Expert Consensus on the Management of Adverse Events from EGFR Tyrosine Kinase Inhibitors in the UK

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) such as gefitinib, erlotinib, and afatinib are standard-of-care for first-line treatment of EGFR-mutant advanced non-small cell lung cancer (NSCLC). These drugs have a proven benefit in terms of higher response rate, delaying progression and improvement of quality of life over palliative platinumbased chemotherapy. The most common adverse events (AEs) are gastrointestinal (GI) (diarrhoea and stomatitis/mucositis) and cutaneous (rash, dry skin and paronychia). These are usually mild, but if they become moderate or severe, they can have a negative impact on the patient's quality of life (QOL) and lead to dose modifications or drug discontinuation. Appropriate management of AEs, including prophylactic measures, supportive medications, treatment delays and dose reductions, is essential. A consensus meeting of a UKbased multidisciplinary panel composed of medical and clinical oncologists with a special interest in lung cancer, dermatologists, gastroenterologists, lung cancer nurse specialists and oncology pharmacists was held to develop guidelines on prevention and management of cutaneous (rash, dry skin and paronychia) and GI (diarrhoea, stomatitis and mucositis) AEs associated with the administration of EGFR-TKIs. These guidelines detail supportive measures, treatment delays and dose reductions for EGFR-TKIs. Although the focus of the guidelines is to support healthcare professionals in UK clinical practice, it is anticipated that the management strategies proposed will also be applicable in non-UK settings.

# Introduction
Lung cancer remains the leading cause of cancer-related death worldwide [bib_ref] Cancer statistics, Siegel [/bib_ref]. Non-small cell lung cancer (NSCLC) represents 85 % of all lung cancer diagnoses and is a heterogeneous disease with several biological events driving tumour growth and progression [bib_ref] Metastatic non-small-cell lung cancer (NSCLC): ESMO Clinical Practice Guidelines for diagnosis, treatment..., Peters [/bib_ref].
Activating epidermal growth factor receptor (EGFR) gene mutations have emerged as the most relevant predictor of response to the EGFR tyrosine kinase inhibitors (EGFR-TKIs) gefitinib, erlotinib and afatinib [bib_ref] Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell..., Lynch [/bib_ref] [bib_ref] EGF receptor gene mutations are common in lung cancers from ''never smokers''..., Pao [/bib_ref] [bib_ref] EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy, Paez [/bib_ref]. These mutations are present in 10-35 % of NSCLC patients and more frequent in never/light smokers, women, patients with adenocarcinoma histology and patients with East Asian ethnicity. Several randomised phase III trials have consistently shown that gefitinib, erlotinib and, more recently, afatinib are more effective in terms of response rate (RR) and progression-free survival (PFS), less toxic and better tolerated than standard platinum-based doublet chemotherapy when given to untreated advanced NSCLC patients harbouring an activating EGFR mutation [bib_ref] Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma, Mok [/bib_ref] [bib_ref] First-SIGNAL: first-line single-agent iressa versus gemcitabine and cisplatin trial in never-smokers with..., Han [/bib_ref] [bib_ref] Updated overall survival results from a randomized phase III trial comparing gefitinib..., Inoue [/bib_ref] [bib_ref] Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR, Maemondo [/bib_ref] [bib_ref] Updated overall survival results of WJTOG 3405, a randomized phase III trial..., Mitsudomi [/bib_ref] [bib_ref] Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring..., Mitsudomi [/bib_ref] [bib_ref] Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive..., Zhou [/bib_ref] [bib_ref] Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced..., Rosell [/bib_ref] [bib_ref] Phase III study of afatinib or cisplatin plus pemetrexed in patients with..., Sequist [/bib_ref] [bib_ref] Afatinib versus cisplatin plus gemcitabine for first-line treatment of Asian patients with..., Wu [/bib_ref]. Furthermore, after a median follow-up of 36.5 months, a prespecified analysis of LUX-Lung 3 and LUX-Lung 6 studies demonstrated longer overall survival (OS) favouring the afatinib arm over chemotherapy for patients with a tumour harbouring an exon 19 deletion (LUX-Lung 3: 33.3 vs. 21.1 months, p = 0.0015; LUX-Lung 6: 31.4 vs..4 months, p = 0.02) [bib_ref] Overall survival (OS) in patients (pts) with advanced non-small cell lung cancer..., Yang [/bib_ref].
On the basis of these phase III clinical data [bib_ref] Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma, Mok [/bib_ref] [bib_ref] First-SIGNAL: first-line single-agent iressa versus gemcitabine and cisplatin trial in never-smokers with..., Han [/bib_ref] [bib_ref] Updated overall survival results from a randomized phase III trial comparing gefitinib..., Inoue [/bib_ref] [bib_ref] Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR, Maemondo [/bib_ref] [bib_ref] Updated overall survival results of WJTOG 3405, a randomized phase III trial..., Mitsudomi [/bib_ref] [bib_ref] Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring..., Mitsudomi [/bib_ref] [bib_ref] Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive..., Zhou [/bib_ref] [bib_ref] Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced..., Rosell [/bib_ref] [bib_ref] Phase III study of afatinib or cisplatin plus pemetrexed in patients with..., Sequist [/bib_ref] [bib_ref] Afatinib versus cisplatin plus gemcitabine for first-line treatment of Asian patients with..., Wu [/bib_ref] , the American Society of Clinical Oncology (ASCO) [bib_ref] American Society of Clinical Oncology provisional clinical opinion: epidermal growth factor receptor..., Keedy [/bib_ref] and European Society for Medical Oncology (ESMO) [bib_ref] Metastatic non-small-cell lung cancer (NSCLC): ESMO Clinical Practice Guidelines for diagnosis, treatment..., Peters [/bib_ref] recommend EGFR mutation analysis to determine whether an EGFR-TKI or chemotherapy is the appropriate first-line treatment for advanced NSCLC.
Gefitinib, erlotinib and afatinib are all approved by the European Medicine Agency (EMA) for use in the first-line setting for EGFR mutation positive advanced NSCLC patients. The most common adverse events (AEs) associated with the use of these drugs are GI (diarrhoea and stomatitis/mucositis) and cutaneous (rash, dry skin and paronychia). These AEs are usually mild, but if they become moderate or severe, they can have a negative impact on the patient's quality of life (QOL) and lead to dose modifications or drug discontinuation. Given that therapy is likely to continue for at least 10 months, appropriate management of AEs, including prophylactic measures, supportive medications, treatment delays and dose reductions, is essential. [fig_ref] Table 1: Incidence of drug reductions/modifications and discontinuations in patients with EGFR mutation positive... [/fig_ref] summarises the incidence of drug reductions/modifications and discontinuations in patients with EGFR mutation positive advanced NSCLC taking EGFR-TKIs first line in phase III randomised clinical trials [bib_ref] Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma, Mok [/bib_ref] [bib_ref] First-SIGNAL: first-line single-agent iressa versus gemcitabine and cisplatin trial in never-smokers with..., Han [/bib_ref] [bib_ref] Updated overall survival results from a randomized phase III trial comparing gefitinib..., Inoue [/bib_ref] [bib_ref] Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR, Maemondo [/bib_ref] [bib_ref] Updated overall survival results of WJTOG 3405, a randomized phase III trial..., Mitsudomi [/bib_ref] [bib_ref] Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring..., Mitsudomi [/bib_ref] [bib_ref] Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive..., Zhou [/bib_ref] [bib_ref] Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced..., Rosell [/bib_ref] [bib_ref] Phase III study of afatinib or cisplatin plus pemetrexed in patients with..., Sequist [/bib_ref] [bib_ref] Afatinib versus cisplatin plus gemcitabine for first-line treatment of Asian patients with..., Wu [/bib_ref].
Supportive care, dose reductions and treatment interruptions are appropriate strategies to manage EGFR-TKIassociated AEs [bib_ref] Management of the adverse events of afatinib: a consensus of the recommendations..., Arriola [/bib_ref]. The management goals for these patients are to support them throughout their treatment so that they can derive the maximum benefit from the therapy while maintaining a good QOL, and to avoid premature discontinuation of these drugs because of the potential loss of clinical benefit [bib_ref] Management of the adverse events of afatinib: a consensus of the recommendations..., Arriola [/bib_ref] [bib_ref] Clinical efficacy and toxicity of anti-EGFR therapy in common cancers, Harandi [/bib_ref] [bib_ref] Mechanisms of cutaneous toxicities to EGFR inhibitors, Lacouture [/bib_ref]. For the appropriate management of AEs, it is important that patients are followed up closely (i.e. bi-weekly) during the first 6 weeks of treatment. After that, clinical reviews can take place on a monthly basis.
In 2009, an expert consensus group published guidelines on the management of erlotinib-associated cutaneous toxicity in the UK [bib_ref] Expert consensus on the management of erlotinib-associated cutaneous toxicity in the, Thatcher [/bib_ref]. By 2014, three EGFR-TKIs were available in the UK and it was considered that a review of management strategies for all of the AEs associated with these drugs would be beneficial.
A consensus meeting of a UK-based multidisciplinary panel composed of medical and clinical oncologists with a special interest in lung cancer, dermatologists, gastroenterologists, lung cancer nurse specialists and oncology pharmacists, was held to develop guidelines on prevention and management of cutaneous and GI AEs associated with the administration of EGFR-TKIs. These guidelines detail supportive treatment measures, treatment delays and dose reductions for EGFR-TKIs. Although the focus of the guidelines is to support healthcare professionals in UK clinical practice, it is anticipated that the management strategies proposed will also be applicable in non-UK settings.

## Cutaneous adverse events
The EGFR has multiple effects on skin physiology, including stimulation of epidermal growth, inhibition of differentiation, and acceleration of wound healing [bib_ref] Mechanisms of cutaneous toxicities to EGFR inhibitors, Lacouture [/bib_ref] [bib_ref] Epidermal growth factor receptor inhibitor-associated cutaneous toxicities: an evolving paradigm in clinical..., Lynch [/bib_ref]. Inhibition of EGFR activity leads to a cascade of cellular events that results in multiple cutaneous AEs including rash, dry skin, pruritus and inflammation of nail/periungual tissues [bib_ref] Mechanisms of cutaneous toxicities to EGFR inhibitors, Lacouture [/bib_ref] [bib_ref] Epidermal growth factor receptor inhibitor-associated cutaneous toxicities: an evolving paradigm in clinical..., Lynch [/bib_ref]. In phase III clinical studies of EGFR-TKIs, 54-89 % of patients experienced any grade of skin AEs and 0-16.2 % experienced grade C3 skin AEs [bib_ref] Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma, Mok [/bib_ref] [bib_ref] First-SIGNAL: first-line single-agent iressa versus gemcitabine and cisplatin trial in never-smokers with..., Han [/bib_ref] [bib_ref] Updated overall survival results from a randomized phase III trial comparing gefitinib..., Inoue [/bib_ref] [bib_ref] Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR, Maemondo [/bib_ref] [bib_ref] Updated overall survival results of WJTOG 3405, a randomized phase III trial..., Mitsudomi [/bib_ref] [bib_ref] Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring..., Mitsudomi [/bib_ref] [bib_ref] Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive..., Zhou [/bib_ref] [bib_ref] Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced..., Rosell [/bib_ref] [bib_ref] Phase III study of afatinib or cisplatin plus pemetrexed in patients with..., Sequist [/bib_ref] [bib_ref] Afatinib versus cisplatin plus gemcitabine for first-line treatment of Asian patients with..., Wu [/bib_ref]. The incidence of skin-related AEs in phase III studies of EGFR-TKIs is presented in. The prevention and management of EGFR-TKI-related cutaneous AEs is summarised in .

## Prevention
To reduce the risk of cutaneous AEs, patients should be advised to moisturise the skin intensively and to protect the skin from excessive exposure to sunshine. [fig_ref] Table 3: Examples of emollients and soap substitutes that are suitable for patients taking... [/fig_ref] detail creams, gels, ointments and soap substitutes that are suitable for patients taking EGFR-TKIs [bib_ref] Expert consensus on the management of erlotinib-associated cutaneous toxicity in the, Thatcher [/bib_ref] [bib_ref] Managing treatment-related adverse events associated with EGFR tyrosine kinase inhibitors in advanced..., Hirsh [/bib_ref] [bib_ref] Dermatologic adverse events associated with afatinib: an oral ErbB family blocker, Lacouture [/bib_ref] [bib_ref] Interdisciplinary management of EGFR-inhibitor-induced skin reactions: a German expert opinion, Potthoff [/bib_ref]. Patients should use an emollient several times a day [fig_ref] Table 5: Guidance for amounts of emollients that patients taking EGFR-TKIs should use per... [/fig_ref]. Ointments are generally more effective for dry, irritable rashes because they have a hydrating effect by improving the skin's lipid barrier. By contrast, water-based creams can further dry the skin and very greasy emollients may increase the risk of folliculitis.
Although there is limited evidence that EGFR-TKIs trigger a photosensitive reaction, encouraging patients to cover their skin and to wear SPF 30 UVA/UVB non-occlusive sunscreen, especially in strong sunshine, is a EGFR epidermal growth factor receptor, TKIs tyrosine kinase inhibitors, NSCLC non-small cell lung cancer, NS not stated, AE adverse event a IPASS and FIRST-SIGNAL STUDY also enrolled patients with EGFR wild type tumours Grade 2 toxicity: continue EGFR TKI at current dose unless rash is prolonged or intolerable or the re are other intolerable AEs (refer to SPC); continue to moisturise regularly and intensify emollient use (check compliance again and advise about appr opriate amount to use per week); apply short term topical ste roids; continue topical antibiotics during and after oral antibiotic course (tetracycline 2 weeks); antihistamines can be considered (usually given at night for their potential sedative effect but be aware of impact on driving/using machinery).
Provide patient education about prevention and management of skin AEs before EGFR TKI treatment starts. Explain that rash is not acne.
Grade 3 toxicity: discontinue EGFR TKI and only reinstate (at reduced dose) when skin AE has resolved to Grade 2 (refer to SPC); manage as for Grade 2; oral antibiotics and topical steroids as appropriate: refer patient to dermatologist who specialises in drug related cutaneous AEs; investigate for cause(s) of infection. Management of skin adverse events in patients taking EGFR-TKIs (UK practice) [bib_ref] Managing treatment-related adverse events associated with EGFR tyrosine kinase inhibitors in advanced..., Hirsh [/bib_ref] [bib_ref] Dermatologic adverse events associated with afatinib: an oral ErbB family blocker, Lacouture [/bib_ref]. EGFR epidermal growth factor receptor, TKis tyrosine kinase inhibitors, AEs adverse events, SPF sun protection factor, UVA ultra-violet A, UVB ultra-violet B, SPC summary of product characteristics pragmatic approach [bib_ref] Expert consensus on the management of erlotinib-associated cutaneous toxicity in the, Thatcher [/bib_ref] [bib_ref] Dermatologic adverse events associated with afatinib: an oral ErbB family blocker, Lacouture [/bib_ref] [bib_ref] Interdisciplinary management of EGFR-inhibitor-induced skin reactions: a German expert opinion, Potthoff [/bib_ref]. For personal hygiene, aqueous emollients and soap substitutes are less dehydrating for the skin than normal soaps; shampoos that reduce the risk of scalp folliculitis, e.g. ketoconazole, betadine and ceanel, should be recommended.

## Management of rash
Patients with grade 1 rash should continue their EGFR-TKI therapy and apply an emollient regularly . If there are signs of superadded infection, the EGFR epidermal growth factor receptor, TKIs tyrosine kinase inhibitors application of topical antibiotics in alcohol-free formulations, as recommended in local guidelines, should be considered for at least 14 days.
If the rash has progressed to grade 2, the EGFR-TKI can be continued at the current dose as the rash improves within 2 weeks in the majority of cases . Dose reduction or interruption of the EGFR-TKI might be appropriate if grade 2 rash is prolonged or intolerable. Physicians should refer to the current EGFR-TKI summary of product characteristics (SPC) for prescribing advice. If a chronic grade 2 rash develops, a dermatologist should be consulted as the rash can have a deleterious effect on the patient's QOL. Moisturising should be intensified and topical steroids (e.g. 1-2.5 % hydrocortisone or eumovate ointment to the face; betnovate, elocon or dermovate ointment to the body) can be applied on a short-term basis (i.e. for 2-3 weeks), and then the patient's condition should be reviewed. Topical antibiotics (as alcohol-free formulations), in accordance with local guidelines, and/or a course of oral antibiotics (e.g. tetracycline C2 weeks) may be indicated. Oral antihistamines are sometimes prescribed for patients with grade 2 itchy rash, but only a limited proportion of the patients derive symptomatic benefit. Patients should be advised about the possible sedative effects of antihistamines on their ability to drive or operate machinery.
In case of grade 3 rash, EGFR-TKI therapy should be temporarily interrupted and the treating physician should refer to the current SPC for each EGFR-TKI for prescribing advice . We recommend restarting EGFR-TKI therapy only when the rash has improved to grade B2. Dose reductions are recommended in the SPCs for erlotinib and afatinib, but not for gefitinib [bib_ref] Cancer statistics, Siegel [/bib_ref]. It is not uncommon in clinical practice to restart gefitinib on alternate days but this is not recommended in the SPC. The rash should be managed as recommended for grade 2 rash, with oral antibiotics and topical corticosteroids as appropriate and referral to a dermatologist who specialises in drug-related cutaneous AEs. Any potential infection associated with the rash should be identified and appropriately treated, as recommended in local guidelines.

## Paronychia
Paronychia is a disorder characterised by an inflammatory process involving the soft tissues around the nail. It is a relatively common AE in EGFR-TKI-treated patients because EGFR-TKIs prevent normal EGFR signalling and this leads to alterations in, and inflammation of, the periungual tissues [bib_ref] Mechanisms of cutaneous toxicities to EGFR inhibitors, Lacouture [/bib_ref].
In phase III studies, between 4 and 56.8 % of patients experienced any grade of paronychia and 0-11.4 % experienced grade C3 paronychia [bib_ref] Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma, Mok [/bib_ref] [bib_ref] First-SIGNAL: first-line single-agent iressa versus gemcitabine and cisplatin trial in never-smokers with..., Han [/bib_ref] [bib_ref] Updated overall survival results from a randomized phase III trial comparing gefitinib..., Inoue [/bib_ref] [bib_ref] Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR, Maemondo [/bib_ref] [bib_ref] Updated overall survival results of WJTOG 3405, a randomized phase III trial..., Mitsudomi [/bib_ref] [bib_ref] Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring..., Mitsudomi [/bib_ref] [bib_ref] Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive..., Zhou [/bib_ref] [bib_ref] Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced..., Rosell [/bib_ref] [bib_ref] Phase III study of afatinib or cisplatin plus pemetrexed in patients with..., Sequist [/bib_ref] [bib_ref] Afatinib versus cisplatin plus gemcitabine for first-line treatment of Asian patients with..., Wu [/bib_ref]. Paronychia can severely impact on a patient's QOL and ability to carry out his/her activities of daily living. It usually emerges 1-6 months after the initiation of EGFR-TKI therapy [bib_ref] Epidermal growth factor receptor inhibitor-associated cutaneous toxicities: an evolving paradigm in clinical..., Lynch [/bib_ref] [bib_ref] Interdisciplinary management of EGFR-inhibitor-induced skin reactions: a German expert opinion, Potthoff [/bib_ref]. Prevention and management of EGFR-TKI-related paronychia is summarised in [fig_ref] Figure 2: Management of paronychia in patients taking EGFR-TKIs [/fig_ref].

## Prevention
Educating patients about the risk of paronychia during EGFR-TKI therapy and how to prevent it is essential [fig_ref] Figure 2: Management of paronychia in patients taking EGFR-TKIs [/fig_ref] [bib_ref] Interdisciplinary management of EGFR-inhibitor-induced skin reactions: a German expert opinion, Potthoff [/bib_ref]. Careful hand protection (as for hand dermatitis) is advisable. Patients should keep their hands and feet as dry as possible and not soak them in soapy water for prolonged periods of time without adequate protection, e.g.

## Management
The prescribed dose of the EGFR-TKI can usually be maintained in the presence of grade 1 paronychia, but dose reductions and/or interruptions should be considered if toxicity becomes grade C2 (consult the summary of product characteristics (SPC) for each EGFR-TKI). At the first signs of nail problems, patients should inform their medical team as grade 1 paronychia can escalate to grade 2 very quickly. For grade 1 toxicity, some patients find warm water or white vinegar soaks beneficial [bib_ref] Acute and chronic paronychia, Rockwell [/bib_ref]. The affected area should be soaked in warm water for approximately 15 min 3-4 times per day. White vinegar soaks (1:1 white vinegar:water) can be used for 15 min every day.
Prevention: Keep feet and hands as dry as possible; do not soak hands and feet in soapy water for a prolonged period of time without adequate protection; avoid nail trauma/injury; moisturise hands and feet regularly; dry feet carefully before putting on shoes; take care when cutting nails; wear cotton gloves underneath washing up gloves to protect hands. Shoes should protect nails but not be restrictive. Avoid skin irritants. Provide patient education about paronychia before EGFR TKI treatment starts; stress the need to alert healthcare professional (HCP) at first signs of paronychia. Usually emerges 1-6 months after EGFR TKI treatment initiation and reduces patient's quality of life.
Grade 3 toxicity: discontinue EGFR TKI and only reinstate when AE has resolved to Grade 2 (check SPC). Refer for specialist support. Continue to apply topical very potent steroid, antifungals, antibiotics and/or antiseptics (preferably as combination preparations). Apply silver nitrate if over-granulation present. Swab any pus for culture and prescribe appropriate antibiotics. Consider surgical intervention. Consult a dermatologist for further assessment and management, such as potassium permanganate soaks. For grade 1-2 paronychia, topical very potent corticosteroids and antimicrobials (antifungals and antibiotics), preferably as combination preparations and as recommended in local guidelines, should be applied as necessary [fig_ref] Table 4: Examples of topical corticosteroid, corticosteroid/antimicrobial and other corticosteroid combination preparations that are... [/fig_ref]. For grade 2 toxicity, supportive treatment, including oral antibiotics, should be started and silver nitrate should be applied by a healthcare professional if over-granulation has developed. Consulting a podiatrist may be useful if the patient experiences feet-related symptoms.
For grade 3 toxicity, the EGFR-TKI should be discontinued and only reinstated when toxicity has improved to grade B2 (consult SPC for details). The patient should be referred for specialist support (a dermatologist or podiatrist as appropriate). Continued application of topical very potent combinations of steroids, antifungals, antibiotics and/or antiseptics, as recommended in local guidelines, and of silver nitrate, if over-granulation is present, is advised. Any pus should be swabbed for culture and antibiotics prescribed accordingly. Surgical intervention, with or without intravenous antibiotics, should be considered if toxicity does not improve.

## Gastrointestinal adverse events

## Diarrhoea
Diarrhoea is the most common AE experienced by patients treated with an EGFR-TKI. The underlying mechanism for this AE is poorly understood, but it is believed that EGFR-TKI-associated diarrhoea is due to excessive chloride secretion, which leads to a secretory form of diarrhoea [bib_ref] Clinical efficacy and toxicity of anti-EGFR therapy in common cancers, Harandi [/bib_ref] [bib_ref] Diarrhea associated with afatinib: an oral ErbB family blocker, Yang [/bib_ref]. In phase III studies, between 25 and 95 % of patients experienced any grade of GI AEs and 1-14 % experienced grade C3 GI AEs . Prevention and management of EGFR-TKI-related diarrhoea is summarised in [fig_ref] Figure 3: Management of diarrhoea in patients taking EGFR-TKIs [/fig_ref].

## Prevention
Prior to initiating EGFR-TKI therapy, the patient's baseline bowel history should be obtained [bib_ref] Diarrhea associated with afatinib: an oral ErbB family blocker, Yang [/bib_ref]. Although there is no validated questionnaire for this patient group, obtaining information about the patient's bowel habits for the 6-week period prior to starting EGFR-TKI treatment will provide a baseline against which any EGFR-TKI-induced GI changes can be assessed [fig_ref] Figure 3: Management of diarrhoea in patients taking EGFR-TKIs [/fig_ref]. Information on the patient's concomitant medications and other clinical conditions should be collected at baseline and assessed for their potential impact on the GI tract by checking the prescribing information for each drug. Drug:drug interactions that might lead to GI AEs should also be evaluated.
The evidence base for interventions (e.g. special diets) to prevent EGFR-TKI-associated GI AEs is very limited [bib_ref] Managing treatment-related adverse events associated with EGFR tyrosine kinase inhibitors in advanced..., Hirsh [/bib_ref]. Following a low-fat, low-fibre diet and minimising intake of fruit, red meat, alcohol, spicy food and caffeine may be a sensible approach for patients experiencing diarrhoea during EGFR-TKI treatment. If feasible, referral to a dietician will provide patients with the most up-to-date information about reducing the risk of diarrhoea and/or managing GI AEs. However, the physician must always be aware that dietary restrictions might have a negative impact on the patient's QOL and promote weight loss in a patient population where maintaining body weight can already be difficult.

## Management
If diarrhoea occurs during EGFR-TKI therapy, it is important to determine whether this is drug-related or infective [bib_ref] Managing treatment-related adverse events associated with EGFR tyrosine kinase inhibitors in advanced..., Hirsh [/bib_ref]. If there is evidence of a GI infection, the patient should be treated appropriately. The aim of EGFR epidermal growth factor receptor, TKIs tyrosine kinase inhibitors, NSCLC non-small cell lung cancer, NS not stated a IPASS and FIRST-SIGNAL STUDY also enrolled patients with EGFR wild type tumours managing GI AEs is to return the patient to his/her baseline state or to grade B1. If grade 1 or grade 2 (for less than 48 h) diarrhoea occurs, patients should be advised to take loperamide at a dose of 4 mg, followed by 2 mg after each episode of diarrhoea, up to a maximum of 16 mg/day (up to 20 mg/day in some countries outside the UK). Drinking 1-1.5 l per day of isotonic, oral rehydration salts (ORS) is recommended; patients should be advised not to drink more than 0.5 l of hypotonic fluids (e.g. water, tea, fruit juice) as this can make the diarrhoea worse [bib_ref] Diarrhea associated with afatinib: an oral ErbB family blocker, Yang [/bib_ref].
Most cases of grade 1 or short duration grade 2 diarrhoea resolve quickly and can be managed via telephone consultation. Patients should be advised to inform the medical team if they develop grade 1 or 2 diarrhoea that does not resolve within 48 h, or if they develop diarrhoea with fever.
If the diarrhoea persists for [48 h, despite administration of the maximum daily dose of loperamide, or is grade 3-4, the patient's condition should be reviewed and EGFR-TKI should be discontinued [bib_ref] Managing treatment-related adverse events associated with EGFR tyrosine kinase inhibitors in advanced..., Hirsh [/bib_ref]. Patients should be advised to phone their clinical nurse specialist if diarrhoea persists for [48 h or is grade 3-4. Adding codeine (starting with 30 mg/day which can be increased up to 60 mg four times a day) to the patient's regimen, on a short-term basis, may be beneficial [bib_ref] The medical management of intestinal failure: methods to reduce the severity, Nightingale [/bib_ref]. If codeine has been added to loperamide, it should be discontinued when the EGFR-TKI is stopped. Stool cultures should be performed and patients should be hospitalised and rehydrated with oral and intravenous fluids if necessary [bib_ref] Diarrhea associated with afatinib: an oral ErbB family blocker, Yang [/bib_ref]. They should be referred to a gastroenterologist if the diarrhoea does not improve despite discontinuing EGFR-TKI therapy. The EGFR-TKI should only be restarted when the patient has returned to baseline bowel habits or grade B1 toxicity [bib_ref] Diarrhea associated with afatinib: an oral ErbB family blocker, Yang [/bib_ref]. Dose reductions to improve treatment tolerability are recommended in the SPC for erlotinib and afatinib, but not for gefitinib.

## Stomatitis and mucositis
In phase III studies, between 13 and 72.1 % of patients experienced any grade of stomatitis/mucositis and up to 8.7 % experienced grade C3 toxicity [fig_ref] Table 8: Provide patient education about stomatitis/mucositis before EGFR TKI treatment starts and throughout... [/fig_ref] [bib_ref] Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma, Mok [/bib_ref] [bib_ref] First-SIGNAL: first-line single-agent iressa versus gemcitabine and cisplatin trial in never-smokers with..., Han [/bib_ref] [bib_ref] Updated overall survival results from a randomized phase III trial comparing gefitinib..., Inoue [/bib_ref] [bib_ref] Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR, Maemondo [/bib_ref] [bib_ref] Updated overall survival results of WJTOG 3405, a randomized phase III trial..., Mitsudomi [/bib_ref] [bib_ref] Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring..., Mitsudomi [/bib_ref] [bib_ref] Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive..., Zhou [/bib_ref] [bib_ref] Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced..., Rosell [/bib_ref] [bib_ref] Phase III study of afatinib or cisplatin plus pemetrexed in patients with..., Sequist [/bib_ref] [bib_ref] Afatinib versus cisplatin plus gemcitabine for first-line treatment of Asian patients with..., Wu [/bib_ref]. Prevention and management of EGFR-TKI-related stomatitis and mucositis is summarised in [fig_ref] Figure 4: Management of stomatitis/mucositis in patients taking EGFR-TKIs [/fig_ref].
A summary of healthcare products that are suitable for use in patients with mucositis is shown in [fig_ref] Table 9: Summary of healthcare products suitable for use in patients with mucositis [36-45]... [/fig_ref].

## Prevention
Patient education about the risk and causes of stomatitis/mucositis is essential before starting therapy [fig_ref] Figure 4: Management of stomatitis/mucositis in patients taking EGFR-TKIs [/fig_ref] ; [fig_ref] Table 9: Summary of healthcare products suitable for use in patients with mucositis [36-45]... [/fig_ref] [bib_ref] NCCN Task Force Report: prevention and management of mucositis in cancer care, Bensinger [/bib_ref]. Patients must be aware of the need to alert a healthcare professional at the first signs of stomatitis/mucositis. Maintaining good oral hygiene is essential; non-alcoholic mouthwashes are recommended. It may be necessary to evaluate the use of dental appliances (braces, dentures, retainers, etc.) before therapy begins, as they can aggravate oral mucositis. Patients should be advised to eat food that will not cause oral lesions, i.e. soft, moist, nonirritating food that is easy to chew and swallow. Patients should drink plenty of water and lip balms can help to reduce mouth dryness.

## Management
Patients with grade 1 stomatitis/mucositis (erythema of the mucosa) can usually continue the EGFR-TKI at the current dose [fig_ref] Figure 4: Management of stomatitis/mucositis in patients taking EGFR-TKIs [/fig_ref]. Oral rinses (0.9 % saline or sodium bicarbonate) can soothe the mouth [bib_ref] NCCN Task Force Report: prevention and management of mucositis in cancer care, Bensinger [/bib_ref] and only nonalcoholic mouthwashes should be used. Prophylaxis against fungal, viral and/or bacterial infections can be considered; infections must be treated as appropriate with topical or systemic antimicrobials, as recommended in local guidelines.
For grade 2 stomatitis/mucositis, it may be necessary to stop the treatment or, if the SPC recommends it, reduce the dose. In the UK, it is common practice to reduce the dose of gefitinib with administration of a tablet every other day, although this is not advised in the SPC 2 and there are no data to support this dosing schedule. EGFR-TKI should be restarted when the stomatitis/mucositis has improved to grade B1. Topical anaesthetics, mucosal coating agents and/or benzydamine HCl may be administered as needed for pain relief [bib_ref] NCCN Task Force Report: prevention and management of mucositis in cancer care, Bensinger [/bib_ref]. Infections should be treated with topical or systemic antimicrobials. Obtaining specialist advice should be considered.
In the case of a grade 3 stomatitis/mucositis, treatment with an EGFR-TKI should be discontinued and the patient is usually hospitalised to receive supportive care. Appropriate pain relief and antimicrobials should be administered [bib_ref] NCCN Task Force Report: prevention and management of mucositis in cancer care, Bensinger [/bib_ref]. The EGFR-TKI can be restarted, at a lower dose as per the SPC, once the toxicity has resolved to grade B1. If grade 4 stomatitis/mucositis develops, a specialist dermatology assessment should be sought, especially if Stevens-Johnson Syndrome is suspected [bib_ref] NCCN Task Force Report: prevention and management of mucositis in cancer care, Bensinger [/bib_ref]. EGFR-TKI therapy should have already been discontinued, and restarting treatment at a reduced dose should only be attempted after complete resolution of toxicity and a careful assessment of the patient. [bib_ref] NCCN Task Force Report: prevention and management of mucositis in cancer care, Bensinger [/bib_ref]. EGFR epidermal growth factor receptor, TKis tyrosine kinase inhibitors, SPC summary of product characteristics appropriately, possibly within a multi-specialty team, in order to minimise the impact of these AEs and preserve the patient's QOL, trying to avoid unnecessary dose reductions or early discontinuation of these effective therapies.

## Compliance with ethical standards
Funding Boehringer Ingelheim provided financial support for medical writing, authorship meetings and submission costs. Boehringer Ingelheim also completed a factual review with respect to afatinib data within the article. Boehringer Ingelheim had no editorial input into the content. Nocte at night, mane in the morning, QDS four times daily, TDS three times daily, BD twice daily, OTC over the counter
[fig] Figure 2: Management of paronychia in patients taking EGFR-TKIs (UK practice). EGFR epidermal growth factor receptor, TKis tyrosine kinase inhibitors, AEs adverse events, SPC summary of product characteristics [/fig]
[fig] Figure 3: Management of diarrhoea in patients taking EGFR-TKIs (UK practice)[32]. EGFR epidermal growth factor receptor, BID twice daily, TKis tyrosine kinase inhibitors, SPC summary of product characteristics [/fig]
[fig] Figure 4: Management of stomatitis/mucositis in patients taking EGFR-TKIs (UK practice) [/fig]
[table] Table 1: Incidence of drug reductions/modifications and discontinuations in patients with EGFR mutation positive a advanced NSCLC taking EGFR-TKIs first line in phase III randomised clinical trials [/table]
[table] Table 3: Examples of emollients and soap substitutes that are suitable for patients taking EGFR-TKIs [/table]
[table] Table 4: Examples of topical corticosteroid, corticosteroid/antimicrobial and other corticosteroid combination preparations that are suitable for patients taking EGFR-TKIs [/table]
[table] Table 5: Guidance for amounts of emollients that patients taking EGFR-TKIs should use per 2 weeks [/table]
[table] Table 9: Summary of healthcare products suitable for use in patients with mucositis [36-45] Prevention of mucositis Treatment of oral mucositis Treatment of anorectal mucositis Review drug history Suitable antacid therapy-see local formulary Prednisolone 20 mg/100 ml retention enema, nocte Dental review (pre-treatment) Saline mouth wash 10 ml QDS (mix 1 teaspoon of table salt into 500 ml water) 10 ml QDS (mix 1 teaspoon of table salt and threequarter teaspoon of bicarbonate of soda [baking soda] into 500 ml water) Mesalazine 1 g/100 ml retention enema, nocte Soft bristle tooth brush Saline-peroxide MW 10 ml QDS Hydrogen peroxide mouthwash BP-can be prescribed, 15 ml (diluted in 250 ml water) BD-TDS Peroxyl mouthwash is available OTC 10 mL QDS Maintain adequate oral fluid intake (1.5 l/day) Benzydamine 0.15 % mouthwash 15 ml QDS Ice cubes/ice chips/ice lollies (including for secondary prophylaxis) Limit consumption of tobacco, alcohol, acidic food, spicy food and hot foods/beverages Antacid and oxcetacaine 15 ml mouthwash QDS (before food) (Unlicensed Special, Rosemont Pharmaceuticals Ltd.) Avoid alcohol-based mouthwashes Caphosol mixed as directed 15 ml mouthwash 4-10 times daily as required (where available) Primary prophylaxis: Caphosol (mixed as directed) 15 ml mouthwash 4-10 times daily as required (where available) Sucralfate 1 g QDS (before meals) Secondary prophylaxis: Gelclair 15 ml mouthwash TDS If oral candida: nystatin suspension 1 ml QDS for 7 days (oral local formulary alternative-caution: check potential interactions with EGFR-TKI) Systemic antifungal as required Systemic antibacterial as required According to local formulary. Caution: check potential interactions with EGFR-TKI [/table]