Oncologist. The. Lung Cancer. Expert Consensus on the Management of Erlotinib-Associated Cutaneous Toxicity in the U.K.

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1 The Oncologist Lung Cancer Expert Consensus on the Management of Erlotinib-Associated Cutaneous Toxicity in the U.K. NICHOLAS THATCHER, a MARIANNE NICOLSON, b RICHARD W. GROVES, c JEREMY STEELE, d BETH EABY, e JOYCE DUNLOP, f JOHN MCPHELIM, g RAJINDER NIJJAR, d IJEOMA UKACHUKWU h ;U.K.ERLOTINIB SKIN TOXICITY MANAGEMENT CONSENSUS GROUP a Christie CRC Hospital NHS Foundation Trust, Department of Medical Oncology, Manchester, United Kingdom; b Aberdeen Royal Infirmary, Foresterhill, Aberdeen, United Kingdom; c Guy s Hospital, London, United Kingdom; d St. Bartholomew s Hospital, London, United Kingdom; e University of Pennsylvania, Philadelphia, Pennsylvania, USA; f The Roy Castle Lung Cancer Foundation, Liverpool, United Kingdom; g Hairmyres Hospital, Lanarkshire, United Kingdom; h Church End Medical Centre, London, United Kingdom Key Words. Cutaneous toxicity Endothelial growth factor receptor inhibitors Erlotinib Non-small cell lung cancer Rash Disclosures: Nicholas Thatcher: Honoraria: Roche, AstraZeneca, Lilly, SanofiAventis, Marianne Nicolson: Consultant/advisory role: Roche; Honoraria: Roche; Richard W. Groves: None; Jeremy Steele: Honoraria: Roche; paid member of the Consensus Group; Beth Eaby: Consultant/advisory role: Roche; Honoraria: Genentech; Joyce Dunlop: None; John McPhelim: Honoraria: Roche; Rajinder Nijjar: None; Ijeoma Ukachukwu: None. The article discusses erlotinib (Tarceva ; Genentech, OSI Pharmaceuticals, and Roche) used to treat non-small cell lung cancer, pancreatic cancer, and several other types of cancer. The content of this article has been reviewed by independent peer reviewers to ensure that it is balanced, objective, and free from commercial bias. No financial relationships relevant to the content of this article have been disclosed by the independent peer reviewers. ABSTRACT Rash has been reported in up to 76% of patients with lung cancer who have received the epidermal growth factor receptor inhibitor (EGFRI) erlotinib. It has also been observed in patients treated with other agents that have a similar mode of action. Erlotinib-associated skin toxicity typically presents as a papulopustular, follicular, acneiform rash. In most cases, it is mild, transient, and well tolerated, but in 8% 12% of patients, it may be sufficiently severe and persistent to necessitate intervention. Increasingly strong data suggest that the incidence and severity of skin toxicity may be predictive of response and survival in patients treated with erlotinib. This has prompted some clinicians to consider treatment to rash (i.e., increasing the dosage until a rash appears) as a rational management strategy. In 2007, an international consensus was developed for the management of EGFRI-associated skin toxicity. Subsequently, a multidisciplinary group (the U.K. Erlotinib Skin Toxicity Management Consensus Group) met to validate and modify the international recommendations for U.K. use, with specific reference to erlotinib. Although many aspects of the international consensus were approved by the group as being relevant for the U.K., certain parts were modified. The resulting expert opinion is a practical and Correspondence: Nicholas Thatcher, M.B., B.Chir., Ph.D., Christie CRC Hospital NHS Foundation Trust, Department of Medical Oncology, Wilmslow Road, Manchester, M20 4BX, United Kingdom. Telephone: ; Fax: ; nick.thatcher@christie-tr.nwest.nhs.uk Received March 18, 2009; accepted for publication May 31, 2009; first published online in The Oncologist Express on August 13, AlphaMed Press /2009/$30.00/0 doi: /theoncologist The Oncologist 2009;14:

2 Thatcher, Nicolson, Groves et al. 841 workable version of the international proposal that considers all applicable national issues regarding the management of erlotinib-associated skin toxicity. The Oncologist 2009;14: INTRODUCTION Targeted therapies that suppress mechanisms of tumorigenesis and proliferation have been developed for the treatment of solid tumors [1]. Drugs targeting the extracellular domain of the epidermal growth factor receptor (EGFR) (e.g., cetuximab, panitumumab) or its tyrosine kinase (e.g., gefitinib, erlotinib) are in clinical use for the treatment of nonsmall cell lung cancer (NSCLC), pancreatic cancer, and colorectal cancer (CRC) [2 5]. Although effective, EGFR inhibitors (EGFRIs) are associated with dermatological toxicities. These toxicities may necessitate dose reduction or interruption or cessation of treatment [6], and significantly reduce patients quality of life (QoL) [7, 8] and the clinical response [4]. EGFRI-related skin toxicity is typically seen in 50% of patients taking these drugs [9]. Clinical trials evaluating EGFRIs have reported a range of adverse cutaneous reactions with variable frequencies (Table 1), the most common being papulopustular rash (also referred to as acne or acneiform rash) on the face and upper torso, which occurs in up to 80% of patients [10]. The median onset of EGFRI-related cutaneous toxicity is 1 2 weeks after the initiation of treatment, with a maximum intensity at 2 3 weeks [2]. EGFRIassociated rash may gradually improve or resolve spontaneously while treatment is continued over 2 3 months [2]. Rash appears to be dose related [11], and most patients experience transient, mild-to-moderate symptoms [2]. Moderate-to-severe rash has been reported in up to 10% of patients receiving EGFRI monotherapy [12]. However, 8% 12% of patients experience rash of such severity that treatment must be interrupted or withdrawn [2, 13]. Preemptive rash management strategies are being investigated in prospective studies to help reduce the incidence and severity of skin toxicity in cancer patients receiving EGFRI therapy [14 16]. One phase II trial in particular the Skin Toxicity Evaluation Protocol with Panitumumab has shown that pre-emptive rather than reactive (moisturizers, sun screens, topical corticosteroids, and doxycycline) treatment is feasible in EGFRI-treated patients with metastatic CRC [15]. In addition, pre-emptive treatment results in a lower incidence of serious skin reactions, compared with reactive treatment, without affecting the anticancer activity of panitumumab. The pathogenesis of EGFRI-associated cutaneous toxicity is incompletely understood. Inhibition of EGFR-mediated signaling pathways has multiple consequences, Table 1. Spectrum of dermatological reactions (all grades) to epidermal growth factor receptor inhibitors [10] Adverse event description Frequency Papulopustular rash affecting the face 60% 80% and upper trunk Abnormalities in hair growth, 5% 6% especially the scalp and eyelashes Dry and itchy skin 4% 35% Periungual inflammation with 6% 12% tenderness including keratinocyte growth arrest and apoptosis, decreased cell migration, increased cell attachment and premature differentiation, and stimulation of inflammation [17, 18]. The release of inflammatory cytokines results in the recruitment of leukocytes; these release enzymes that cause apoptosis and tissue damage [19]. The end result is a decrease in epidermal thickness and the development of a thin stratum corneum that lacks the characteristic basketweave configuration, indicating abnormal differentiation [20]. EGFRI-associated dermatological toxicities can have a considerable detrimental effect on patients QoL. In a recent survey of patients and clinicians, physical, functional, emotional, and social well-being were all reported to be affected, with patients principal complaint being physical discomfort, manifested as pain, burning sensation, and skin sensitivity [8]. In addition to this negative impact on QoL, some patients may have reactions that are sufficiently severe and persistent to warrant dose interruption or treatment cessation [2, 13], which may compromise treatment outcomes. Erlotinib was demonstrated to have an overall survival benefit as a second- or third-line treatment option in patients with stage IIIB/IV NSCLC in a pivotal, placebocontrolled, phase III trial [13]. The median survival time was 2 months longer with erlotinib than with palliative care: at 1 year of follow-up, the overall survival time was 6.7 months with erlotinib, versus 4.7 months for patients in the placebo group (p.001), and 31% of treated patients were alive at 1 year. At 2 years, 15% of patients treated with erlotinib were alive. Rash was the most common toxicity, affecting 76% of patients, 12% of whom required erlotinib dose reduction.

3 842 Managing Erlotinib-Associated Cutaneous Toxicity There is growing evidence that, in patients receiving erlotinib, the incidence and severity of skin toxicity are positively correlated with treatment outcomes (objective response rates and survival duration) [2, 21]. In support of these data, Wacker et al. [22] analyzed results from the National Cancer Institute of Canada Clinical Trials Group studies BR.21 [13] and PA3 (erlotinib versus placebo in the treatment of pancreatic cancer). Overall survival, progression-free survival, and tumor response were compared in a rash-evaluable subset of patients who did or did not develop a rash. The presence of rash was strongly correlated with overall survival in both studies: in BR.21, all grades of rash were strongly correlated with longer survival; in PA3, only more severe rash (grades 2 4) showed this association [22]. These findings have prompted some clinicians to consider the feasibility of increasing the dose of erlotinib until a tolerable rash occurs, as a rational management strategy [2, 23]. There is thus a need to develop U.K. guidelines for optimal management, to limit the impact of rash on patients and on the overall therapeutic effectiveness of erlotinib. Various protocols have been adopted to manage erlotinib-associated rash in the U.K., but they are disparate in both their approaches and effectiveness. Moreover, accepted practice in classifying and managing erlotinib-related skin toxicity is questionable. Few trials of treatment options for EGFRI-associated dermatological reactions have been reported, and evidence-based treatment recommendations are not yet possible. However, in 2007, international consensus was reached on management strategies for EGFRI-associated skin toxicity [12]. We instigated a project to validate and modify the recommendations of the international panel for use in the U.K., with specific reference to erlotinib, because substantial anecdotal and sufficient clinical trial derived toxicity data exist for it as the only EGFRI in regular use in the U.K. Table 2. Objectives of the erlotinib-associated cutaneous toxicity management meeting Provide all members of the consensus group with relevant information regarding the pharmacology, clinical action, and toxicity of erlotinib Explore the incidence and severity of rash in patients treated with erlotinib and other EGFRIs a Explore the typical management pathways and options relevant to erlotinib-treated patients with skin rash Review published international guidelines for management of EGFRI-associated skin toxicity Discuss which aspects of the international guidelines are relevant to the U.K., or how the guidelines may be adapted for application in the U.K. Agree upon a draft algorithm and test its validity using case scenarios Agree upon a final consensus guideline for management of EGFRI-initiated rash in the U.K. a The group agreed that the final consensus guidelines would apply specifically to erlotinib, rather than generally to EGFRIs. Abbreviation: EGFRI, epidermal growth factor receptor inhibitor. ERLOTINIB SKIN TOXICITY MANAGEMENT CONSENSUS GROUP An erlotinib skin toxicity forum was held on October 2, 2007 in Manchester, U.K., to discuss the underlying mechanisms of erlotinib-associated dermatological toxicity and to provide a current consensus on management strategies. This was an interdisciplinary meeting, attended by principal stakeholders in EGFRI-associated rash management, including three oncologists, a dermatologist, two specialist oncology nurses, a specialist oncology pharmacist, a general practitioner (GP) with a special interest in dermatology, and a representative of the Roy Castle Lung Cancer Foundation (a cancer patient advocacy group). This meeting was instigated and funded by Roche Products Ltd., who paid participants for their advice. The meeting was organized by Phase IV communications on behalf of Roche. Table 2 shows the objectives of the meeting, which sought to arrive at an informed consensus by sharing knowledge and pooling expertise. Findings The group arrived at a consensus on the following points. Rash Grading The wording used to describe the severity of rash in the current algorithm [12] was not considered sufficiently user friendly or descriptive, and some modifications were agreed upon (Table 3). Patient Advice The group developed and generally agreed upon the consensus recommendations for patients, including the importance of informing patients and their primary care team about the possibility of rash, educating them about erlotinib-related rash, and providing all with guidance on its management, including prophylactic measures. These points were considered important to ensure compliance. For most patients with skin reactions, there is no clinical necessity to withdraw erlotinib therapy, although interventions for skin toxicity need to be vigorous. The overriding importance of not losing tumor control was stressed. The U.K. consensus group also reviewed suggestions for patients to help them camouflage the rash and alleviate discomfort. The international EGFRI dermatological toxic-

4 Thatcher, Nicolson, Groves et al. 843 Table 3. Modifications to rash grading system International EGFRI dermatological toxicity forum grading system [12] Mild toxicity Generally localized papulopustular reaction Minimally symptomatic No impact on daily activities No sign of superinfection Moderate toxicity Generalized papulopustular reaction Mild pruritus or tenderness and can cause near intolerable itching, which may start before appearance of the rash Minimal impact upon daily activities No sign of superinfection Severe toxicity Generalized papulopustular reaction Severe pruritus or tenderness Significant impact upon daily activities Potential for superinfection, or has become superinfected Abbreviation: EGFRI, epidermal growth factor receptor inhibitor. ity group had considered that makeup was generally safe to use. However, the erlotinib skin toxicity forum advised care in the use of occlusive preparations. The rash is acneiform in nature, and centered around the hair follicles. Occlusion (e.g., with petroleum jelly) may potentially exacerbate hair follicle inflammation, and aggravate the rash. Careful consideration is therefore needed as to which of the particular aspects of the EGFRI-mediated eruptions are to be treated in any particular patient. For example, dryness is likely to be generalized and will be helped by emollients, whereas acneiform eruptions may be exacerbated by the same treatment. It was agreed that patients should be directed not to use emollients on the papulopustular eruptions, but only on dry skin, or prophylactically to prevent dryness occurring. The group agreed that the most appropriate formulations are those that treat the rash, rather than cover it up. Although the EGFRI rash may be most pronounced on the face and upper trunk [24], there is currently little evidence that it is truly photosensitive in nature. Although the international treatment algorithm for rash management includes sunscreen (SPF 15), the U.K. consensus group advised caution and careful patient selection in the use of these agents, because many sunblocks are occlusive and may aggravate the acneiform element of the rash. Physical shields would be preferable to sunscreens and should always be recommended. U.K. Erlotinib Skin Toxicity Management Consensus Group grading system Mild Usually localized Minimally symptomatic No impact on activities of daily living No ulceration, weeping, or infection Moderate Localized or generalized Mild symptoms (e.g., pruritus, tenderness) Minimal impact on activities of daily living No ulceration, weeping, or infection Severe Usually generalized Severe symptoms (e.g., pruritus, tenderness) Significant impact on activities of daily living Ulceration, weeping, or other evidence of infection present It was agreed that a statement emphasizing the need to take erlotinib on an empty stomach should be more prominent on labeling. Food increases the bioavailability of the drug [25], and this may lead to the development or exacerbation of rash because rash appears to be dose related [11]. Management and Intervention The group agreed that the key issue in EGFRI rash is at what stage systemic treatment (e.g., tetracyclines) should be introduced. Evidence to date supports early systemic treatment, rather than dependence on topical agents [26]. There appears to be good experiential evidence (if not trial data) that this approach is effective. The management pathway for erlotinib-associated rash is highly individualized and varied, based on how the dermatological toxicity manifests (e.g., dryness or pustular rash). If the toxicity is grade 1 in severity, the international consensus recommendation is that practitioners should manage macular rashes with hydrocortisone cream or lotion. If grade 1 inflammatory pustular or papular rash is present, the use of clindamycin, a topical antibiotic with anti-inflammatory activity, is recommended, as a gel for isolated lesions or as a lotion for scattered lesions. Clindamycin gel tends to cause skin dryness and irritation, and an aqueous preparation of clindamycin (available in the U.K.) may be preferable when applied generally to the rash-prone area. The use of hydrocortisone preparations may also be

5 844 Managing Erlotinib-Associated Cutaneous Toxicity considered for rashes with a significant inflammatory element. In addition, the use of pimecrolimus is an acceptable alternative to hydrocortisone, according to guidance drawn up by the British Association of Dermatologists [27]. The international consensus recommendation for doxycycline was not supported by the group, because of its potential for photosensitivity. Furthermore, minocycline is associated with a number of adverse drug reactions, including (at 200 mg/day) pigmentation [28]. A key suggestion from the forum was to use either oxytetracycline (500 mg twice daily) or lymecycline (408 mg once daily), a longacting tetracycline. The use of oral prednisolone was approved if the rash does not respond to systemic tetracycline therapy. For optimal efficacy, prednisolone should be used for at least 5 days and can be continued for up to 1 month. There was, however, reluctance among the group to recommend highdose corticosteroids for 2 weeks, and a preference to reduce the dose or interrupt treatment in these patients. The group took into consideration the prednisolone dose pack used in the U.S., which contains a low dose, decreasing over 7 days. Although consensus on the use of prednisolone was not readily achieved, it was agreed that a reducing dose of prednisolone, given over 2 weeks, should be recommended. Experience within the group showed that, in cases of severe rash, the dose of erlotinib is reduced in only 25% of patients generally those who experience intolerable adverse effects. A more common practice is to interrupt therapy in the worst cases and then restart it at a reduced dose when the rash has improved. A key recommendation from the forum was to reassess after 2 weeks, and not stop or reduce the dose unless requested by the patient or warranted by the patient s clinical condition. Care/Referral Pathways Considerations for key points of presentation and the referral pathway are summarized in Table 4. A key recommendation from the U.K. forum was that oncologists should involve dermatologists sooner, because they are highly experienced in managing the impact of skin conditions on QoL. However, experience among the group shows that the normal referral pattern in the U.K. is first to a GP, then to a GP with a special interest, who would be working closely with a dermatologist. Because pruritus is a common symptom, patients who are taking erlotinib may present to a GP with itching but no rash. It is therefore important that GPs be made aware that there is no interaction between antihistamines and erlotinib. GPs should also be discouraged from discontinuing erlotinib treatment. Table 4. Considerations for key points of presentation and the referral pathway in the U.K. Erlotinib rash generally appears early in treatment; therefore, affected patients will typically re-present to an oncologist or specialist nurse. Some patients may present initially to their GP or to an off-hours primary care service; therefore, it is essential that primary care professionals do not stop erlotinib or undertake intervention, but refer the patient back to the cancer center. Because an on-call pharmacist may be contacted, it is important that pharmacists are familiar with the algorithm and advise the patient to continue erlotinib and re-present to the cancer center. NHS Direct a staff should be trained to advise patients that they should continue therapy and consult their oncologist at the earliest opportunity. Relevant charities should also be informed that they should advise patients to contact their cancer center. Health care professionals and patient groups should be proactive in encouraging patients to look out for rash and be properly informed to advise patients according to accepted practice. a A U.K.-wide, nurse-led health care advisory service for patients with telephone access and a network of walk-in clinics. Abbreviations: GP, general practitioner; NHS, National Health Service. Consensus Following the discussions regarding erlotinib rash management outlined above, and critical assessment of the current international recommendations [12], the following points of consensus were reached, culminating in the algorithm presented in Figure 1. General Advice The importance of taking erlotinib on an empty stomach (at least 1 hour before and 2 hours after eating, at the same time each day) should be emphasized to both health care professionals and patients. Patients should be fully informed about the possibility and implications of skin toxicity on initiation of erlotinib therapy. Patients should be advised not to stop taking erlotinib until they (or their GP) have consulted an oncologist. The need to use a recommended emollient prophylactically to avoid drying of the skin should be stressed. Physical shields and nonocclusive sunscreen (SPF 15) should be recommended (in line with the international guidance) if there is evidence of photosensitivity. Patients are advised to avoid grapefruit or grapefruit juice, because it inhibits the metabolic enzyme cytochrome P450 3A4, leading to increased plasma levels of erlotinib.

6 Thatcher, Nicolson, Groves et al. 845 RASH SEVERITY MILD INTERVENTION Continue EGFR inhibitor at current dose and monitor for change in severity Usually localized Minimally symptomatic No impact on activities of daily life (ADL) No ulceration, weeping, or infection No treatment OR Topical hydrocortisone 1% or 2.5% cream and/or topical clindamycin 1% Reassess after 2 weeks (either by health care professional or patient self-report): if reactions worsen or do not improve, proceed to next step MODERATE Continue EGFR inhibitor at current dose and monitor for change in severity Continue treatment of skin reaction with the following Localized or generalized Mild symptoms (e.g., pruritus, tenderness) Minimal impact on ADL No ulceration, weeping, or infection Caution is required in patients taking concomitant medication, especially warfarin, certain antibiotics, antacids, and anti-inflammatory agents. Intervention SEVERE Usually generalized Severe symptoms (e.g., pruritus, tenderness) Significant impact on ADL Ulceration, weeping, or infection present Mild Rash Treatment with erlotinib should be maintained at the current dose. Topical hydrocortisone (1% or 2.5% cream) for macular rash and/or topical clindamycin (1%) for pustular rash is recommended. The patient should be reassessed after 2 weeks. Topical clindamycin 1% PLUS hydrocortisone 2.5% cream or pimecrolimus 1% cream PLUS oxytetracycline 500 mg twice daily or lymecycline 408 mg once daily Reassess after 2 weeks (either by health care professional or patient self-report): if reactions worsen or do not improve, proceed to next step Reduce EGFR inhibitor dose as per label and monitor for change in severity; continue treatment of skin reaction with the following: Topical clindamycin 1% PLUS hydrocortisone 2.5% cream or pimecrolimus 1% cream PLUS oxytetracycline 500 mg twice daily or lymecycline 300mg once daily PLUS prednisolone 25 mg for 1 week; reduce by 5 mg/day over 4 days Reassess after 2 weeks If reactions worsen, dose interruption or discontinuation may be necessary Figure 1. U.K. treatment algorithm for the management of erlotinib-associated skin toxicity. (a) Ensure patient is taking erlotinib on an empty stomach (at least 1 hour before and 2 hours after eating) at the same time each day. (b) Ensure patient is fully informed about the possibility and implications of skin toxicity. (c) Consider the prophylactic use of an emollient cream, such as Diprobase, E45, or Doublebase, to avoid drying of the skin. (d) Advise patient to use a sunscreen of SPF 15 if indicated. (e) If patient presents with rash, verify appropriate administration of erlotinib, and proceed with the therapy algorithm. Abbreviation: EGFR, epidermal growth factor receptor. Adapted from Lynch TJ Jr, Kim ES, Eaby B et al. Epidermal growth factor receptor inhibitor-associated cutaneous toxicities: An evolving paradigm in clinical management. The Oncologist 2007;12: Moderate Rash Treatment with erlotinib should be maintained at the current dose, and the rash should be closely monitored for change in severity. Doxycycline or minocycline are not recommended, and should be replaced with oxytetracycline or lymecycline. The full consensus recommendation was: topical clindamycin (1%) plus either hydrocortisone (2.5% cream) or pimecrolimus (1% cream) plus oxytetracycline (500 mg twice daily) or lymecycline (408 mg once daily). Severe Rash The dose of erlotinib should be reduced in line with the manufacturer s recommendations, and the rash should be closely monitored for any change in severity. In addition to the interventions recommended for moderate rash, prednisolone may be given as a reducingdose regimen after 1 week (25 mg for 7 days, subsequently decreasing the dose by 5 mg/day every day to 0). The patient should be reassessed at 2 weeks. If toxicity worsens, interruption or discontinuation of erlotinib should be considered. DISCUSSION EGFRIs are important anticancer agents, but all are associated with a range of dermatological toxicities. Most of these

7 846 Managing Erlotinib-Associated Cutaneous Toxicity reactions are effectively managed by symptomatic treatment and do not necessitate EGFRI treatment cessation. To date, there are very few robust data to support the use of tetracycline antibiotics and topical steroids to decrease the severity of EGFRI-induced rashes [14 16], and evidencebased treatment recommendations are therefore not possible. Current practice for management of these toxicities thus relies on qualitative rather than quantitative data, and upon expert opinion [2]. Controlled trials are needed to test the validity of any guidelines. Until such evidence is available, consensusbased tools, such as the proposed algorithm described here, are necessary to adapt international recommendations for U.K. use, with specific reference to erlotinib. The findings of the BR.21 trial, in which the presence of rash was strongly correlated with overall survival [22], raise the question of whether rash is an independent predictor of response, and if so, whether we should treat to rash. Because rash and severity of rash are both strongly associated with superior outcome from erlotinib treatment, it would be useful to be able to predict the likelihood of a patient developing rash. Attempts to identify this predisposition have so far been unsuccessful. Data from a phase II erlotinib dosing-to-rash study [23] support the assertion that dose escalation of erlotinib is feasible and tolerable in most patients. However, the strategy of erlotinib dose escalation to induce rash as a means of improving outcome could not be validated in that study; the efficacy reported was similar to that from erlotinib studies using the standard dosage regimen. However, the occurrence of a target rash (defined as tolerable with minocycline intervention) appeared to correlate with a better outcome. Primary and secondary health care professionals and patient groups in the U.K. need to be familiar with the algorithm presented here, in order to be aware that there is usually no clinical need to withdraw erlotinib treatment if skin rash develops. Even in severe cases, where suspension of erlotinib treatment is necessary, withdrawal is usually only temporary, to allow time for the rash to resolve. The algorithm will typically be implemented in the U.K. by specialist nurses or oncologists, to whom affected patients usually re-present, because erlotinib rash generally appears early in the treatment program. Barriers to implementation of the algorithm should be considered at the primary and secondary care interfaces, where patients may present initially to a GP or an off-hours primary care service. It is essential that primary care professionals are aware of the algorithm, and do not undertake intervention but refer the patient back to the cancer center. Further barriers to implementation need to be addressed in communicating the algorithm to National Health Service Direct staff, to ensure that service users are advised to continue treatment and consult their oncologist, rather than interrupt or discontinue therapy. In addition, informing the patients themselves that they should not stop taking their medication until they have received appropriate advice from their oncologist may be one of the most efficient ways of distributing the message to avoid unnecessary treatment withdrawal. One limitation of this document is that it is merely an expert consensus for local adaptation where appropriate based on clinical experience, safety data from erlotinib clinical trials, and anecdotal reports. It is simply intended to assist health care professionals with managing rash and making decisions regarding patient management. Further research or review is needed after approximately months of implementation to investigate the utility of the algorithm. Well-controlled clinical studies are clearly warranted if we are to better understand the cause of this rash and provide effective, evidence-based treatment recommendations. CONCLUSION Erlotinib is increasingly being prescribed for patients with NSCLC who fail one or more chemotherapeutic regimens. Although generally well tolerated, erlotinib is associated with skin toxicity, which itself appears to be a surrogate marker for response and survival. The expert consensus presented here, following development by the U.K. Erlotinib Skin Toxicity Management Consensus Forum, is a pragmatic and workable adaptation of international recommendations. ACKNOWLEDGMENTS The U.K. Erlotinib Skin Toxicity Management Consensus Forum was funded by a grant from Roche Products Ltd. AUTHOR CONTRIBUTIONS Conception/Design: Nicholas Thatcher, Marianne Nicolson, Richard W. Groves, Jeremy Steele, Beth Eaby, Joyce Dunlop, John McPhelim, Rajinder Nijjar, Ijeoma Ukachukwu Collection/assembly of data: Nicholas Thatcher, Marianne Nicolson, Richard W. Groves, Jeremy Steele, Beth Eaby, Joyce Dunlop, John McPhelim, Rajinder Nijjar, Ijeoma Ukachukwu Data analysis: Nicholas Thatcher, Marianne Nicolson, Richard W. Groves, Jeremy Steele, Beth Eaby, Joyce Dunlop, John McPhelim, Rajinder Nijjar, Ijeoma Ukachukwu Manuscript writing: Nicholas Thatcher, Marianne Nicolson, Richard W. Groves, Jeremy Steele, Beth Eaby, Joyce Dunlop, John McPhelim, Rajinder Nijjar, Ijeoma Ukachukwu Final approval of manuscript: Nicholas Thatcher, Marianne Nicolson, Richard W. Groves, Jeremy Steele, Beth Eaby, Joyce Dunlop, John McPhelim, Rajinder Nijjar, Ijeoma Ukachukwu Medical writer Lindsay Queen, B.Sc., Ph.D., Darwin Grey Communications, was responsible for drafting the manuscript, author liaison, and collation and input of author comments and changes. Medical writing support was paid for by Roche Products Ltd.

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