Pre-emptive therapy versus reactive therapy
This has been evaluated in two separate studies: The Skin Toxicity Evaluation Protocol with Panitumumab (STEPP) study compared pre-emptive (including a combination of sunscreen, emollients, a weak topical steroid and doxycycline 100 mg twice daily) with reactive treatment.r Pre-emptive treatment commenced the day before the administration of the panitumumab and continued over a six week period. The regimen was as follows:
- apply skin moisturiser to face, hands, feet, neck, back, and chest in the morning on rising
- sunscreen (PABA free, SPF 50+, UVA and UVB protection) applied to skin areas before going outdoors
- hydrocortisone 1% cream applied to face, hands, feet, neck, back and chest at bedtime
- doxycycline 100 mg twice daily
In the pre-emptive group, the incidence of specific grade 2 skin toxicities was 29% compared with 62% in the reactive group (OR 0.3; 95% CI 0.1. to 0.6) resulting in a more than 50% decrease in these toxicities when compared with the reactive group.r
Pre-emptive therapy was compared with reactive therapy or therapy only on severe rash. Melosky et al. 2016,r assessed the effects of prophylactic treatment of erlotinib-induced skin rash in patients with lung cancer. There were three treatment groups: Those who received prophylactic minocycline (100 mg BD for 4 weeks), those who received reactive treatment based on the grade of the rash (which included topical clindamycin, topical steroids and oral minocycline) or no treatment until grade 3 toxicity. Although the incidence of rash was the same in all three groups, the time to rash was significantly prolonged in the prophylactic group, and the incidence of grade three rash was significantly higher in the no treatment arm. The study concluded that both prophylactic and reactive treatment are acceptable options.
Tetracyclines in patients having EGFR inhibitors with radiation therapy
Minocycline has evidence of safety in combination with radiation therapy in head and neck cancer based on a small trial.r Patients having radiation therapy alone for either oropharyngeal or nasopharyngeal carcinoma were randomised to receive minocycline 100 mg BD or placebo during their radiation therapy. The incidence of adverse events and patient reported symptoms were similar in both groups (20 patients per group). Another phase II study is ongoing (NCT01746043) looking at minocycline and armodafinil alone and in combination, in patients having chemoradiation for oesophageal cancer to learn which is better for controlling side effects.
Topical doxycycline in patients having EGFR inhibitors
Topical administration of doxycycline as an adjunct to EGFR inhibitors has been shown to be safe and well tolerated, and appeared to prevent the onset of rash, especially severe rash in patients with colorectal cancer. Patients having either cetuximab or panitumumab plus chemotherapy were randomised to receive topical doxycycline 4% twice a day on one side of the face and vehicle on the other for 5 weeks starting 7 ± 3 days prior to EGFR inhibitor therapy. The incidence of moderate to severe rash (grade 2-3) was lower with doxycycline 4% vs vehicle (p=0.047).r
Therefore, a pre-emptive or reactive approach to EGFR related skin rash is appropriate. This includes oral tetracyclines, topical tetracyclines and topical steroids. There is some evidence to suggest that prophylactic oral tetracyclines are safe in patients having radiation therapy (and ongoing research to assess if they reduce the incidence of general radiation induced side effects).
Treatment (of established disease)
Dermatologic treatment is supportive and aims at maintaining quality of life while continuing treatment. If patient presents with a rash:
- review medications to ensure there are no other possible causes for the rash
- verify appropriate administration of EGFR inhibitor
- assess skin and ensure patient is following an appropriate skin care regimen
- prophylactic or early therapy with a tetracycline antibiotic (e.g. doxycycline or minocycline ) and 1% hydrocortisone cream to affected areas may be considered
Patients should be referred to a dermatologist if there is necrosis, blistering, petechia/purpuric lesions or have an atypical dermatological presentation associated with EGFR inhibitor therapy.
It is difficult to make evidence based recommendations for the management of acneiform rash due to paucity of randomised control trials in this area. To date, the management of EGFR inhibitor skin toxicity mainly relies on reported personal experience, anecdotal or small case reports and should therefore be tailored to the individual patient.
The following recommendation is a suggested regimen which has been extrapolated from the literature and agreed by the eviQ reference committee.
Note: for patients having concurrent radiation therapy it is important that radiation skin care protocols are followed (read more about radiation skin care)
Approach/grade |
Intervention |
General advice (all patients) |
- moisturise the skin with an alcohol-free thick moisturising/emollient cream at least twice a day
- avoid sun exposure as rash may be more severe in areas of skin that are exposed to sunlight (i.e. the face and upper chest)
- apply sunscreen (PABA free, SPF 50+, UVA and UVB protection) to skin before going outdoors and repeated during prolonged exposure (note: sunscreen should not be applied to skin in radiation treatment fields)
- wear loose protective clothing e.g. long sleeve shirt, hat when outside
- avoid situations that may raise body temperature e.g. steam, saunas, hot baths, heating pads, vigorous exercise
- take short baths or showers in lukewarm water and use a bath/shower oil instead of shower gel or soap which can dry the skin
- wear loose-fitting cotton clothing
- avoid over the counter acne preparations (retinoids and benzoyl peroxide), topical anaesthetics and diphenhydramine creams during treatment as these can exacerbate skin toxicity
- report skin changes such as infection and pruritus to their medical officer as soon as possible
|
Pre-emptive approach
(in addition to above) |
- hydrocortisone cream applied to face, hands, feet, neck, back and chest at bedtime
- oral tetracycline twice daily (doxycycline or minocycline)
|
Reactive approach
grade 1 |
- EGFR inhibitor dose reduction not indicated
- moisturise skin and protect from sun exposure
- no topical treatment OR
- topical hydrocortisone 1% or 2.5% cream AND/OR
- topical clindamycin 1% gel/lotion or metronidazole 0.75% cream twice daily to the affected area(s)
- consider doxycycline 100 mg twice daily OR oral minocycline 100 mg twice daily or in divided doses; for a minimum of 4 weeks and continuing for the duration of treatment
- reassess after 2 weeks and if rash progresses or there is no improvement proceed to management for grade 2
|
Reactive approach
grade 2 |
- EGFR inhibitor dose reduction not indicated
- moisturise skin and protect from sun exposure
- if not previously instituted commence topical therapy as per grade 1 PLUS
- doxycycline 100 mg twice daily OR oral minocycline 100 mg twice daily or in divided doses for a minimum of 4 weeks and continuing for the duration of treatment
- assess for pain and prescribe regular analgesia if indicated
- reassess after 2 weeks and if rash progresses or there is no improvement proceed to management for grade 3 & 4
|
Reactive approach
grade 3 & 4 |
- EGFR inhibitor dose reduction is recommended. See eviQ treatment protocol for dose reduction recommendations
- continue management as per grade 2 (note: avoid topical corticosteroids in combination with antibiotics as this may prolong the recovery period of late-phase papulopustular rash)
- if infection is suspected culture pustules to determine the bacterial strain before treating with appropriate antibiotic
- assess for pain and prescribe regular analgesia if indicated
- consider the application of saline soaks (2 to 3 times daily)
- if toxicities do not sufficiently abate despite treatment and dose reduction then the interruption of EGFR inhibitor therapy is recommended
- consider referral to a dermatologist
|