After describing the association of a rash on EGFR inhibitors with overall better outcomes on this class of agents, we can now take a step back and recognize that the rash can be an annoyance at the very least and sometimes a real problem. While there are no established guidelines, both treating physicians and patients have developed experience with the rash over the past few years that we should be able to use to minimize the impact for the majority of patients and reduce the proportion of people who need stop a potentially helpful agent due to this toxicity.
First, we need to clarify that multiple types of EGFR inhibitors can induce skin toxicities. Although Iressa and Tarceva, oral small molecules that block the “tyrosine kinase” signalling of the receptor, have been the best studied of these, monoclonal antibodies against EGFR, such as erbitux/cetuximab and others that are less well studied in lung cancer also produce skin toxicities. And while we generally think of this as a “rash”, other skin symptoms such as dry skin and itching are very common and are in the same category as a visible rash. And while it is most commonly the skin and particularly the face, neck, and trunk that are affected, other parts of the body can be affected. Eyes (leading to dry eyes/irritation), mouth, nose, and other mucosal surfaces can also be involved.
Second, we need to define the grading system. Technically, there is a formal scale for defining rash. Grade 1 is flat spots (macules) or raised spots (papules) or skin redness not associated with other symptoms. Grade 2 is the same kind of rash, covering less than 50% of the body surface and associated with itching or other symptoms. Grade 3 would be a symptomatic generalized rash over more than half of the body surface or whole body redness (”eythroderma” - not necessarily a rash of spots, but the skin uniformly red and thicker than usual). And grade 4 is with ulcerations and is fortunately quite rare with these agents. Most of these rashes are grade 1 or 2, but some are grade 3. That said, many times in clinical practice we just consider a rash as mild, moderate, or severe. A small patch of pimples around the nose that are itchy would be considered grade 2 by the toxicity grading system, but the patient and the doctor would often just consider this mild.
OK, so why do EGFR inhibitors cause a rash and/or other skin side effects? Well, EGFR stands for Epidermal Growth Factor Receptor, and this molecule is on the skin and hair follicles. EGFR plays a role in the normal development (or differentiation) and functioning of these, and EGFR inhibitors can block that and lead to occlusion of skin follicles. And EGFR inhibitors can lead the sebaceous glands connected to hair follicles to increase production of inflammatory mediators. So, to summarize the cause, we don’t really know.
What can be done? One of the issues is to ensure that patients take oral EGFR inhibitors like Tarceva at roughly the same time of day, and very importantly, on an empty stomach, as in at least one hour before or two hours after eating. That is important because the blood levels after taking tarceva, for instance, on an empty stomach are much more predictable than taking it with food. The studies used tarceva on an empty stomach because they previously found that the blood levels were often higher but very unpredictably so after taking it with food.
One of my friends and colleagues, Dr. Ed Kim at MD Anderson Cancer Center in Houston, has generated some summary concepts and ideas. Here’s a slide/figure based on his key points:
(click to enlarge)
What are those key points? Be proactive in dealing with problems before they become major issues. As the slide suggests, I give my patients prescriptions for clindamycin (an antibiotic, also known as Cleocin) gel, and also topical hydrocortisone 1% cream (also available over the counter), along with the prescription for tarceva. I advise to use these early if a rash appears. I also advise patients to avoid significant sun exposure. Then I have patients return to the clinic two weeks after starting tarceva, to check how they’re feeling, to check labs, and primarily to ensure that patients are not experiencing a terrible rash. For more significant rashes (grade 2 or higher), we often give oral antibiotics such as minocycline, and oral steroids. Some people distinguish between a flat rash and a bumpy, angrier one, and use steroids preferentially for flat rashes and antibiotics for pustules. Another approach that has recently been described uses a combination of an antibiotic like minocycline and the prescription non-steroidal topical cream for eczema called Elidel (1%). I haven’t had a patient who needed this since learning about this, but I’ve heard other doctors describe very good results with it in their experience for EGFR-induced rashes.
The rash tends to be worst after about 2-3 weeks and then tends not to get worse and often gets a bit better over time. I have seen several patients who develop more skin side effects later, but that’s not the typical scenario.
For dry skin and itching, we recommend emollients. Vaseline intensive care may do the job. There’s also lotions like “Lac-Hydrin” (Lactic Acid 12%) that can effectively help. For generalized itching, I give antihistamines like atarax or benadryl, which seem to help some.
The consensus from the people who have really been concentrating on this is that it isn’t acne and should be treated with over-the-counter acne medications or prescription acne medications like Accutane (isotretinoin).
Even with these interventions, sometimes the rash is severe enough to need to take a break or cut the dose. Stopping treatment temporarily will generally lead to a rapid improvement in skin symptoms, usually in just a few days. A significant minority of patients will need to decrease the dose of Tarceva to 100 mg, or sometimes lower than that. Tarceva tablets come not only in the 150 mg dose, but also 100 mg and 25 mg tabs, so it’s possible to cut down to 100 mg or lower if needed. Clearly, some patients are very sensitive to these agents, and we have NOT seen any evidence that patients who need to take a lower dose because of severe rash or other side effects do less well than the patients who took 150 mg. If anything, we see that the patients who developed a significant rash at some point (some of whom would have received subsequent dose reductions) did particularly well.
There are plenty of other issues, like hair changes of all types, and breaks in the skin or infections at the tips of the fingers and toes, that can also be seen. Most of these don’t have any standard approaches, but I’d love to learn if people have found helpful. I learn from the experiences of other docs and also patients and will be eager to try to aggregate our knowledge to make this type of therapy as easy to tolerate as possible.
posted by Dr. West @ 2:20 pm link to this post
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October 23rd, 2008 at 5:38 am
[…] I generally use the approaches advocated in a couple of prior posts here and here to manage problematic rashes. For more moderate to severe rashes, I add minocycline twice daily, and a few patients start and stop this periodically as needed when their rash flares up. I have rarely added oral steroids, a “Medrol dose pack” that is advocated for severe rashes, mostly because I tend to have people hold it for a few days until the rash has subsided and then restart it at the same or, often, a lower dose of 100 mg per day for tarceva, the main one I’ve been using for the past several years. Most of the time, patients who have a hard time at 150 mg daily do much better with 100 mg per day, but very occasionally I’ve had patients who require a further dose reduction. But because the patients who are most sensitive to the adverse effects of these drugs are also probably most sensitive to the beneficial effects as well, I’d give 50 mg per day to the rare patient who just can’t manage on a higher dose. I’ve even heard of patients on 25 mg per day who managed to continue to respond, and I have a single patient who is struggling even at 50 mg daily (an Asian never-smoking woman, so I’d suspect she may be exquisitely sensitive and benefit from just about any amount she can manage). I’d be happy to have patients continue on the standard dose or the highest below that they can truly tolerate and that is enough to control the cancer, which means maintain a response or keep it from progressing. […]
October 29th, 2007 at 10:11 pm
Mark,
I don’t know details of the BATTLE trial, but I would say that I do routinely prescribe both hydrocortisone cream and cleocin (clindamycin) T gel prophylactically when I give a prescription for tarceva. I also give a prescription for loperamide in case of diarrhea.
I agree that it does sound like you’re in the range of a very small minority who are remarkably susceptible. My general approach is that these agents need to be manageable for a long-term approach. So if this is a treatment that is on the outer limits of tolerability for a few weeks, I just think that begins to undermine the beauty of this as a potentially chronic medication. My approach is that if there is a clear benefit to treatment, whether with standard chemo or tarceva, if it’s toxic the next question is what is the least amount of treatment that is required to continue to see benefit?
I have heard of people having good improvements in the rash with Elidel but have not used it personally yet with my own clinic patients.
I certainly think it would be interesting to know more details about the molecular markers of your cancer, the real proof is in how your cancer responds to treatment. Please do keep me/us informed.
-JW
October 29th, 2007 at 7:11 pm
Greetings Jack,
I have not kept up with my promise to be more active on these forums but thought I might provide a quick update now and pose a few questions. I entered the MD Anderson BATTLE trial and got assigned to the standard treatment arm of erlotinib. After 13 days at 150 mg/day, my face cheeks and nose were scabbed over. There were lesions all through my scalp and my trunk was covered with what was at first a flat red rash that later coalesced into the red rash with very small pustules that would break open and bleed when scratched.
I had some initial problems communicating with MD Anderson regarding the availability and need for various prophylactics as the standard answer from nursing staff was tylenol and otc hydroccortizone. Dr. Kim was with you in Korea at the time and I was in great pain so got treatment at local oncologist and local GI who set me up with antibiotics and prescription hydrocortisone and some hydrocodone for the pain. After 13 days I was advised to stop the erlotinib by Dr Kim.
2 weeks passed and the rash did heal somewhat, at least the scabs are gone from my face, but I still have redness and pustules over my trunk, face and scalp. I just visited Dr Kim and he convinced me to continue the trial at 100 mg and provided me with prescriptions for more oral antibiotics, antihistamine for rash and itching, medrol prednisolone dose pack and clydamyacin topical antibiotic, none of which were offered to me just in case for first cycle. Is this typical in the clinical trial setting?
Dr Kim’s assessment is that I am in the 1% category on rash reactivity, so if the rash is a god thing, then I got it good. I am now back on tarceva at 100 mg/day and this is day 5. The redness is getting worse and my skin is once again beginning to itch, even with all the prophylactics. I am going to keep thinking positive and try to push my way through the rest of this treatment cycle. I have a cruise scheduled for Nov 3 that I booked some time ago. It is a MacGeek cruise where they bring in Macintosh computer experts to lead seminars on mainly comparisons of digital photo editing programs which I am interested in as a digital photographer. I may end up in bed in my stateroom, at least a nice one with private verandah, for much of the cruise, but it seems like there would be no better place to lay around and feel bad as I try to push through this cycle of treatment. Do you think this is foolish? I will still have email contact with MD Anderson and can stop treatment if things get out of hand. But the way I look at it is I might not be as miserable resting on the cruise, than staying at home with the daily grind here.
Lastly, should I ask Dr. Kim about obtaining Elidel, since I am already beginning to have repeat symptoms on day 5 at 100 mg? That seems to be the only thing I have yet to try. My impression is that the clinical trial staff thinks I am desperate and are reluctant to offer me any additional comfort agents.
If I make it through this cycle, I am scheduled for CT, 2nd core biopsy and visit with Dr. Kim at the end of November.
There was some suggestion that they may finally reveal at the end of November if I had any and if so what type of EGFR markers from the initial bloodwork and core biopsy.
Thanks for listening. I will keep you posted as more develops.
Best Regards
Mark Pate
April 13th, 2007 at 6:32 am
in less severe cases, cortisone cream. If severe and diffuse enough, an oral steroid like prednisone or other alternatives are often used.
April 12th, 2007 at 6:16 pm
Do you mean a cortisone cream or a pill like prednisone?
April 11th, 2007 at 11:35 pm
It’s definitely in the realm of side effects seen with tarceva. Aside from antibiotics, I would consider trying steroids to see if that improves it, but if not, if it’s bad enough it might be worth adjusting the dose down to 100 mg and seeing if that controls the problem. It would be her call whether this is just an annoyance or problematic enough to consider dropping the dose to manage the symptom, but that’s what at least one of my patients with a very similar symptom decided to do. It’s been fine for her at 100 mg daily.