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Randomized Double-Blind Trial of Prophylactic Oral Minocycline and Topical Tazarotene for Cetuximab-Associated Acne-Like Eruption

Alon Scope, Anna Liza C. Agero, Stephen W. Dusza, Patricia L. Myskowski, Jocelyn A. Lieb, Leonard Saltz, Nancy E. Kemeny, Allan C. Halpern

From the Dermatology Service and Gastrointestinal Oncology Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY

Address reprint requests to Allan C. Halpern, MD, Dermatology Service, Memorial Sloan-Kettering Cancer Center, 160 East 53rd St, New York, NY 10022; e-mail: halperna{at}mskcc.org

	ABSTRACT

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Purpose To evaluate the ability of either oral minocycline, topical tazarotene or both, to reduce or prevent cetuximab-related acneiform rash when administered starting on day 1 of cetuximab therapy.

Patients and Methods Metastatic colorectal cancer patients preparing to initiate cetuximab were randomly assigned to receive daily oral minocycline or placebo, and to receive topical tazarotene application to either left or right side of the face. Both therapies were administered for 8 weeks.

Results Forty-eight eligible patients were randomly assigned to minocycline (n = 24) or placebo (n = 24). Total facial lesion counts were significantly lower in patients receiving minocycline at weeks 1 through 4. At week 4, a lower proportion of patients in the minocycline arm reported moderate to severe itch than in the placebo arm (20% v 50%, P = .05). Facial photographs, obtained at week 4, were reviewed for rash global severity. Patients in the minocycline arm trended toward lower frequency of moderate to severe rash than patients receiving placebo (20% v 42%, P = .13). The differences in total facial lesion counts and subjectively assessed itch were diminished by week 8. Cetuximab treatment was interrupted because of grade 3 skin rash in four patients in the placebo arm, and none in the minocycline arm. There was no observed clinical benefit to tazarotene application. Tazarotene treatment was associated with significant irritation, causing its discontinuation in one third of patients.

Conclusion Prophylaxis with oral minocycline may be useful in decreasing the severity of the acneiform rash during the first month of cetuximab treatment. Topical tazarotene is not recommended for management of cetuximab-related rash.

	INTRODUCTION

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The epidermal growth factor receptor (EGFR) has become an important target for cancer therapy. Two classes of EGFR inhibitors (EGFRIs) have been developed: humanized monoclonal antibodies (mAbs) generated against the extracellular, ligand-binding domain of the receptor, and small molecular tyrosine kinase inhibitors (TKIs) that compete with the intracellular adenosine triphosphate binding domain of the receptor.¹ Both classes of EGFRI drugs have been consistently associated with a specific papular and pustular acne-like rash that affects mainly the face, scalp, and upper torso.² Cetuximab is an immunoglobulin (Ig) G1 chimeric mAb type of EGFRI currently approved by the US Food and Drug Administration (FDA) for EGFR-expressing metastatic colorectal carcinoma.³ Cetuximab has been associated with a high incidence of acneiform rash seen in up to 86% of patients.^4,5

The rash is a therapeutically limiting adverse effect. Grade 3 rash can be seen in 5% to 18% of patients receiving EGFRI,^4-6 and intermittent breaks in treatment or dose reduction are currently employed to control severity of the rash. Given the otherwise favorable safety profile of cetuximab, the rash may seem a reasonable trade-off. But in our and others' experience, if left untreated, the acneiform rash may compromise patient compliance; the facial involvement is often cosmetically distressing to patients.⁷ Treatment for the rash is based solely on unsubstantiated anecdotal reports and has included systemic and topical antibiotics, antihistamines, topical corticosteroids and retinoids.⁸ Formal clinical trials addressing the EGFRI acneiform rash have been lacking. We studied the potential of a systemic tetracycline and a topical retinoid as prophylaxis against cetuximab-associated acneiform rash. Although minocycline is a systemic antibiotic, it has been used for various dermatologic conditions because of its anti-inflammatory effects. Similarly, topical tazarotene, a retinoic acid receptor–specific retinoid, has the potential to normalize keratinocyte proliferation and differentiation and reduce inflammation in pathologic skin conditions.

	PATIENTS AND METHODS

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The study was designed as a single-institution, randomized, double-blind, placebo-controlled trial, and approved by the institutional review board at Memorial Sloan-Kettering Cancer Center. Informed consent was obtained from each participant.

Patients
Patients 18 years or older with metastatic colorectal cancer who were preparing to initiate cetuximab treatment with or without additional chemotherapy were enrolled. Study exclusion criteria included pregnancy; known hypersensitivity to tetracyclines, tazarotene cream, or other topical retinoids; history of lupus; serum bilirubin more than 2.0 mg/dL; AST or ALT more than 185 U/L; and use of anti-inflammatory or antibiotic drugs for other conditions.

Treatment
Eligible patients were randomly assigned to receive minocycline 100 mg/d or oral placebo, along with daily open-label tazarotene 0.05% cream (Tazorac, Allergan Inc, Irvine, CA) application to one side of the face. Topical and oral treatment were started on the same day as initiation of cetuximab therapy and continued for 8 weeks. Patients were instructed to take the pill orally once a day at dinnertime. Patients were also instructed to apply the tazarotene cream twice a day, at morning and bedtime. We tried to minimize irritation from tazarotene by encouraging liberal use of emollients, sun protection, and application frequency reductions in response to irritation. Patients recorded use of study oral and topical medications, as well as any potential medication adverse effects in a study diary.

Evaluation
Baseline evaluation (week 0) included (1) brief clinical history—demographic data, medical history and medication list, history of drug reactions, and history of acne or rosacea (2); complete skin examination by participating dermatologists; and (3) standardized digital photography of the face and upper torso. Follow-up clinical assessment, including questionnaires and skin examination, were performed at week 1 (end of first week of therapy), and weeks 2, 4, and 8. Patients were asked about presence and perceived severity of the rash, associated symptoms, adverse effects of the topical or oral study medications, and the presence of other reported cutaneous adverse effects of cetuximab (itch, dry skin, nail discomfort, hair changes, and mucosal lesions). Response categories to the questionnaire were recorded on a Likert scale, ranging from none to severe. In addition, a dermatologist performed a skin examination that included counts of facial lesions on right versus left sides, assessment of facial erythema, and presence, distribution, and density of skin lesions in nonfacial areas. In some cases, the facial rash consisted of confluent plaques. However, one could usually appreciate multiple small pustules or follicular accentuation overlying the confluent plaque. These follicular lesions overlying a plaque were counted as individual lesions. Digital photography utilizing the same standard poses as baseline was also performed at weeks 4 and 8.

In addition, images of both sides of the face were reviewed by two dermatologists blinded to treatment arm. The reviewers assessed global rash severity on each side of the face categorized into none, mild, moderate, and severe, according to a predefined qualitative diagram. For assessment of tazarotene effect, both sides of the face were compared. For assessment of systemic treatment effect, only the observation side of the face was considered.

Statistical Analysis
The prespecified primary end point was difference in total face lesion counts between minocycline- and placebo-treated patients at completion of the study period (week 8). As secondary end points, we analyzed (1) differences in total face lesion counts between minocycline- and placebo-treated patients at the other follow-up intervals (weeks 1-4), and (2) the effect of topical tazarotene via difference in lesion count, in a paired fashion, between treated and observed sides of the face.

The study was designed to detect a lesion count difference of 5 with more than 80% power, based on sample size of 24 patients in each systemic treatment arm. Because of the right-skewed nature of the lesion count data, statistical analyses were based on the log transformation of lesion count. Means and standard deviations were calculated for log lesion counts in each of the treatment groups. Frequencies and relative frequencies were used to describe the study populations. To further assess lesion differences across study time points, and to account for the correlated nature of the data, linear regression models using generalized estimating equations were created. For the analysis of subjective rash and itch, the responses were dichotomized in to none/mild and moderate/severe. Similarly, for analysis of the photographic global assessment of facial rash severity, responses were dichotomized into none/mild and moderate/severe rash. ² analyses were performed at each study time point to assess the association between treatment arm and rash/itch response. To assess rash and itch across the study time points, logistic regression models using generalized estimating equations were created. All analyses were performed with Stata SE version 9.1 (Stata Corporation, College Station, TX).

	RESULTS

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Between October 2005 and July 2006, 48 stage IV colorectal cancer patients were randomly assigned to receive oral prophylaxis with minocycline (n = 24) or placebo (n = 24) on the same day of initiation of cetuximab treatment (Fig 1). Patients were also randomly assigned for tazarotene application to the right (n = 24) or left (n = 24) sides of the face, with balanced stratification for each systemic treatment arm. The mean age of patients was 60 years (range, 39 to 83 years; standard deviation [SD], 11 years), and 32 (67%) were male. There were no significant differences between the minocycline and placebo arms in age, sex, skin type, history of acne or rosacea, and concomitant chemotherapy.

View larger version (43K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. Study schema, patient disposition, and attrition data by study week. Values represent number of patients assessed at follow-up (number of patients compliant with oral medication and with tazarotene application). POD, progression of disease.

There was a fairly rapid increase in lesion counts over the first 4 weeks of the study (Fig 2) which began to stabilize by study completion (week 8). Similarly, subjective assessments of rash and itch followed the same trend (Fig 3). On the basis of the regression analysis, there was a significant overall difference in log lesion counts between minocycline and placebo arms (P = .005), with the minocycline arm having lower log lesion counts than the placebo arm. This difference (Fig 2; Table 1) was apparent by study week 1, peaked at study weeks 2 and 4, and tapered by end of the study (week 8). A lower proportion of patients in the minocycline arm reported moderate to severe itch and rash. This subjective assessment paralleled the course of lesion counts (Figs 3A and 3B) with differences peaking at week 4 between minocycline and placebo arms and tapering off by week 8. However, the overall difference in subjective assessment of rash and itch across all study time points did not reach statistical significance. Consistent with these findings, the photographic review of global facial rash severity at week 4 showed that four patients (20%) in the minocycline arm had moderate to severe facial rash compared with eight patients (42%) in the placebo arm (P = .13; Table 2). Of note, there was no significant difference in the frequency of skin dryness, and nail and mucosal toxicities at week 4 between the minocycline and placebo arms.

View larger version (14K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 2. Scatter plot of log lesion counts for minocycline and placebo groups for each of the four study time points. LOWESS curves were added for the minocycline group (solid line) and placebo group (dotted line).

View larger version (9K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 3. Line plots of subjective (A) itch (P = .047 at week 4) and (B) rash (P = .20 at week 4) for minocycline and placebo patients across the study assessment time points.

View larger version (61K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 4. Patients with grade 3 acneiform rash, showing dense pustules with diffuse erythema on the scalp (A) and center of the face (B, C).

View larger version (12K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 5. Scatter plot of differences in lesion counts for tazarotene and observation sides of the face for each of the four study time points. The dotted line indicates the mean difference in lesion counts for treated and nontreated sides of the face, while the solid line depicts the null hypothesis value of zero, or no difference. Negative results indicate lower lesion counts for the tazarotene (treated) side of the face. A statistically significant difference was observed at study week 4, P = .03.

	DISCUSSION

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EGFR is expressed by the epidermal and follicular epithelium.¹⁵ The pathogenesis of the rash remains to be elucidated, but it has been shown to involve abnormalities in the follicular epithelium together with inflammation. The histologic findings depend on the time course and severity of the rash, ranging from an infiltrate of T lymphocytes surrounding the follicular infundibulum to suppurative folliculitis.^14,16 Animal studies suggest that the inflammation may be a reaction to abnormal follicular keratinization,^17,18 and possibly direct enhancement of immune response induced by EGFR blockade.¹⁹ With this background information, we theorized that we could counteract the abnormalities in follicular differentiation and inflammation with prophylactic administration of systemic tetracycline and topical retinoid.

Tetracyclines are a class of antibiotics, but their use as anti-inflammatory agents has been advocated for various diseases including acne vulgaris,²⁰ rosacea,²¹ bullous pemphigoid,²² pyoderma gangrenosum,²³ cutaneous sarcoidosis,²⁴ and rheumatoid arthritis.²⁵ Minocycline, a semisynthetic tetracycline, appears to harbor greater anti-inflammatory effects than that of first-generation tetracyclines, including effects on mitogen-induced lymphocytic proliferation,^26,27 suppression of neutrophilic migration and chemotaxis,^28,29 upregulation of anti-inflammatory cytokine interleukin (IL)-10³⁰ and reduced synthesis in IL-6 production.³¹ Minocycline has a good safety profile and is convenient for patients in that it can be taken once a day with excellent absorption.³² Severe reported adverse effects, including pseudotumor cerebri, hypersensitivity syndrome, autoimmune hepatitis and drug-induced lupus erythematosus are rare.³³ In addition, several anecdotal studies have reported beneficial effect of tetracyclines for EGFR-associated rash.^8,34,35

Tazarotene is a retinoic acid receptor–specific retinoid. Tazarotene is hydrolyzed to tazarotenic acid, which binds with high affinity and selectivity to retinoid acid receptors β and in the nucleus. The latter is the most frequent retinoid receptor in keratinocytes. By regulating gene transcription, tazarotene is able to normalize the abnormal keratinocyte proliferation and differentiation in psoriatic skin for example.³⁶ Tazarotene also reduces expression of inflammatory markers on keratinocytes, including HLA-DR, ICAM-1 and IL-6.³⁶ Topical tazarotene at 0.1% concentration has been FDA approved for treatment of psoriasis and acne.^37,38 Adverse effects of tazarotene are local and mild to moderate in severity, including erythema, pruritus, burning/stinging, desquamation, and dryness.³⁹

The kinetics of the acneiform rash in our study is compatible with previous observations^2,7; the rash developed rapidly following cetuximab initiation, peaked between weeks 2 to 4, and thereafter tended to steadily abate in severity with continuation of cetuximab. The group of patients receiving minocycline prophylaxis had a lower mean facial lesion count at the peak of the rash, and concordantly, fewer patients treated with minocycline reported moderate to severe itch and rash at the peak of the rash than patients receiving placebo. The review of the photographs obtained at week 4 revealed a similar trend, with patients in the minocycline arm having lower frequency of moderate to severe rash than patients in the placebo arm. In addition, all four patients who developed a grade 3 rash leading to cetuximab treatment withholding (n = 3) or discontinuation (n = 1; treatment discontinued by patient request) were observed in the placebo arm and none in the minocycline arm. Interestingly, in three of the four patients with grade 3 rash, skin toxicity was observed after one to two cetuximab treatments, corresponding with the overall early peak in lesion count observed in the placebo group. However, facial lesion counts were not significantly different between the minocycline and placebo groups at the end of the study, 8 weeks after initiation of cetuximab; and correspondingly, subjective assessments of moderate to severe itch and rash severity were similar between the groups. Taken together, these findings suggest that minocycline was most effective in reducing the severity of the rash during the first month of cetuximab treatment and that this effect was diminished by the end of the second month. If further substantiated, these findings could form the basis for up to 2-month course of prophylactic treatment with minocycline in patients initiating EGFRI therapy.

Recent studies have shown that severity of cetuximab-associated rash may be correlated with clinical outcome. Two potential concerns with the prophylactic use of minocycline could be possible interference with EGFR blockade in the tumor and masking of the rash as a cutaneous marker of response. However, in this study, no differences in response to cetuximab treatment between the minocycline and placebo arms were observed; we recognize that this is a small study and that additional follow-up data are warranted to exclude an impact of minocycline treatment on cetuximab efficacy. Because the severity of the rash was similar in both arms by week 8, this time point could be used to assess the rash as a marker of response in patients receiving minocycline. In addition, because the skin rash is considered a dose-limiting toxicity, prophylaxis with minocycline can have double-fold benefit; it may potentially allow elevation of the maximum-tolerated cetuximab dose, or alternatively, if a standard dose is used, prophylaxis may increase patient compliance and tolerability to cetuximab treatment.

In addition, patients were randomly assigned to either left- or right-side application of tazarotene to mitigate possible underlying differences in facial lesions. We did not employ a topical placebo as it was anticipated that the irritating effects of tazarotene would preclude observer blinding. Tazarotene treatment did not translate to a meaningful clinical benefit. Review of week 4 photographs showed no significant difference in rash severity between both sides of the face, and in few cases, more severe rash on the tazarotene-treated side. We attribute the latter finding to irritation from tazarotene, and indeed, there was a high incidence of irritation leading to tazarotene discontinuation. Furthermore, the combination of minocycline and tazarotene did not translate to synergistic attenuation in the facial rash.

In conclusion, prophylactic treatment with minocycline appears to significantly decrease the severity of the acneiform rash during the first month of cetuximab therapy. Given the early and rapid increase in lesion counts and high incidence of the rash, prophylactic minocycline treatment with cetuximab initiation appears reasonable. Our data suggest that continuation of prophylaxis for the rash beyond 8 weeks is not beneficial. Topical tazarotene showed no clinical benefit and some evidence of detriment, suggesting that it has no role in the management of cetuximab-related skin rash.

	AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

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Employment or Leadership Position: None Consultant or Advisory Role: Leonard Saltz, Amgen (C), Bristol-Myers Squibb (U), Imclone (U), Genentech (U) Stock Ownership: Stephen W. Dusza, Bristol-Myers Squibb Honoraria: Nancy E. Kemeny, Pfizer; Allan C. Halpern, Bristol-Myers Squibb Research Funding: Leonard Saltz, Bristol-Myers Squibb, Imclone, Genentech; Nancy E. Kemeny, Pfizer; Allan C. Halpern, Bristol-Myers Squibb Expert Testimony: None Other Remuneration: None

	AUTHOR CONTRIBUTIONS

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Conception and design: Alon Scope, Anna Liza C. Agero, Stephen W. Dusza, Leonard Saltz, Allan C. Halpern

Administrative support: Patricia L. Myskowski, Allan C. Halpern

Provision of study materials or patients: Patricia L. Myskowski, Leonard Saltz, Nancy E. Kemeny

Collection and assembly of data: Alon Scope, Anna Liza C. Agero, Stephen W. Dusza, Patricia L. Myskowski, Jocelyn A. Lieb

Data analysis and interpretation: Alon Scope, Anna Liza C. Agero, Stephen W. Dusza, Nancy E. Kemeny, Allan C. Halpern

Manuscript writing: Alon Scope, Anna Liza C. Agero, Stephen W. Dusza, Allan C. Halpern

Final approval of manuscript: Patricia L. Myskowski, Jocelyn A. Lieb, Leonard Saltz, Nancy E. Kemeny, Allan C. Halpern

	ACKNOWLEDGMENTS

 
We thank Deborah L. Phelan, RN; Ellen M. Hollywood, RN; Patricia Gabriel, NP; Sandra Arida, RN; Karen J. Ragusa, RN; Daphne Demas; and Maureen K. Heneghan for their help with accrual of patients and study logistics.

	NOTES

 
Supported by an investigator-initiated grant from Bristol-Myers Squibb and ImClone Systems Inc.

Presented in part as poster and oral presentation at the 65th Annual Meeting of the American Academy of Dermatology, February 2-6, 2007, Washington, DC.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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Submitted May 30, 2007; accepted August 28, 2007.

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