontinuing treatment until the patient experiences improvement in symptoms is effective, and often treatment can be resumed with dose reduction without recurrence of severe PPE (Almeida da Cruz et al., 2012). In addition to the aforementioned treatments recommended to prevent the occurrence of PPE, topical treatment has been found to be beneficial for treating PPE. The treatment guidelines are dependent on the manifestation of the PPE and the cancer treatment agent:
Treatment by Manifestation
Treatment by Cancer Treatment Agent
Research has been conducted on effectiveness of pharmacological treatments in treating PPE. For example, there has been considerable research as to the efficacy of pyridoxine (Vitamin B6) to prevent or treat PPE, with mixed results. While the most recent randomized trials have found pyridoxine (200 mg/day) to have no effect on PPE outcomes for patients receiving capecitabine or liposomal doxorubicin (Almeida da Cruz, 2012; von Grueniger et al., 2010; Wolf et al., 2010), there have been case studies that have found pyridoxine (150-300 mg/day) has been successful in limiting the severity of PPE in patients receiving docetaxel and 5-FU (Degen et al., 2010). Non-pharmacological treatments have also been investigated. An analysis of case studies by Bos et al. (2012) found that topical UV-A controlled the severity of PPE in patients receiving TKI therapy. Researchers have theorized that UV-A might have an anti-inflammatory effect, reducing chemokines involved in the neuropathic pain process.
Palmar-Plantar erythrodysesthesia (PPE) is a common adverse affect from many chemotherapies and multikinase inhibitors, including capecitabine, 5-FU, docetaxel, doxorubicin, sorafenib and sunitinib. While not a life threatening reaction, PPE can severely affect the quality of life for the patient, inhibiting self-care and often resulting in non-adherence to the treatment plan. The etiology of PPE is unknown, although it is widely understood to be a toxic reaction to the therapeutic agent, and there are reasonable theories as to the underlying process. Prevention and treatment of PPE is primarily based on clinical experience, with little research-based evidence. However, there are easily implemented activity modifications and preventative measures that patients can use to reduce the incidence and severity of PPE. The primary tool for preventing PPE is patient education about PPE symptoms, preventative measures, and treatment, and ongoing surveillance with timely treatment.
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