NE Oncology Issue – June 2007
Targeting the epidermal growth factor receptor: novel therapeutics in the management of cancer
Overexpression of the epidermal growth factor receptor (EGFR) has frequently been correlated with a poor prognosis in epithelial tumours, including head and neck; lung; breast; colon; and other solid tumours. This has led to efforts to develop new cancer therapies that target EGFR. Preclinical and clinical studies have shown that targeting EGFR (HER1/EGFR) is a useful strategy for anticancer therapy, since it is known to be involved in carcinogenetic processes such as cell proliferation, apoptosis, angiogenesis, cell motility, and metastasis. The anti-EGFR agents that are most studied include monoclonal antibodies (MAbs) and small-molecule tyrosine kinase inhibitors (TKIs). Evidence from clinical studies suggests that these agents can be used alone or in combination with radiation or chemotherapy. Surrogate markers of efficacy, including rash, are also being investigated, since they can be used to monitor and optimize antitumour activity. The challenges of evaluating EGFR-targeted agents include selecting optimal dosages and determining long-term toxicity. If toxicities are recognized and managed effectively, optimum dosages can be maintained. This article outlines anti-EGFR therapy-related skin toxicities and their management, based on literature data and clinical practice experience.
Anti-EGFR agents in phase II and III clinical development and their use in the treatment of cancer
Several approaches have been designed to abrogate EGFR function, such as the use of MAbs and small-molecule TKIs (Table 1). Each works through a different pathway. MAbs bind to the extracellular domain of EGFR, and prevent ligand binding, which interrupts the signalling cascade. Small-molecule TKIs bind to the intracellular domain of EGFR and inhibit the downstream effects of EGFR-ligand binding. The U.S. Food and Drug Administration (FDA) has approved anti-EGFR agents for cancer therapy, including MAbs such as cetuximab (Erbitux®) and panitumumab (VectibixTM)(Table 1), and TKIs such as erlotinib (Tarceva®).1
Cetuximab has demonstrated efficacy in phase III trials for patients with metastatic colorectal cancer, either alone or in combination with irinotecan, and it has been approved by Health Canada for use in the treatment of colorectal cancer.2 It has further been approved by the FDA for the treatment of patients with non-resectable head and neck cancers, in combination with radiation.3,4 Cetuximab has been shown to demonstrate clinical activity in combination with docetaxel in patients with refractory non–small cell lung cancer (NSCLC).5 The most frequent adverse events with cetuximab include fever and chills, asthenia, transaminase elevation, nausea, and skin toxicities pertaining to the face, scalp, chest, and upper back.6 Rash was observed in 90% of individuals undergoing cetuximab therapy, of which 8% were grade 3/4.7 A very small number of patients (1.5%) experienced grade 3 or 4 infusion reactions within minutes of the initial infusion.7 Since the half-life of cetuximab in humans is seven days, it allows once-weekly dosing and is compatible with standard chemotherapy regimens.
Panitumumab is a fully human MAb and has been shown to demonstrate antitumour activity in various advanced cancers, including renal carcinomas and metastatic colorectal cancer.1 Panitumumab has been approved by the FDA for the treatment of metastatic colorectal cancer, and a Notice of Compliance from Health Canada is pending. The principal toxicity seen with panitumumab is skin rash and it has been reported to occur in 22% of patients, of which only 1% were grade 3/4.8 Other toxicities include pruritus, dyspnea, fatigue, diarrhea, abdominal pain, and asthenia.
Several small-molecule TKIs that selectively target and inhibit EGFR function are in various stages of clinical testing (Table 2). Two TKIs that have been approved by the FDA to treat lung cancers are gefitinib and erlotinib. They are frequently used at or near their maximum tolerated dose, are readily diffusible, and are administered orally. The most common adverse events observed with these inhibitors include skin rash, diarrhea, nausea, and emesis. Acute lung injury and gastrointestinal toxicities associated with TKIs have also been reported and may be dose limiting or suspend treatment.1 Health Canada has withdrawn approval for the use of gefitinib in treatment of non-smallcell lung cancer (NSCLC), since it was found to have no signifi- cant survival benefit.9 Erlotinib has been approved in Canada as monotherapy for the treatment of patients with locally advanced or metastatic NSCLC after failure of at least one prior chemotherapy. This is based on the results of a pivotal phase III trial (BR.21), in which erlotinib was found to prolong median survival by 42.5% over best supportive care (6.7 months versus 4.7 months; p <0.001) in patients after one or two prior chemotherapy regimens.10
Toxicity associated with targeted therapies
Targeted therapies offer advantages over traditional chemotherapy, such as a higher therapeutic index with less toxicity than conventional cytotoxics. Karen Levy, an advanced practice nurse at the British Columbia Cancer Agency, says that anti-EGFR therapy is a very promising alternative therapy to conventional chemotherapy, with minimal side effects. Epidermal growth factor receptor (EGFR) inhibitors such as cetuximab are associated with dermatologic manifestations, but are not associated with the bone marrow–suppressive properties of chemotherapy.11 In patients who continue anti-EGFR therapy after completion of chemotherapy, toxicities such as anemia and fatigue are generally resolved, yielding an overall improvement in quality of life.
The toxicity of anti-EGFR therapies is generally manageable and does not overlap with other treatment options such as chemotherapy and radiotherapy.
Incidence of Rash
Although EGFR agents have been implicated specifically in the development of acneiform-like rash, similar skin manifestations also occur with different chemotherapy agents. Rash that develops during conventional chemotherapy is usually distributed throughout the head and body. However, an adverse event related to HER1/EGFR–targeted therapy is a papulopustular rash, usually on the face and upper torso, which generally occurs in a dose-dependent manner or is related to a specific drug class.12 In clinical trials related to anti-EGFR therapy, the overall incidence of rash was found to vary between 60% and 80% (Table 3).2,13 A review of the incidence and severity of rash and other dermatologic adverse effects in selected phase II and III trials shows that between 45% and 100% of patients develop rash.10 Differences in trial protocols and patient populations have made it difficult to compare the incidence of rash between agents, or between trials of the same agent.
Grades of rash
Rash associated with EGFR therapy is mostly mild (grade 1) to moderate (grade 2), and in some cases severe (grade 3) leading to dose reduction, dose interruption, or cessation of treatment when considered intolerable by the patient or oncologist. The National Cancer Institute Common Toxicity Criteria (NCI-CTC) is used in the United States for grading rash intensity (Table 4). However, this grading system is not widely applied in Canadian practice. Most Canadian physicians grade rash as mild, moderate, and severe
Other skin toxicities
Other common skin toxicities include dry skin; pruritus; xerosis; hand, finger, and heel fissures; palmar/plantar desquamation; telangiectasias; trichomegaly; nail and cuticle cracking; nasal ulcers; and vaginal dryness.14,15 Cutaneous effects of chemotherapy can also occur sporadically.16,17 In addition, EGFR and TKI therapy may cause changes in hair growth. It is imperative for physicians to monitor patients for EGFR-therapy–related common skin toxicities other than rash, and to collaborate with their physician colleagues to discuss management and treatment of rash, notes Ms. Levy.
Some nondermatologic toxicities such as diarrhea are common, while interstitial lung disease and infusion reactions are rare with anti-EGFR therapy.18 These toxicities are rarely severe, but may be fatal if not managed appropriately. Anaphylactic or anaphylactoid infusion reactions are associated with cetuximab and other MAbs. Interstitial lung disease is a rare but potentially fatal reaction that has been reported with gefitinib and erlotinib.19 Hypomagnesemia reported in association with cetuximab may be related to an EGFR blockade in the kidney.20
Diagnosis of Rash
According to Dr. Melosky, a medical oncologist at the British Columbia Cancer Agency, the diagnosis of rash and its treatment is not well documented in randomized trials where primary endpoints were survival and response. As well, she comments that it is difficult to interpret incidence of toxicity from the randomized trials, since rash is graded according to the NCI criteria that may not accurately reflect the clinical situation in Canada. Skin reactions are classified as mild, moderate, and severe. Rash is considered to be a noninfectious, inflammatory, epidermal reaction. Diagnostic proposals for improving assessment and treatment of rash caused by EGFR inhibitors vary widely because different experts use different criteria for rash evaluation in their clinics. Moreover, some experts don’t treat rash.
Common terminology used to describe acne-like rashes includes acneiform rash, maculopapular rash, pustular rash, dry skin, or exfoliative dermatitis.
Recommendations for rash management include continued analysis of the correlation between rash and the clinical outcome, and improving the accuracy and reproducibility of terminology and grading systems. Dr. Melosky suggests that the grading system could be used as a guide towards the treatment of patients with toxicities.
Presentation of Rash
Clinical experience of anti-EGFR therapy suggests that rash generally appears between the first and third week of therapy. Usually grade 1 (asymptomatic) rash appears first and is localized to the face, anterior chest, and upper back. Discomfort is minimal.21 Skin rash, consisting of moderate to severe itching on the face, scalp, chest, and back can become grade 2 or 3 in a matter of days. Measures need to be taken to treat these symptoms to maintain the patient’s quality of life (Table 2).22 At higher doses more severe rash is generally seen with higher incidence.23,24 There are no published controlled clinical trials on optimum treatment for skin side effects associated with HER1/ EGFR inhibitors. Many interventions are based on individual clinical experience and patient response.
Management of anti-EGFR–induced toxicities
According to Ms. Levy, it is important to assess rash as mild, moderate, or severe, since evidence suggests that greater rash severity correlates with better treatment response. Treatment of rash may include alcohol-free skin lotions and emollients to treat dryness. Rash can be covered up with makeup, and sunscreen should be used by patients to help avoid aggravation caused by sun exposure. In her clinical practice, Dr. Melosky prescribes a combination of 1% hydrocortisone and 2% clindamycin gel to treat mild rash. She treats moderate rash by combining steroids (1% hydrocortisone or 2.5% clindamysin gel) with tetracycline antibiotics. For a patient with severe rash associated with symptoms affecting daily activities of living, treatment with steroids and oral antibiotics is encouraged. When rash is severe, symptomatic, intolerable, and affecting daily activites of living, dose modification is recommended. Treatment may be interrupted or withheld (seven to ten days), or may be continued with dose reduction or alternate dosing. Dose delay and interruption has been reported to be helpful in controlling the severity of reactions, but this approach still needs further validation.25
Lesions and plaques on the scalp
Anti-EGFR therapy can cause patients to develop lesions and plaques on the scalp. A topical 2% clindamycin, 0.1% triamcinolone acetonide in equal parts of propylene glycol and water can be used to treat scalp lesions until resolution. In the treatment of pustular lesions and severe erythroderma with associated fever and secondary infections, topical antibiotics can be combined with systemic antibiotics. However, the course of steroids should be brief to prevent long-term sequelae associated with their use.14
Dry skin is very common skin toxicity. Perfume-free creams and ointments with an alcohol base can be used to treat dry skin.
Patients report cuticle changes after approximately eight weeks of continuous therapy. These nail changes are consistent with paronychial inflammation.19 Intervention is aimed at treating infection and decreasing discomfort. Apart from systemic antibiotics, treatment can include soaking the areas in hot water three times daily, or in a bacteriostatic solution; epsom salt solutions are beneficial in promoting drainage of purulent discharge. These later measures are often instituted as part of the daily hygiene in individuals who remain mainly on EGFR inhibitors. In severe cases, removal of the nail bed may be helpful.
Alopecia associated with HER1/EGFR inhibition is mainly characterized by sporadic thinning of hair that may become patchy in appearance. Conversely, hypertrichosis is seen with women patients who have taken erlotinib for more than six months. Photodynamic therapy or laser treatment is the best option to manage this condition.
Anticipatory counselling about the management of antiEGFR–related skin toxicities is desirable, according to Ms. Levy. “Patients need to be educated about initial symptoms associated with treatment, especially about acne. The use of the term ‘acne’ must be avoided, and patients need to be advised against the use of over-the-counter medication for acne.” From a nursing perspective, good hygiene is essential in order to prevent and manage skin toxicities. Food increases the bioavailability of the oral agents, perhaps leading to increased exposure and enhanced adverse effects. Therefore, patients need to be advised to take pills one or two hours after meals. Nurses can provide for early intervention and optimum supportive care if they are aware of the timing of side effects. Dr. Melosky says that with proper patient education, careful monitoring, and early intervention, rash can be successfully managed to allow patients to benefit from anti-EGFR therapy.
When oncologists, nurses, and cancer patients become more familiar with the common toxicity profiles associated with EGFR inhibitors, it is likely that further refinements in toxicity management strategies will emerge to help maximize the beneficial impact of these highly promising anticancer agents.
References: 1. Marshall J. Clinical implications of the mechanism of epidermal growth factor receptor inhibitors. Cancer 2006;107(6):1207–1218. 2. Cunningham D, Humblet Y, Siena S, et al. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med 2004;351(4):337–345. 3. Baselga J, Trigo JM, Bourhis J, et al. Phase II multicenter study of antiepidermal growth factor receptor monoclonal antibody in combination with platinum-based chemotherapy in patients with platinum-refractory metastatic and/or recurrent squamous cell carcinoma of the head and neck. J Clin Oncol 2005;23:5568-5577. 4. Herbst RS, Arquette M, Shin DM, et al. Phase II multicenter study of epidermal growth factor receptor antibody cetuximab and cisplatin for recurrent and refractory squamous cell carcinoma of the neck. J Clin Oncol 2005;23:5578-5587. 5. Govindan R. Cetuximab in advanced non-small cell lung cancer. Clin Cancer Res 2004;10(12 Pt 2):4241s–4244s. 6. Baselga J, Pfister D, Cooper MR, et al. Phase I studies of anti-epidermal growth factor receptor chimeric antibody C225 alone and in combination with cisplatin. J Clin Oncol 2000;18(4):904–914. 7. Patel DD, Goldberg RM. Cetuximab-associated infusion reactions: pathology and management. Oncology 2006;20(11):1–3. 8. Giusti RM, Shastri KA, Cohen MH et al. FDA Drug Approval Summary: Panitumumab (VectibixTM). Oncologist 2007;12(5):577-583. 9. New Labeling and Distribution Program for Gefitinib (Iressa). FDA. http://www.fda.gov/cder/drug/advisory/iressa.htm/. Accessed May 30, 2007. 10. Bezjak A, Tu D, Seymour L, et al. Symptom improvement in lung cancer patients treated with erlotinib: quality of life analysis of the National Cancer Institute of Canada Clinical Trials Group Study BR.21. J Clin Oncol 2006;24(24):3831–3837. 11. Rhee J, Oishi K, Garey J, et al. Management of rash and other toxicities in patients treated with epidermal growth factor receptor-targeted agents. Clin Colorectal Cancer 2005;5 Suppl 2:S101–106. 12. Perez-Soler R, Saltz L. Cutaneous adverse effects with HER1/EGFR-targeted agents: is there a silver lining? J Clin Oncol 2005;23(22):5235–5246. 13. Agero AL, Dusza SW, Benvenuto-Andrade C, et al. Dermatologic side effects associated with the epidermal growth factor receptor inhibitors. J Am Acad Dermatol 2006;55(4):657–670. 14. Morse L and Calarese P. EGFR-targeted therapy and related skin toxicity. Semin Oncol Nurs 2006;22(3):152–162. 15. Segaert S, Van Cutsem E. Clinical signs, pathophysiology and management of skin toxicity during therapy with epidermal growth factor receptor inhibitors. Ann Oncol 2005;16(9):1425–1433. 16. Payne AS, James WD, Weiss RB. Dermatologic toxicity of chemotherapeutic agents. Semin Oncol Nurs 2006;33(1):86–97. 17. Alley E, Green R, Schuchter L. Cutaneous toxicities of cancer therapy. Curr Opin Oncol 2002;14(2):212–216. 18. Sandler AB. Nondermatologic adverse events associated with anti-EGFR therapy. Oncology (Williston Park) 2006;20(5 Suppl 2):35–40. 19. Camus P. Interstitial lung disease in patients with non-small-cell lung cancer: causes, mechanisms and management. Br J Cancer 2004;91 Suppl 2:S1–2. 20. Carson EJ, Novak AM, Stella PJ. Hypomagnesemia in patients with stage IV colorectal cancer treated with cetuximab as a single agent. J Clin Oncol 2005;23 (16S Part 1):284s. Abstract 3655. 21. Sipples R. Common side effects of anti-EGFR therapy: acneform rash. Semin Oncol Nurs 2006;22(1 Suppl 1):28–34. 22. Busam KJ, Capodieci P, Motzer R, et al. Cutaneous side-effects in cancer patients treated with the antiepidermal growth receptor antibody C225. Br J Dermatol 2001;144(6):1169–1176. 23. Ranson M, Hammond LA, Ferry D, et al. ZD1839, a selective oral epidermal growth factor receptor-tyrosine kinase inhibitor, is well tolerated and active in patients with solid, malignant tumors: results of a phase I trial. J Clin Oncol 2002;20(9):2240–2250. 24. Baselga J, Hammond LA. HER-targeted tyrosine-kinase inhibitors. Oncology 2002;63 Suppl 1:6–16. 25. Shah NT, Kris MG, Pao W, et al. Practical management of patients with non-small-cell lung cancer treated with gefitinib. J Clin Oncol 2005;23(1):165–174.
Vera Hirsh, MD, FRCPC
Chief of the Hematology-Oncology Service, Santa Cabrini Hospital
Associate Professor, Medicine and Oncology, McGill University
Associate Physician, Oncology Service, at the Royal Victoria, Montreal General, and Montreal Chest Hospitals
With a current practice in both hematology and oncology, Dr. Vera Hirsh is an associate professor of medicine and oncology at McGill University. Her research at the Quebec Pulmonary Unit focuses on the treatment of lung cancer, and she continues to chair ongoing international chemotherapy trials. Dr. Hirsh chaired the Quebec Lung Cancer Committee to establish guidelines for the treatment of lung cancer. In addition, she has published abstracts, articles, and book chapters. Dr. Hirsh is a member of advisory boards for many pharmaceutical companies and the Medical Oncology Standing Committee of RTOG.
Christine Cripps, MD, FRCPC
Medical Oncologist, Director,
Continuing Medical Education,
Ottawa Hospital Regional Cancer Centre
Dr. Christine Cripps is a medical oncologist and director of the Continuing Medical Education Department at the Ottawa Hospital Regional Cancer Centre. She also holds a position of Associate Professor, Medicine at the University of Ottawa. A keen teacher, Dr. Cripps’ main areas of interest include gastrointestinal cancer and head and neck cancer. She also enjoys cycling, skiing, and sailing when time permits.
Stephen K. L. Chia, MD, FRCPC
Assistant Professor of Medicine Department of Medicine
University of British Columbia
British Columbia Cancer Agency
Dr. Chia is a staff oncologist with the British Columbia Cancer Agency (BCCA), Vancouver, Canada. He also serves as physician coordinator for both the breast cancer and head and neck cancer clinical trials at the BCCA – Vancouver Cancer Centre. He is an active researcher in phase I-III trials in breast cancer, head and neck cancer and investigational new drugs. He is currently carrying out studies in breast cancer with grant funded research from the National Cancer Institute of Canada, Canadian Breast Cancer Alliance and Canadian Breast Cancer Foundation – British Columbia/Yukon Chapter. Dr. Chia is an active member of the British Columbia Breast Tumor Group, Breast Cancer Systemic Policy Group and Head and Neck Tumor Group.
José Chang, MD, FRCPC
Head of Medical Oncology, RS
McLaughlin Durham Regional Cancer Centre, Oshawa
Dr. José Chang is the principal investigator and site representative for the National Cancer Institute of Canada Clinical Trials Group, and is an examiner for the Medical Council of Canada. His research interests lie in the areas of breast cancer, melanoma, lymphoma, and quality of life during chemotherapy. Dr Chang has presented at major oncology meetings of the American Society of Clinical Oncology, San Antonio Breast Cancer Symposia, and European Breast Cancer Conference. A member of the editorial board of the journal Current Oncology, Dr. Chang has published in journals such as the Journal of Clinical Oncology, European Journal of Cancer, and Canadian Medical Association Journal.