Epidermal growth factor receptor tyrosine kinase inhibitors are widely used in the management of metastatic non-small cell lung cancer. Adverse events, their impact on quality of life and treatment adherence with these oral drugs are discussed
Nathalie Letarte BPharm MSc BCOP
Pharmacist, Centre hospitalier de l’Université de Montréal, Montréal, Canada;
Assistant Clinical Professor, Faculty of Pharmacy, Université de Montréal;
Co-chair of the Chaire pharmaceutique Famille Sabourin en santé des femmes
Lung cancer is the leading cause of death by cancer in Europe, Canada and the US.(1) In the last few years, treatment of metastatic lung cancer has evolved and has become more personalised based on new characterisations of the disease. Lung cancer is classified as small cell lung cancer (20%) and non-small cell lung cancer (NSCLC) (80%), which is also subdivided into three other histological subtypes: adenocarcinoma, squamous cell and large cell. Mutations have been identified in the adenocarcinoma subtype. Metastatic adenocarcinoma of the lung is now being treated according to the presence or absence of mutations and/or overexpression of various oncogenes: EGFR, EML4-ALK fusion, KRAS, etc. Studies are ongoing to discover the meaning and clinical implications of these and other molecular abnormalities.
Epidermal growth factor receptor
Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (EGFRi) are widely used in metastatic lung cancer. Gefitinib, erlotinib and afatinib are used in first- and second-line therapy, which may differ in various jurisdictions. In Europe, afatinib is indicated in EGFRi-naïve patients with locally advanced or metastatic NSCLC. Gefitinib is indicated in patients with locally advanced or metastatic NSCLC with activating mutations of EGFR. Erlotinib is approved in first-line treatment of locally advanced or metastatic NSCLC with EGFR-activating mutations. It is also approved in maintenance and in second-line treatment after failure of chemotherapy, regardless of the EGFR mutation status.2 Other agents, such as dacomitinib, are now being evaluated in clinical trials. The adverse events of the EGFRi differ significantly from adverse events usually encountered with conventional chemotherapy (alopecia, nausea and vomiting and haematological toxicity). This article aims to review the management of some adverse events related to EGFRi, the impact on quality of life (QoL) and to discuss treatment adherence with oral oncology drugs.
Managing EGFRi adverse events
In clinical trials and in clinical practice, EGFRi, such as gefitinib, erlotinib and afatinib, caused many adverse events (>90% all grade, up to 60% grades 3–4).(3–6) The most common adverse events with EGFRi, as presented in Table 1, include gastrointestinal disorders (nausea, diarrhoea), constitutional symptoms (fatigue) and dermatological toxicities.
Dermatological toxicity is common with EGFRi. The array of symptoms varies from dry skin, pruritus to maculopustular eruptions, and present in various severities with each agent. The mechanism of dermatologic toxicity is not fully understood, although some hypotheses have been suggested. EGFR is expressed on skin cells such as keratinocytes in the epidermis, hair follicles and sebaceous and eccrine glands. Inhibition of the EGFR by the tyrosine kinase inhibitors leads to apoptosis, inflammation, atrophy and telangectasia of the skin cells, thereby affecting the epidermal barrier function.(7–9)
The most frequent dermatological adverse event is the papulopustular rash, sometimes called acneiform rash. The rash usually presents one to two weeks after the start of EGFRi. The symptoms begin with dry skin, erythema and often inflammation. The papules and pustules that appear shortly after are usually sterile, although there have been some reports of Staphylococcus aureus cultures in secondary infections. The usual areas affected by the rash include the face, thorax, upper back and scalp where the sebaceous glands are mostly located. The rash usually peaks at four weeks and decreases in severity about six to eight weeks after the start of therapy. Erythema and hyperpigmentation have occurred as late post-inflammatory effects.(10,11)
In oncology practice, adverse events are often graded by using tools such as the National Cancer Institute-Common Terminology Criteria for Adverse Events (CTCAE) or the World Health Organization (WHO) grading systems. These two scales are usually used in clinical trials and were not modified with the event of the new targeted therapies and the new toxicities that ensued. The Multinational Association of Supportive Care in Cancer (MASCC) has developed a specific tool to grade dermatological toxicities with EGFRi: the MASCC EGFR Inhibitor Skin Toxicity Tool (MESTT) (available at www.mascc.org). This tool accounts for the number of lesions and associated symptoms and is thereby more precise in assessing the extent of toxicity.(12)
Prevention or treatment?
When EGFRi became more widely used, clinicians were faced with this new dermatological complication to overcome. Treatment options included topical (corticosteroids, antibiotics, acne treatments) and systemic treatments (antibiotics and oral steroids). Evidence-based data were not available at the time and clinicians used whatever treatments were available for skin rash. Retrospective studies were then published and more structured clinical trials emerged. Some clinical trials have evaluated if preventative measures, rather than a reactive treatment only after skin lesions occurred, might prevent occurrence or delay toxicity. Two trials evaluated patients treated with EGFR-inhibiting antibodies, such as cetuximab and panitumomab. The first study evaluated the impact of minocycline versus placebo plus tazarotene on face lesions in patients receiving cetuximab.(13) There was a 50% reduction in the number of lesions for two to four weeks, but the difference was not present at week eight. Tazorotene did not have any effect. The Skin Toxicity Evaluation Protocol with Panitumumab (STEPP) trial studied topical treatments (moisturisers, sunscreen, steroids) and doxycycline in patients receiving panitumomab in prevention or as a reactive treatment.(14) There was a reduction from 62% to 29% of the grade 2 skin toxicity. Following the publication of these trials, many clinical practice guidelines emerged to help clinicians manage dermatological toxicities, both in prevention and treatment.(10,15–18) Table 2 summarises the guidelines. Typically, a grade 1 rash can be treated with a topical treatment comprising hydrocortisone 1% and clindamycine 1% lotion. A grade 2 rash usually requires a stronger topical steroid such as bethamethasone 0.05% and systemic antibiotics (minocycline or doxycycline). In the presence of a grade 3 or 4 rash, the rash is treated with systemic antibiotics, oral steroids and treatment with the EGFRi is withheld until resolution to a grade 1. Treatment with EGFRi can then recommence at a lower dose.
Other dermatological adverse events include erythema, pruritus, eyelash change, nail change, paronychia, hair loss and hyperpigmentation of the skin. Conventional treatment is then established and is beyond the scope of this article.
If not treated early, skin toxicity may have serious consequences on the patient’s treatment. On top of affecting the patients’ psychological wellbeing, it can cause delay in cancer treatment or dose reductions and even treatment discontinuation, affecting the overall efficacy of treatment. It can also lead to secondary infections and increased costs.
Nausea is reported in 15–25% of patients receiving EGFRi, but is normally mild and responds to usual antiemetics. Loss of appetite has also been reported. Vomiting is rare. Diarrhoea, however, is the most frequent gastrointestinal toxicity with this class.(3–6,19) Incidence varies from 46% with gefitinib to more than 90% with afatinib, including 14% of grade 3–4. Early recognition of symptoms and management are crucial to prevent complications. Diarrhoea often presents in the first weeks of EGFRi therapy and can become moderate to severe if not taken into account. If treated early, the symptom resolves and seems to be controlled in time, becoming a grade 1 chronic manageable adverse event.
After excluding other potential causes of diarrhoea, such as medications or infectious causes like Clostridium difficile or viral infections, an antidiarrhoeal medication such as loperamide can be used. Loperamide should be started at the first sign of diarrhoea. Monitoring patient hydration status and electrolyte replacements is recommended. Usual non-pharmacological measures such as dietary changes (that is, the BRAT diet: banana, rice, apple sauce and toast), and hydration should be established. If standard-dose loperamide does not improve diarrhoea within 24 hours, high-dose loperamide may be administered (4mg, followed by 2mg every two hours during the day; 4mg every four hours during the night) until 12 hours have passed without diarrhoea. Patients with grade 3 or 4 diarrhoea not responding to loperamide should be sent to hospital for hydration and investigation, and treatment with EGFRi should be withheld.(15)
Patients with advanced or metastatic lung cancer are often symptomatic of their disease. The objectives of treating metastatic cancer are to reduce tumour burden, alleviate symptoms, prolong life and improve QoL. New drugs such as EGFRi that cause so many adverse events, for example, dermatological toxicities and diarrhoea, may worsen QoL. Patients receiving afatinib, gefitinib or erlotinib were included in QoL evaluations. In the afatinib studies, QoL was improved compared with chemotherapy for global health status and other functional scales. Their cancer symptoms improved and were not worsened by the treatment. Although in the LUX-lung 3 study, some categories (emotional and social functioning subsets) were not statistically significant.(20) The EURopean TArceva vs Chemotherapy (EURTAC) trial could not evaluate QoL because of low questionnaire retrieval, but other trials involving erlotinib did.(21) The IPASS study (gefitinib) evaluated the QoL and showed that cancer symptoms improved in patients that responded to treatment.(22)
Patient compliance is somewhat of a recent problem in oncology. Ten years ago, patients would go to an oncology clinic and receive intravenous chemotherapy every three weeks. Today, patients have responsibilities and have to take ownership of their treatment. Some actually prefer taking oral drugs over intravenous treatments. Many factors may contribute to the success or failure of patient compliance and pharmacists have a role in detecting those factors. Social matters, complexity of treatment, adverse events, comorbidities, stage of disease, understanding of treatment, cognitive problems or poor literacy are some of the factors that can lead to adherence concerns.(23–28)
The data support the theory that compliance to treatment has an effect on treatment efficacy. Tyrosine kinase inhibitors, such as imatinib, used in chronic myeloid leukaemia are susceptible to treatment adherence. It has been shown that missing only a few doses per month reduces efficacy, increases resistance rates and mutations and increases costs.(25)
Role of pharmacists
Oncology pharmacists, and even community pharmacists who might dispense these new drugs in some jurisdictions, have a major role in patient education. Early recognition of symptoms and pre-emptive management of adverse events will contribute to improve cancer treatment. Multidisciplinary teams composed of oncology nurses, oncologists and pharmacists can help to optimise treatment.
- Dermatological toxicities are frequent with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors. Prevention with moisturisers or mild corticosteroid cream with or without systemic antibiotics may be used.
- Early recognition of dermatological toxicity and early management is central to prevent complications such as dose reductions, treatment delays and treatment discontinuation.
- Diarrhoea, a common adverse event of EGFRi, needs to be recognised and treated early.
- Patient compliance with oral chemotherapy agent is crucial in the overall efficacy of treatment.
- Pharmacists, in collaboration with a multidisciplinary team, have a leading role in patient and professional education in recognising and managing adverse events with EGFRi.
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- Lacouture ME et al. Skin toxicity evaluation protocol with panitumumab (STEPP), a phase II, open-label, randomized trial evaluating the impact of a pre-Emptive Skin treatment regimen on skin toxicities and quality of life in patients with metastatic colorectal cancer. J Clin Oncol 2010;28:1351–7.
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