Managing treatment-related adverse events associated with egfr tyrosine kinase inhibitors in advanced non-small-cell lung cancer

First-line treatment for nsclc is usually platinum-based two-drug combination chemotherapy, with or without bevacizumab for non-squamous pathology. For patients with poor performance status, single-agent chemotherapy is often recommended, but little evidence exists to guide recommendations in this patient group 4–6. Despite the success of platinum doublets in first-line treatment, the introduction of a third chemotherapeutic agent increases toxicity without improving efficacy 7. The standard approach is to give a chemotherapy agent as second-line treatment or an epidermal growth factor receptor (egfr) tyrosine kinase inhibitor (tki). The egfr-tkis are better tolerated, have a more convenient method of administration, and can be given for longer periods of time 7. In addition, patients with late-stage nsclc are often symptomatic and experience comorbidities that affect quality of life 8. Effective treatment options of lower toxicity are therefore needed for patients with advanced nsclc. The need for more effective and less toxic treatment options for nsclc has led to the development of targeted agents such as egfr inhibitors. A number of solid tumours, including 40%–80% of nsclc tumours, express or overexpress egfr. Several studies showed that high egfr expression is associated with poor prognosis in lung cancer patients. Consequently, egfr is an attractive target for the treatment of nsclc 8,9. Various clinical trials have demonstrated that egfr inhibitors are clinically efficacious in the management of several solid tumour types, such as those of breast, colon, pancreas, head and neck, kidney, gastrointestinal stroma, and lung 10. The egfr-tkis impede phosphorylation of the intracellular tyrosine kinase component of egfr and thus block signal transduction pathways associated with the proliferation and survival of cancer cells 8. Given as secondor third-line therapy in advanced nsclc, the egfr-tkis are clinically efficacious compared with supportive care or chemotherapy 8,11–14. Erlotinib is an egfr-tki that has been approved in the United States, Canada, and many other countries ABSTRACT


INTRODUCTION
Lung cancer remains the second most common cancer and the leading cause of cancer-related mortality in Canada.In 2010, 24,400 new lung cancer cases and 20,600 related deaths were predicted, representing a significant health care burden 1 .The most common form of lung cancer, non-small-cell lung cancer (nsclc), consists of a heterogeneous group of histologies, of which adenocarcinoma, squamous cell carcinoma, and large-cell anaplastic carcinoma are the most frequent 2 .Despite recent advances in treatment, prognosis is generally poor in patients with advanced nsclc, and the median survival rate is only 10-12 months with treatment 3 .around the world for use in nsclc, based on clinical trial results showing it to be safe and efficacious.Another egfr-tki, gefitinib, was recently granted marketing authorization by the European Medicines Agency, the United States, and Canada for the treatment of EGFR mutation-positive nsclc 7 .Newer egfrtkis such as afatinib (BIBW 2992) and PF-00299804 are currently in development 15-21,a .
Although targeted agents are generally less toxic than traditional anti-neoplastic agents, egfr-tkis are associated with a number of bothersome adverse effects that need to be managed in most patients.Because egfr is expressed mainly on cells of epithelial origin, such as those of the skin and gastrointestinal tract, the most common adverse events of the egfr inhibitors are rash and diarrhea, which are the focus of the present paper.Strategies to improve the assessment and management of egfr-tki-related adverse events such as rash and diarrhea should result in superior clinical outcomes, better compliance, and improved quality of life for patients with advanced nsclc 10 .

Patient Monitoring
Before initiating treatment with an egfr-tki, physicians should educate their patients about the associated potential side effects so that such reactions can be managed early and effectively.Because symptoms of rash generally appear as early as 2 weeks into treatment, early monitoring is essential 10 .
Patients should be advised that rash is a common complication of egfr inhibitors and an indication of treatment efficacy 22 .To prevent dose reduction or discontinuation of therapy, it is also important to inform patients that early treatment of rash can prevent symptoms from worsening.
Although not recommended in current guidelines, prophylactic treatments to prevent egfr-tki-induced rash have been studied in a number of trials.One randomized double-blind trial compared prophylactic oral minocycline with placebo in patients treated with cetuximab for metastatic colorectal cancer (n = 48) 23 .Patients were also randomized to receive topical tazarotene applied either to the left or the right side of the face.After 4 weeks of treatment with cetuximab, the minocycline group had a significantly lower total facial lesion count (p = 0.005).A trend was also observed suggesting that a lower proportion of treated patients were experiencing moderate-to-severe itching (20% vs. 50% receiving placebo, p = 0.05).The use of topical tazarotene provided no clinical benefit and was associated with significant skin irritation.
A second randomized double-blind trial in patients (n = 61) receiving egfr-tkis compared prophylactic tetracycline treatment (500 mg twice daily) with placebo over 4 weeks 24 .Although tetracycline did not prevent rash, a reduction in the severity of rash was observed.At week 4, grade 2 rash was reported in 17% of the tetracycline group and in 55% of the placebo group (p = 0.04).Treatment also improved certain quality-of-life measures, including skin burning or stinging and skin irritation.
The stepp (Skin Toxicity Evaluation Protocol with Panitumumab) study compared primary pre-emptive skin treatment with reactive skin treatment in patients receiving panitumumab in a randomized prospective study 25 .Patients on the pre-emptive arm received daily skin treatment for a total of 6 weeks, starting 24 hours before the first dose of panitumumab.Pre-emptive treatment included skin moisturizer, sunscreen, 1% hydrocortisone cream, and doxycycline 100 mg twice daily.Patients on the reactive arm received treatment after the development of rash.Compared with reactive treatment, pre-emptive treatment reduced the incidence of grade 2 or greater rash by more than 50%, without additional side effects.Time to first occurrence of grade 2 or greater rash was also significantly delayed in the pre-emptive arm.Additional research is needed to determine the benefit of prophylactic treatment for the prevention of egfr-tki-induced rash.
During the first 6 weeks of treatment, patients should be assessed weekly for any signs of rash.When symptoms of rash are apparent, early intervention is of key importance to prevent more serious complications.After 6 weeks of treatment, assessment of skin toxicities can be performed less frequently-for example, every 6-8 weeks.Rash assessment can be performed by any member of the health care team who is able to reliably evaluate it.

Causes and Incidence
Epidermal growth factor plays an integral role in the growth and keratinization of skin epithelium, and egfrs are expressed within the follicular epithelium, sebaceous glands, and dermal capillaries.It is therefore not surprising that egfr inhibition leads to a number of skin reactions 10,26 .
Adverse skin reactions occur in more than 50% of patients given egfr inhibitors; they are the most common treatment-related adverse events.Skin reactions associated with egfr inhibitors include xerosis (dry skin), pruritus, hair changes and alopecia, nail alterations, and hand and foot reactions 10,26,27 .The most common skin reaction reported in patients treated with egfr-tkis is a follicular acneiform eruption also known as "acne-like rash" or "folliculitis."Inhibition of egfr is thought to alter keratinocyte proliferation, differentiation, migration, and attachment, which may explain the papulopustular reaction and xerosis seen with egfr-tkis 30 .
Incidence of rash with egfr-tkis varies from 37%-78% in phase iii clinical trials and appears to be a See also NCT01085136, NCT01121393, NCT01000025, and NCT00769067 at clinicaltrials.gov/ct2/search.When rash is not adequately managed, treatment compliance may be negatively affected, leading to dose modifications or treatment discontinuation, and ultimately reducing the overall clinical benefits of treatment.Appropriate strategies are therefore needed to assess and manage egfr-tki-induced rash 10,45 .

Assessment and Grading
Acneiform rash is defined as an eruption of papules and pustules, typically appearing on the face, scalp, upper chest, and back 46 .Although egfr-tki-induced rash most closely resembles acneiform rash in presentation, no comedones or blackheads are visible 10 (Figure 1).Rash induced by egfr-tki usually appears within 2 weeks of treatment start and generally presents on the face, shoulders, and upper part of the back and chest.The rash tends to improve over time with continued use of the medication and resolves fully after discontinuation of treatment 10,26 .However, in about 35% of patients, dry itchy skin of the arms and legs may occur, which can potentially become secondarily infected with a Staphylococcus aureus or Herpes simplex infection 10 .
The U.S. National Cancer Institute (nci) Common Terminology Criteria for Adverse Events (ctcae) are typically used to grade symptoms for clinical trials, but those criteria have some limitations for describing egfr-tki-induced rash 46 (Table iii).The ctcae grading uses the affected percentage of body surface area to assess rash severity, but egfr-tki-induced rash is typically restricted to the face, scalp, and upper torso.The ctcae grading also does not take into account the severity of rash complications, which may include oozing, burning, crusting, or disfigurement 47 .Given that no other standard exists for grading egfr-tki-induced rash, the ctcae grading remains the standard for assessment.

Management
Before initiating egfr-tki therapy, physicians should counsel their patients about preventive measures to reduce the risk of skin rash.The educational messages that need to be communicated to patients being prescribed egfr-tkis are these 10,22,27,45 : • Any areas of dry skin should be moisturized twice daily using a thick, alcohol-free emollient.• Sun exposure should be minimized.Where sun exposure is unavoidable, a broad-spectrum sunscreen with a sun protection factor of 15 or higher should be applied 1-2 hours before exposure, especially on the face and upper body.Physical sunscreens that contain zinc oxide or titanium dioxide are preferable to chemical sunscreens.• Products that dry the skin-such as soaps, alcohol-based or perfumed products, and overthe-counter acne products-should be avoided.
Because long hot showers can also dry the skin, shower time should be limited, and lukewarm water should be used.
A number of treatment algorithms have been proposed for the management of skin rash induced by egfr inhibitors; the algorithm presented in Figure 2 represents an amalgam of existing frameworks 10,27,[48][49][50] .
The egfr-tki dosage should remain unchanged for all patients, except those with severe rash (grade 3 or higher).Patients with mild toxicities (grade 1) may need no intervention; however, treatment with topical hydrocortisone (1% or 2.5% cream) or clindamycin (1% gel) is reasonable.For patients with moderate toxicities (grade 2), treatment with hydrocortisone (2.5% cream), clindamycin (1% gel), or pimecrolimus (1% cream) is recommended, with the addition of either oral doxycycline (100 mg twice daily) or minocycline (100 mg twice daily).For patients with severe toxicities (grade 3 or higher), concomitant intervention is the same as for moderate toxicities, with the addition of a methylprednisolone dose pack (a package containing a specific number of pills to be taken at designated times over a period of a few days).If the rash does not dissipate sufficiently within 2-4 weeks, interruption of egfr inhibitor therapy is recommended in accordance with the prescribing information 10,27 .Novel treatments for egfr-tki-induced rash, such as menadione lotion, retinoids, and alpha-hydroxy acids, are under investigation in preliminary studies.However, until controlled studies are performed, their efficacy remains unknown, because rash often resolves spontaneously in patients taking egfr-tkis 47 .
Because the half-life of egfr-tkis is long, management of adverse skin reactions should continue  until those reactions have sufficiently diminished or resolved, even if treatment is discontinued or reduced.Once adverse reactions have sufficiently resolved, egfr-tki therapy may be restarted or escalated to the original dosing scheme, with reasonable confidence that toxicities will be well managed 27 .

Rash As an Indicator of Treatment Response
Numerous studies have shown a significant correlation between skin rash severity and response to egfr inhibitor treatment 10,26,47 .In nsclc, several gefitinib and erlotinib trials have supported that finding 22,39,51 .
A phase ii study by Kris et al. 39 (ideal) examined the efficacy and safety of gefitinib (250 mg vs. 500 mg daily) in patients with pre-treated advanced nsclc.Although efficacy outcomes were similar across dose groups, skin toxicity was reported in 86% of patients (72 of 84) with symptom improvement [a 2-point increase in score on the Functional Assessment of Cancer Therapy-Lung (fact-L) scale], but in only 58% of patients (76 of 132) with  10 .a Guidelines presented here recommend treatment with minocycline for moderate-to-severe rash only.However, early treatment of mild rash can prevent the development of more severe forms and the need for higher, more toxic doses of minocycline.Early treatment of mild rash with 50 mg minocycline plus 1% hydrocortisone is therefore a reasonable option.b Topical steroids should be pulsed according to institution guidelines.

Current OnCOlOgy-VOlume 18, number 3
Copyright © 2011 Multimed Inc.Following publication in Current Oncology, the full text of each article is available immediately and archived in PubMed Central (PMC).no symptom improvement (observed difference: 28%; 95% confidence interval: 17% to 39%).A retrospective study by Mohamed et al. 51 analyzed the clinical characteristics of patients who were associated with survival after treatment with gefitinib as part of the Expanded Access Program.Median survival was longer in patients who developed skin rash than in those who did not (10.8months vs. 4.0 months, p < 0.0001) 26,51 .
A phase iii study by Shepherd et al. 11 (br.21)examined the efficacy and safety of erlotinib in patients with pre-treated advanced nsclc.Rash occurred in 76% of patients given erlotinib (368 of 485), with 9% experiencing severe (grade 3 or higher) rash.A retrospective study by Wacker et al. 22 analyzed the association between rash and clinical outcome using data from the study by Shepherd and colleagues and also data from a phase iii study comparing single-agent gemcitabine with gemcitabine plus erlotinib as first-line therapy for advanced pancreatic cancer (pa.3) 52 .The response rate was 1% among patients who did not develop rash compared with 10% among those who developed grade 1 rash and 13% among those who developed grade 2 or higher rash (grade 1 vs. grade 0, p = 0.048; grade 2 vs. grade 0, p = 0.017).After controlling for baseline factors in multivariate analyses, the presence of rash correlated strongly with overall and progressionfree survival; the correlations increased with rash severity ( p < 0.05) 22,26 .
The positive relationship between skin rash and response or survival (or both) suggests that rash could be a potential surrogate marker for egfr-tki efficacy.Whether rash reflects the local effects of egfr inhibition in skin or indicates a systemic inflammatory reaction, it may serve as a useful pharmacodynamic marker of target inhibition 22 .The relationship between rash and survival is currently being evaluated in ongoing studies, and results should help guide the use of egfr-tkis.

Patient Monitoring and Diarrhea Causes and Incidence
Patients should be advised to immediately discuss any symptoms of diarrhea with their health care team.The diarrhea can then be managed early and effectively, preventing dose reductions or treatment discontinuation.Because diarrhea is a common side effect of many cancer treatment regimens, management of diarrhea in the oncology setting is well established [53][54][55] .Diarrhea induced by egfr-tkis is thought to be a result of excess chloride secretion, causing a secretory form of diarrhea 10 .Severe diarrhea can result in fluid and electrolyte losses, which may lead to dehydration, electrolyte imbalances, and renal insufficiency.
Nutritional deficiencies can also develop from alterations in gastrointestinal transit and digestion, negatively affecting a patient's quality of life 55 .
The incidence of diarrhea with egfr-tkis varies from 27% to 87% in phase iii clinical trials, with up to 25% of patients experiencing severe reactions (grade 3 or higher; Table iv).Table ii gives a detailed description of the clinical trials that have examined the incidence of diarrhea with egfr-tkis in nsclc.

Assessment and Grading
The first step in the assessment of egfr-tki-induced diarrhea is to rule out other potential causes.Possible causes of diarrhea include medications such as laxatives, stool softeners, antacids, or antibiotics; dietary factors, such as excess consumption of fibre or lactose; comorbid infections; intestinal obstruction; fecal impaction; surgeries such as short-bowel or gastrectomy; and radiation toxicity.
Laboratory investigations are also useful to rule out other causes of diarrhea.Recommended Additional information-such as the duration of the episode, stool characteristics, and co-existing symptoms-should also be obtained during the patient evaluation 54,55 .
The nci ctcae are generally used to grade diarrhea severity (Table v).However, because the nci criteria do not provide a complete assessment, the additional information already described should be obtained during the patient evaluation 54,55 .

Management
Although egfr-tki-induced diarrhea is usually mild to moderate, early management is essential to prevent dose reduction or discontinuation of anticancer therapies.The management of egfr-tki-induced diarrhea is identical to that of chemotherapy-induced diarrhea and can generally be handled using dietary changes and antidiarrheal medications [53][54][55] .
Dietary modifications are not recommended in anticipation of diarrhea, and patients without symptoms may eat an unrestricted diet.Patients experiencing diarrhea should avoid foods that exacerbate symptoms, such as greasy, spicy, and fried items.An initial "brat" diet of bananas, rice, apple sauce, and toast is often helpful until symptoms begin to resolve.Foods that are difficult to digest-such as cabbage, Brussels sprouts, and broccoli-should be avoided, because those foods may increase abdominal cramping and bloating.Once diarrhea begins to improve, other foods such as pasta, chicken without skin, and eggs may be added as tolerated [53][54][55] .
Daily fluid intake of approximately 3-4 L is recommended to avoid dehydration from volume loss attributable to diarrhea.At least some of the fluids should contain sugar or salt to avoid hyponatremia and hypokalemia caused by electrolyte loss.Good options include non-caffeinated beverages, gelatine products, and clear broths.Milk products should be avoided for about a week after a diarrhea episode because lactase activity may be diminished during prolonged diarrhea, resulting in temporary lactose intolerance [53][54][55] .
The pharmacologic management of diarrhea is usually limited to treatment with over-the-counter loperamide (Figure 3).Patients should begin taking loperamide at the first sign of diarrhea, starting with 4 mg (2 tablets), followed by 2 mg (1 tablet) every 4 hours or after each loose stool to a maximum dose of 20 mg (10 tablets) daily.If diarrhea persists for more than 24 hours, the dose of loperamide may be increased to 4 mg, followed by 2 mg every 2 hours.After 12 hours have passed with no episodes of diarrhea, pharmacologic treatment can be stopped, and the patient's diet can be expanded as tolerated [53][54][55][56] .
If patients present with grade 3 or 4 diarrhea, dose reduction or discontinuation of egfr-tkis may be necessary.If diarrhea fails to resolve after dose reduction or discontinuation, use of octreotide may be considered.It is very unlikely that octreotide would be needed to combat egfr-tki-induced diarrhea as it is for chemotherapy-induced diarrhea; no evidence supports its use in the egfr-tki setting.In general, most physicians would therefore discontinue egfr-tki therapy rather than start treatment with octreotide.Once severe diarrhea has subsided, egfr-tkis may be restarted at a lower dose.

SUMMARY
Despite the success of platinum doublets, the need for more effective agents in the treatment of advanced nsclc remains.Because nsclc patients are often symptomatic and may have a number of comorbidities, effective, low-toxicity treatment options are also required.The advent of targeted therapies has led to the development of a number of less toxic anticancer agents 8,10 .
Targeting the egfr pathway has proved to be an effective strategy in a number of cancers, including nsclc.Clinical trials using egfr-tkis in nsclc have demonstrated promising anticancer activity, resulting in improved tumour control and patient survival 8,10 .
Although egfr-tkis have been successful in improving clinical outcomes, they often result in a number of bothersome side effects, such as rash and diarrhea.Strategies to manage those adverse effects are essential to increase patient compliance,

figure 2
figure 2 Management of rash induced by epidermal growth factor receptor (egfr) tyrosine kinase inhibitor (tki).ctcae = Common Terminology Criteria for Adverse Events; adl = activities of daily living.Adapted from Eaby et al., 2008 48 ; Harandi et al., 2009 27 ; Lynch et al., 200710 .a Guidelines presented here recommend treatment with minocycline for moderate-to-severe rash only.However, early treatment of mild rash can prevent the development of more severe forms and the need for higher, more toxic doses of minocycline.Early treatment of mild rash with 50 mg minocycline plus 1% hydrocortisone is therefore a reasonable option.b Topical steroids should be pulsed according to institution guidelines.

Current OnCOlOgy-VOlume 18, number 3 Copyright
© 2011 Multimed Inc.Following publication in Current Oncology, the full text of each article is available immediately and archived in PubMed Central (PMC).dose-dependent(Table i).
Table ii presents a detailed description of the clinical trials that have examined the incidence of rash with egfr-tkis in nsclc.

table i
Incidence of acneiform rash with epidermal growth factor receptor (egfr) tyrosine kinase inhibitors (tkis) in non-small-cell lung cancer trials a No phase iii study results using PF-00299804 are available to date.Current OnCOlOgy-VOlume 18, number 3Copyright © 2011 Multimed Inc.Following publication in Current Oncology, the full text of each article is available immediately and archived in PubMed Central (PMC).tableiiIncidence of rash and diarrhea with epidermal growth factor receptor (egfr) tyrosine kinase inhibitors (tkis) in non-small-cell lung cancer (nsclc) clinical trials nr Erlotinib: nr nr ≤10 Current OnCOlOgy-VOlume 18, number 3 Copyright © 2011 Multimed Inc.Following publication in Current Oncology, the full text of each article is available immediately and archived in PubMed Central (PMC).Current OnCOlOgy-VOlume 18, number 3Copyright © 2011 Multimed Inc.Following publication in Current Oncology, the full text of each article is available immediately and archived in PubMed Central (PMC).Current OnCOlOgy-VOlume 18, number 3Copyright © 2011 Multimed Inc.Following publication in Current Oncology, the full text of each article is available immediately and archived in PubMed Central (PMC).

table iv
Incidence of diarrhea with epidermal growth factor receptor (egfr) tyrosine kinase inhibitors (tkis) in non-small-cell lung cancer trials a No phase iii study results using PF-00299804 are available to date.Current OnCOlOgy-VOlume 18, number 3Copyright © 2011 Multimed Inc.Following publication in Current Oncology, the full text of each article is available immediately and archived in PubMed Central (PMC).

table v
U.S. National Cancer Institute grading for diarrhea a 46Adapted from the Common Terminology Criteria for Adverse Events, v4.03, 201046.