What is the role of topical creams, skin moisturisers and maintenance antibiotics in the treatment of rash from anti-EGFR therapy in patients with lung cancer?

From Cancer Guidelines Wiki

Introduction

A distinctive rash is a common side-effect of treatment with a range of pharmaceutical agents that interact with the epidermal growth factor receptor (EGFR). In relation to lung cancer, the current agents in use are two orally-administered small molecules, erlotinib[1] and gefitinib2, and a monoclonal antibody cetuximab[2] that is given by intravenous infusion. Similar cutaneous adverse effects are seen with other EGFR antagonists used for separate indications.

Although commonly referred to as acne-like, the pathology and clinical appearance is quite dissimilar. Papules and pustules predominate without some specific features of acne such as comedones.[3] A variety of alternate or umbrella descriptions have been used but it is best thought of as papulopustular, Onset occurs typically within weeks of treatment onset and some fluctuation of rash severity is commonly seen. The extent of rash can vary from one that is localised and causing few symptoms to a generalized reaction that may be associated with severe itch or tenderness. There is anecdotal evidence that some patients self-adjust the dose or dosing frequency in an attempt to manage the impact of rash. Resolution is seen after cessation of treatment.

Unfortunately, there are limited data derived from randomised clinical trials and a profusion of strategies to address the problem of rash have been proposed and used. A review from a single centre found that 26 different strategies had been initially employed to address rash in 49 patients.[4]

Dry skin is a separate, important adverse effect. It tends to occur later in the treatment than does rash. Management of this has generally been along the lines of dermatological treatment of dry skin for other known or unknown causes. Hence little evidence, specific for this clinical setting, has been generated and the prescriber should follow general expert-driven consensus guidance.[5]

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Rash - prophylactic management

The aim of prophylactic treatment is to commence this at the same time as the EGFR antagonist, in order to reduce the severity and/or frequency of rash. This is important in patients who may have significant symptoms at the time of treatment commencement and as rash is the side-effect most likely to result in treatment interruption. A number of single or compound interventions have been trialled in this setting. Tetracycline did not reduce the frequency of rash, but it did reduce severity and quality of life scores were better.[6] The combination of lymecyline and a non-steroidal skin moisturiser reduces severity, although increasing the frequency of low grade rash in colorectal and lung cancer patients receiving Cetuximab or Erlotinib.[7] Doxycycline in combination with moisturisers, in addition to topical steroids and sunscreen, given as prophylaxis was superior to a reactive management plan in patients with colo-rectal cancer given another EGFR-antagonist.[8] However, it is known from other studies that steroids and sunscreen have limited or no efficacy so that the treatment effect is likely to be resident in the antibiotic or moisturiser elements of that treatment plan. Minocycline reduced rash severity and there was no additional benefit from adding tazarotene.[9]

Patients receiving Panitumumab (a monoclonal antibody targeteting EGFR) and concurrently commenced prophylactically applying a moisturiser in addition to Minocycline found it to be superior to the reactive management treatment plan when treating colorectal cancer patients.[10] Vitamin K cream for the prophylaxis of rash in colorectal patients has a lack of convincing data, with limited or no efficacy.[11][12] Sunscreen does not prevent rash.[13]

It is unclear to what extent the individual interventions of antibiotics and moisturisers, contributes to prophylactic rash management when used in combination and data is lacking as to which moisturisers are superior and how often to apply.

Quality of life data suggest the daily use of multiple skin moisturisers is acceptable to patients for the purpose of reducing skin toxicity.[7]


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Rash is a common adverse effect and at the commencement of treatment, patients may be informed of this possibility.

Patients can be made aware that the severity of rash may be reduced by prophylactic antibiotic treatment.
Last reviewed December 2015


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Patients may have reduced severity of skin rash by the addition of prophylactic skin moisturiser, however data suggesting frequency and product selection is lacking.
Last reviewed December 2015


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Vitamin K cream can not be recommended for the purpose of reducing rash.
Last reviewed December 2015


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Sunscreen cannot be recommended for the purpose of reducing rash. Barrier methods – clothing, hats and limiting time in the sun can be employed in preference.
Last reviewed December 2015

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Rash-reactive management

The approach to rash as a clinical problem will be influenced to a great extent by the nature of the response of the tumour itself to treatment. The positive association of rash with treatment responses vexes this issue. Where tumour progression has occurred on treatment the EGFR antagonist can be simply ceased. Where treatment must continue, the strongest evidence for treatment effect exists for antibiotics – clindamycin, docycycline and minocycline. This evidence is derived largely from uncontrolled studies and by inference from the few studies in the prophylactic setting. Apparently positive responses in uncontrolled studies could be influenced by natural fluctuations or patient-initiated dose adjustments unknown to investigators. Other agents have been added including isotretinoin,[14] but the added value of the second agent is uncertain. There are no meaningful comparative data to support a preference for one or other antibiotic. Uncertainties expressed in consensus guidelines underscore the lack of quality evidence.[5]


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For very severe rash, alone or in combination with other skin adverse effects, treatment can be discontinued or suspended.
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Evidence for treatments supplementary to antibiotics for rash is presently lacking, but a useful effect cannot be disproven.
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Topical formulations of steroids and tacrolimus do not add to the benefit of antibiotic treatment.
Last reviewed December 2015

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Dry skin

Drying of the skin occurs on a continuum from a trivial effect to formation of severe fissures for which interventions such as glue can be required. The use of skin moisturising products are presently commonly recommended, generally an emollient.[15] There is no meaningful data on which specific recommendations can be based for dry skin in this clinical setting. Empirical treatment has been based on that employed for other xerostoses.


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Anecdotal evidence supports the use of skin moisturisers but data for product selection, frequency of use and consequential outcomes are lacking.

The routine use of moisturisers can be justified at the outset of EGFR-TKI but this is based on expert opinion and reasonable fear of the consequences of inaction not controlled trials.

Severe drying with fissuring can be regarded as a serious complication and the opinion of a Dermatologist, ideally one with an interest in this clinical area, may be sought.

Last reviewed December 2015

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Other adverse skin and eye effects

Other skin adverse effects including paronychia are seen and are important.Grading of paronychia is related to the extent to which it impacts patient lifestyle. Lack of robust evidence limits recommendations however expert consensus suggests where no infection present, the preferred treatment is topical steroids combined with systemic antibiotic treatment. In severe cases with suspected infection, swab to be taken, and refer to dermatologist.[15]

Ocular side-effects including but not limited to drying of secretions, conjunctivitis, blepharitis and eyelash misgrowth are also described and can be clinically significant.

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Evidence summary and recommendations

Evidence summary Level References
Prophylactic antibiotic treatment may reduce the severity or frequency of rash.


Last reviewed December 2015

II [6], [8], [9]
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A tetracycline can be prescribed in conjunction with anti-EGFR therapy, as it may reduce the severity and frequency of rash.


Last reviewed December 2015

C



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Patients with clinically significant rash may be commenced on oral antibiotic therapy with tetracycline, minocycline or doxycycline.
Last reviewed December 2015


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The treatment for paronychia is based on expert opinion as no randomised controlled trials have evaluated the therapies.

The consensus of expert opinion suggests where there is no signs of infection, the topical application of a corticosteroid combined with a systemic cycline antibiotic.

In severe cases and signs of infection, it is recommended to swab, treat with appropriate systemic antibiotic and refer to dermatologist.
Last reviewed December 2015

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References

  1. Bonomi P. Erlotinib: a new therapeutic approach for non-small cell lung cancer. Expert Opin Investig Drugs 2003 Aug;12(8):1395-401 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/12882624.
  2. Baselga J. The EGFR as a target for anticancer therapy--focus on cetuximab. Eur J Cancer 2001 Sep;37 Suppl 4:S16-22 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/11597400.
  3. Agero AL, Dusza SW, Benvenuto-Andrade C, Busam KJ, Myskowski P, Halpern AC. Dermatologic side effects associated with the epidermal growth factor receptor inhibitors. J Am Acad Dermatol 2006 Oct;55(4):657-70 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/17010747.
  4. Solomon BM, Jatoi A. Epidermal growth factor receptor (EGFR) inhibitor-induced rash: a consecutive patient series that illustrates the need for rigorous palliative trials. J Palliat Med 2011 Feb;14(2):153-6 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/21226620.
  5. 5.0 5.1 Burtness B, Anadkat M, Basti S, Hughes M, Lacouture ME, McClure JS, et al. NCCN Task Force Report: Management of dermatologic and other toxicities associated with EGFR inhibition in patients with cancer. J Natl Compr Canc Netw 2009 May;7 Suppl 1:S5-21; quiz S22-4 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/19470276.
  6. 6.0 6.1 Jatoi A, Rowland K, Sloan JA, Gross HM, Fishkin PA, Kahanic SP, et al. Tetracycline to prevent epidermal growth factor receptor inhibitor-induced skin rashes: results of a placebo-controlled trial from the North Central Cancer Treatment Group (N03CB). Cancer 2008 Aug 15;113(4):847-53 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/18543329.
  7. 7.0 7.1 Grande R, Narducci F, Bianchetti S, Mansueto G, Gemma D, Sperduti I, et al. Pre-emptive skin toxicity treatment for anti-EGFR drugs: evaluation of efficacy of skin moisturizers and lymecycline. A phase II study. Support Care Cancer 2013 Jan 13 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/23314653.
  8. 8.0 8.1 Lacouture ME, Mitchell EP, Piperdi B, Pillai MV, Shearer H, Iannotti N, et al. Skin toxicity evaluation protocol with panitumumab (STEPP), a phase II, open-label, randomized trial evaluating the impact of a pre-Emptive Skin treatment regimen on skin toxicities and quality of life in patients with metastatic colorectal cancer. J Clin Oncol 2010 Mar 10;28(8):1351-7 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/20142600.
  9. 9.0 9.1 Scope A, Agero AL, Dusza SW, Myskowski PL, Lieb JA, Saltz L, et al. Randomized double-blind trial of prophylactic oral minocycline and topical tazarotene for cetuximab-associated acne-like eruption. J Clin Oncol 2007 Dec 1;25(34):5390-6 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/18048820.
  10. Yamada M, Iihara H, Fujii H, Ishihara M, Matsuhashi N, Takahashi T, et al. Prophylactic Effect of Oral Minocycline in Combination with Topical Steroid and Skin Care Against Panitumumab-induced Acneiform Rash in Metastatic Colorectal Cancer Patients. Anticancer Res 2015 Nov;35(11):6175-81 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/26504047.
  11. Jo JC, Hong YS, Kim KP, Lee JL, Kim HJ, Lee MW, et al. Topical vitamin K1 may not be effective in preventing acneiform rash during cetuximab treatment in patients with metastatic colorectal cancer. Eur J Dermatol 2013 Jan;23(1):77-82 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/23238388.
  12. Pinta F, Ponzetti A, Spadi R, Fanchini L, Zanini M, Mecca C, et al. Pilot clinical trial on the efficacy of prophylactic use of vitamin K1-based cream (Vigorskin) to prevent cetuximab-induced skin rash in patients with metastatic colorectal cancer. Clin Colorectal Cancer 2014 Mar;13(1):62-7 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/24332355.
  13. Jatoi A, Thrower A, Sloan JA, Flynn PJ, Wentworth-Hartung NL, Dakhil SR, et al. Does sunscreen prevent epidermal growth factor receptor (EGFR) inhibitor-induced rash? Results of a placebo-controlled trial from the North Central Cancer Treatment Group (N05C4). Oncologist 2010;15(9):1016-22 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/20798191.
  14. Bidoli P, Cortinovis DL, Colombo I, Crippa A, Cicchiello F, Villa F, et al. Isotretinoin plus clindamycin seem highly effective against severe erlotinib-induced skin rash in advanced non-small cell lung cancer. J Thorac Oncol 2010 Oct;5(10):1662-3 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/20871265.
  15. 15.0 15.1 Reguiai Z, Bachet JB, Bachmeyer C, Peuvrel L, Beylot-Barry M, Bezier M, et al. Management of cutaneous adverse events induced by anti-EGFR (epidermal growth factor receptor): a French interdisciplinary therapeutic algorithm. Support Care Cancer 2012 Apr 27 Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/22539049.

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Appendices

Further resources

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