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STRATEGIES FOR MANAGING EGFR INHIBITOR-INDUCED RASH
The treatment of EGFR inhibitor-induced rash starts with a method to identify and grade the rash. The National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) scale is the most commonly used way to grade cancer treatment toxicities. The current version 4.0 lists different skin rashes and skin conditions that can occur and be graded but does not describe EGFR inhibitor rash in particular.6 The Multinational Association for Supportive Care in Cancer (MASCC) utilized a panel of experts to propose an update to the current scale, a specific EGFR inhibitor-dermatologic grading scale, which incorporates 17 different skin, nail, eye, hair, and oral toxicities that can occur with EGFR inhibitors.7 The online version of this article contains a link to that scale.
Nonpharmacologic approaches to the prevention of rash are important and can help patients to maintain autonomy and continue treatment uninterrupted.
- Since the rash tends to be drying, ask the patient to apply a thick, emollient cream to the face and body once or twice a day as soon as the medication is started. Creams tend to be better as lotions are usually thinner and water-based. Also, be sure that the cream is without dyes or fragrances that may irritate the skin.
- Patients who anticipate sun exposure should be instructed to apply a sun block of SPF15 or higher. Note your patient’s occupation. If she sits close to a window where thesun may shine on her, or if he drives a truck where the sun is shining on him through the windshield all day, sun protection is especially important.
- Another prevention technique is to take the oral EGFR inhibitors on an empty stomach. Taking them with food will increase their bioavailability, thus causing heightened side effects.
- Nurses should also be aware of concomitant medications that the patient is taking because erlotinib is metabolized via the CYP3A4 pathway in the liver. Potent CYP3A4 inhibitors, such as certain antifungals, clarithromycin, and grapefruit juice, can dramatically increase the plasma levels of erlotinib, which can in turn worsen the side effects.
Treatment of the papulopustular rash can be challenging. No randomized trials of treatment have been performed, and in the absence of clinical trial data, best practice guidelines have been put forth, as have data from pre-emptive trials and strategies documented by dermatology clinics.
The first guidelines published for EGFR inhibitor rash management came from a group of dermatologists, oncologists, pharmacists, and oncology nurses who met at a summit in 2006 to formulate a “best practice” algorithm. This algorithm utilizes a step-wise approach based on severity of the rash, using topical corticosteroids and antibiotics to treat minor rash as well as oral antibiotics and oral corticosteroids if necessary for moderate or severe rashes.8 Also published is the work of dermatologist Dr. Mario Lacouture and his experiences in the S.E.R.I.E.S. clinic (Skin and Eye Reactions to Inhibitors of EGFR and kinaseS).9 This approach, again based on clinical practice, recommends lower doses of synthetic tetracycline (STCN) antibiotics along with pimecrolimus cream (Elidel), an immunomodulator cream, for mild/moderate rashes. It recommends STCNs at higher doses with stepwise addition of corticosteroids for more severe rashes.
Another approach is to prevent the rash by using these medications when EGFR inhibitor therapy is initiated. Most rash prophylaxis trials have involved panitumumab (Vectibix), a monoclonal antibody that has the highest rate of grade 3/4 rash among the EGFR inhibitors. The STEPP trial compared preventive rash therapy using oral doxycycline and topical hydrocortisone 1% cream versus reactive treatment of EGFR inhibitor rash in patients receiving panitumumab for metastatic colorectal cancer.10 Patients who received the prophylactic therapy had a 50% reduction in grade 2 or higher rash compared to the patients who were treated reactively.10 Patients in the preventive therapy arm also had improved quality of life compared to those in the reactive arm. Since rash can correlate with disease response and survival in some EGFR inhibitor cancer trials, there is concern that preventing the rash from developing could also make the drug less efficacious. Based on the STEPP trial results, future study of rash prevention therapies and any possible correlation with survival is warranted.
TREATMENT STRATEGIES FOR OTHER SIDE EFFECTS
The second most common side effect of EGFR inhibitors is diarrhea. This adverse reaction is usually very manageable, although elderly patients may be at greater risk for dehydration and should be monitored closely. Patients should be advised to avoid spicy or greasy foods and to follow the BRAT (bananas, rice, applesauce, toast) diet if loose stools occur. OTC medications such as loperamide (Imodium) can relieve the diarrhea. If OTC products are not effective, a prescription medication such as diphenoxylate/atropine (Lomotil) can offer stronger relief. Reduction in EGFR inhibitor dose may be necessary if the diarrhea persists. A patient who is having persistent diarrhea should be monitored for electrolyte imbalances, such as low magnesium and potassium levels.
Magnesium wasting is seen mostly with cetuximab and is less common with the EGFR TKIs. This side effect is certainly exacerbated when there is simultaneous diarrhea, but it can occur independent of loose bowels. Checking serial magnesium levels is important. Symptoms of hypomagnesemia are muscle weakness, confusion, decrease in reflexes, and cardiac arrhythmias, although these symptoms are usually present only when magnesium levels are dangerously low. The best way to replenish magnesium is to give it intravenously, 1 g over 15 minutes. Higher amounts of magnesium given IV need to be run slower because of cardiac safety concerns. Oral repletion is less effective but is often done for convenience. The most common form prescribed is usually magnesium oxide, though magnesium gluconate and magnesium chloride are also available. Oral replacement dosing is often limited by diarrhea as a side effect.
After longer-term use of EGFR inhibitors, other dermatologic effects can occur. Inflammation and soreness around the nail beds, known as paronychias, are difficult to treat, but topical antibiotics or antifungals, or soaks with Epsom salts or diluted betadine, can sometimes help (Figure 2). Oral antibiotics may work, especially if erythema or pus is present. Prevention is key. Teaching patients up front to keep nails clean and trimmed can hopefully prevent this complication. Fingertip splitting from very dry skin is also a later side effect (Figure 3). Prescription-strength urea moisturizers and glues such as Superglue or Liquid Bandaid can be utilized for treatment. Also, be sure that the patient is not exposing the fingers to extreme temperatures or friction that may exacerbate the splitting or paronychias.
Alopecia or hair thinning can occur from EGFR inhibitor use. The alopecia is usually partial rather than complete, as occurs with chemotherapy; however, the hair can become brittle and fall out in clumps. This side effect can be worse if the papulopustular rash is present on the scalp (Figure 4). 
Therapeutic shampoos, such as OTC t-gel shampoos or prescription-strength shampoos such as fluocinolone acetonide (Capex), can help moisturize the scalp. The eyelashes and eyebrows can also grow long and brittle, sometimes curling inward toward the eye. To avoid corneal abrasions, the eyelashes should be kept trimmed.
CONCLUSION
EGFR inhibitors are a mainstay in the treatment of lung cancer, and oncology nurses play a vital role in their effective use. Prevention and management of EGFR inhibitor side effects can allow the patient to remain on therapy at either a full or decreased dose, an important goal if the patient’s cancer is responding well to treatment. Educating patients about strategies to prevent and manage EGFR inhibitor side effects is a key factor to helping them maintain body image while on these medications and remain adherent to therapy. ONA
Beth Eaby-Sandy is a nurse practitioner at the Abramson Cancer Center of the University of Pennsylvania, Philadelphia, Pennsylvania.
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REFERENCES
1. American Cancer Society Facts & Figures 2009. http://209.135.47.118/downloads/STT/500809web.pdf. Accessed July 22, 2010.
2. Shepherd FA, Rodrigues Pereira J, Ciuleanu T, et al. Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med. 2005;353(2):123-132.
3. Pirker R, Pereira JR, Szczesna A, et al. Cetuximab plus chemotherapy in patients with advanced non-small-cell lung cancer (FLEX): an open-label randomized phase III trial. Lancet. 2009;373(9674):1525-1531.
4. Thatcher N, Chang A, Parikh P, et al. Gefitinib plus best supportive care in previously treated patients with refractory advanced non-small cell lung cancer: results from a randomised, placebo-controlled, multicentre study (Iressa Survival Evaluation in Lung Cancer). Lancet. 2005;366(9496):1527-1537.
5. Cohen MH, Williams GA, Sridhara R, et al. FDA drug approval summary: gefitinib (ZD1839) (Iressa) tablets. Oncologist. 2003;8(4):303-306.
6. National Cancer Institute. Common terminology criteria for adverse events (CTCAE). Version 4.0. http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5×11.pdf. May 28, 2009 (v4.03: June 14, 2010). Accessed August 4, 2010.
7. Lacouture ME, Maitland ML, Segaert S, et al. A proposed EGFR inhibitor dermatologic adverse event-specific grading scale from the MASCC skin toxicity study group. Support Care Cancer. 2010;18(4):509-522. Epub 2010 Feb 10. http://www.ncbi.nlm.nih.gov/pubmed/20145956. Accessed August 4, 2010.
8. Lynch TJ, Kim ES, Eaby B, et al. Epidermal growth factor receptor inhibitor-associated cutaneous toxicities: an evolving paradigm in clinical management. Oncologist. 2007;12(5):610-621.
9. Lacouture M, Basti S, Patel J, Benson A 3rd. The SERIES Clinic: an interdisciplinary approach to the management of toxicities of EGFR inhibitors. J Support Oncol. 2006;4(5):236-238.
10. Lacouture ME, Mitchell EP, Piperdi B, 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;28(8):1351-1357.
HOW TO TAKE THE POST-TEST: To obtain CE credit, please click here after reading the article to take the post-test on myCME.com.
