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How to deal with toxicity of targeted therapies
Liesbeth Lemmens, BSc, MSc, Coordinator clinical trials digestive oncology, University Hospitals, Leuven, Belgium ‘mouse' part of the chimeric drug. Nurses must be aware that this During the last decade, targeted therapies such as epidermal growth reaction can occur immediately after the start of the factor receptor (EGFR) inhibitors have shown their efficacy in the administration. The rates of occurrence are 2.5 % in patients treatment of several types of cancer. The epidermal growth factor treated with cetuximab and irinotecan in combination and 1.8% in receptor is a transmembrane glycoprotein tyrosine kinase family of patients treated with cetuximab monotherapy. The symptoms in growth factors that is expressed in many normal human tissues. Its case of a severe reaction are: airway obstruction, dyspnoea, activity is finely regulated to control cell growth and proliferation.
severe urticaria and hypertension (3). Should a severe reaction In many solid tumours, dysregulation of the EGFR gene results in its occur, the administration of the EGFR-inhibitor should be stopped overexpression and increased production of EGFR – a condition at once and emergency treatment implemented. Patients who correlated with increased metastasis, reduced survival, and a poor experience a severe hypersensitivity reaction should not be prognosis (Figure 1).
treated again with this monoclonal antibody.
The EGFR can be successfully blocked either by antibodies against the extracellular domain of the receptor (i.e., cetuximab, panitumumab) or It is important to tell patients who are discharged to home that by small-molecule tyrosine kinase inhibitors (i.e., erlontinib, gefitinib) this kind of reaction may also occur up to 24h after administration which target the EGFR at the intracellular site (1). Blocking of the of the antibody. Patients may experience headache, a slight fever, receptor in tumours leads to beneficial effects, in terms of reduced shivers and sometimes mild dyspnoea which occur in 15% to 23% tumour growth, but in skin and appendages this action leads to of patients. Patients should be told to inform the nurse about undesirable reactions, including acne-like rash, hair growth disorders, these symptoms so that the infusion rate can be reduced at the periungual and nail plate abnormalities, xerosis and sometimes pruritis next infusion (4).
Figure 1: EGFR activation (Merck KGa)
The diarrhoea seen with EGFR inhibitors is usually mild and transient and varies in incidence depending on whether the EGFR inhibitor is taken orally (54% of patients treated with erlotinib and 40% to 57% with gefitinib) or is administered i.v. Loperamide is the treatment of choice and nurses should advise patients to have loperamide on hand if they start to have diarrhoea. The recommended dosing of loperamide is 4mg initially, then 2mg after every loose bowel movement up to 10 tablets (2mg)/day for 24 to 48 hours until they are free of diarrhoea for This gastrointestinal side effect can be managed easily. However in some patients, doses of EGFR inhibitors should be reduced or, although rare, dose cessation may be required for severe Treatment with EGFR-inhibitors can also result in some systemic diarrhoea which is unresponsive to treatment with loperamide (5).
disorders such as hypersensitivity reactions (especially with monoclonal antibodies), gastrointestinal discomfort and metabolic disorders such as hypomagnesaemia and secondary Preliminary evidence suggests that magnesium wasting occurs in hypocalcaemia. These side-effects need a special treatment patients who are treated with EGFR-targeting monoclonal approach. Although many of the suggested treatments and antibodies for colorectal cancer. The mechanism of this side effect therapies are empirical and based on experience, our knowledge is unknown and whether all or just a subset of patients is affected about the toxicity profile steadily increases. is unclear. Results from clinical trials using cetuximab in combination with irinotecan or oxaliplatin showed that 97% of the Nurses are pioneers in tackling these toxicities. Nurses need to patients had a decreased serum magnesium concentration. understand the mechanism of action of these new drugs not only Of course, not all hypomagnesaemia may be the result of to enrich their knowledge base, but also to have a strong treatment with an EGFR-inhibitor; patients with advanced cancer foundation for patient education. They need to know about side might have a pre-existing, sub-clinical hypomagnesaemia unrelated effects and possible interventions, and to participate in research to treatment.
to identify effective interventions.
The symptoms of hypomagnesaemia are: fatigue, somnolence, Systemic Side effects
mental alterations, seizures, QT changes, muscle cramps secondarily to hypocalcaemia and, in severe cases, arrhythmias.
A hypersensitivity reaction is a sign of ‘intolerance' against the However, only a small proportion of patients have symptoms of administered drug and is seen after treatment with monoclonal hypomagnesaemia. Therefore, nurses should monitor patients by antibodies (incidence is 4.5%). Patients can react against the regular blood sampling (every two weeks) and, if indicated, 12 - NEWSLETTER FALL 2007
patients should undergo an ECG.
Figure 2: Multidisciplinary approach to treating skin toxicities
The treatment of hypomagnesaemia consists of high doses of secondary to EGFR-inhibitors
magnesium, approximately 9g orally. Treating patients with magnesium intravenously is not comfortable and requires hospitalisation every 36h (6).
Non-systemic side effects: skin toxicity
EGFR-inhibitors and tyrosine kinase-inhibitors are responsible for a number of class-specific side effects on the skin which occur in most patients (7-8). This is probably due to the abundant expression of EGFR in the epidermis and its appendages (hair follicles, sebaceous glands). The clinical pattern of skin toxicity is unique and consists of an acneiform eruption, xerosis (skin dryness) sometimes leading to eczema and fissures, paronychia, hair changes (trichomegaly of the eyelashes, vellus (downy)hair, and frontal alopecia (9). The ocular, oral, nasal and vaginal mucosa can also be affected (10-12). Skin toxicity is graded according to the NCI-CTC criteria (version 3.0) Although skin toxicity is not life threatening and rarely requires the Despite growing knowledge about the treatment of these toxicities, discontinuation of EGFR- inhibitor therapy, there is a clear need for uncertainty about the extent of the burden of the toxicities related supportive treatment and dermatological referral if severe. The to EGFR-inhibition exists. Nurses should take an active role in rash usually affects the skin of the face and often has a dramatic providing education to patients that skin reactions can be impact on self-esteem and patients' quality of life (13).
effectively treated if treatment measures are properly followed.
The intensity of the acneiform rash may be correlated with the clinical effectiveness of the EGFR-inhibitor therapy: more rash, means better tumour response. Nurses should be careful about Treatment of solid tumours with EGFR-inhibitors offers a clear benefit using this information, because there are also patients who don't and these drugs have a generally tolerable safety profile. It is known develop the acne-like rash and have a good response to that specific adverse skin reactions occur in a large percentage of patients but these are usually mild and can be managed effectively.
Appropriate education of patients is needed and nurses again play As the number of patients treated by EGFR-inhibitors is increasing a pivotal role in explaining skin problems and the general rapidly in European oncology centres, it is essential that existing measures that can be taken, and the ‘do's and dont's' that help knowledge and experience about managing both the systemic and manage skin problems. A nurse is also the first person the patient non-systemic side effects is rapidly disseminated. Nurses should contact in case of concern. While mild to moderate cases administering these agents should take available opportunities to of skin toxicity can be managed by standard treatment, patients increase their knowledge about mechanism of action, safe with severe skin toxicity should be referred to a dermatologist administration, and side effects.
(Table 1) (14-16).
Table 1: Experience-based treatment of skin toxicity
1. Reff ME et al: Depletion of B cells in vivo by a chimeric mouse human monoclonal antibody to CD20.
Blood 83(2):435-445, 1994.
* Based on the NCI-CTC version 3.0 2. Johnston JB et al: Targeting the EGFR pathway for cancer therapy. Curr Med Chem 13:3483-3492, 2006.
3. TARGET Initiative: EGFR inhibitors in the treatment of cancer. EONS, 2006.
4. Thomas M: Cetuximab: adverse event profile and recommendations for toxicity management.
Clinical Journal of Oncology Nursing 9:332-8, 2005. 5. Kris M et al: Efficacy of gefitinib, an inhibitor of the epidermal growth factor receptor tyrosine kinase in asymptomatic patients with non-small cell lung cancer: a randomized trial. JAMA 290:2149-58, 2003. doxycycline 100 mg/day 6. Tejpar S et al: Magnesium wasting associated with EGFR-targeting antibodies in colorectal cancer: a prospective study. Lancet Oncol 8:387-94, 2007.
Propyleneglycol 50% aqua solution, covered with 7. Busam KJ et al: Cutaneous side-effects in cancer patients treated with the anitepidermal growth plastic (30 min./day) factor receptor antibody C225. Br J Dermatol 1441:1169-1176, 2001.
doxycycline 200 mg/day Strong emollients 8. Segaert S et al: Clinical signs, pathophysiology and management of skin toxicity during therapy with Hydrocolloid bandage epidermal growth factor receptor inhibitors. Annals of Oncology 16:1425-1433, 2005.
9. Gallimont-Collen AFS et al: Classification and management of skin, hair, nail and mucosal side- application weekly effects of epidermal growth factor receptor (EGFR) inhibitors. European Journal of Cancer 43 (5):845-851, 2007.
10. Busam KJ et al: Cutaneous side-effects in cancer patients treated with the antiepidermal growth factor receptor antibody C225. Br J Dermatol 1441:1169-1176, 2001.
NaCl 0.9% compresses (15 minutes, 2 - 3x/day) 11. Segaert S et al: Clinical signs, pathophysiology and management of skin toxicity during therapy with plus metronidazole cream epidermal growth factor receptor inhibitors. Annals of Oncology 16:1425-1433, 2005.
–topic fucidin penicillin x 5 days 12. Lacouture ME et al: Cutaneous Reactions to Anticancer Agents Targeting the Epidermal Growth antibiotic x 5-10 Superinfection: oral Factor Receptor: A Dermatology-Oncology Perspective. Skin Therapy Letter 12 (6):1-4, 2007.
13. Segaert S et al: Clinical signs, pathophysiology and management of skin toxicity during therapy with epidermal growth factor receptor inhibitors. Annals of Oncology 16:1425-1433, 2005.
* Based on the NCI-CTC version 3.0 14. Guillot B et al: Aspects cliniques et prise en charge des effets secondaires cutanés des inhibiteurs The management of side effects is multidisciplinary and all du récepteurs à l'EGFR. Ann Dermatol Venereol 133:1017–1020, 2006.
participants need proper education and training to help patients 15. Segaert S et al: The management of skin reaction in cancer patients receiving epidermal growth understand and cope with these toxicities. (Figure 2).
factor targeted therapies. JDDG 3:599-606, 2005.
16. Lacouture ME et al : The SERIES clinic: an interdisciplinary approach to the management of toxicities of EGFR inhibitors NEWSLETTER FALL 2007 - 13

Source: http://www.cancernurse.eu/documents/newsletter/2008spring-en/EONSnewsletter2008spring-enPage12.pdf