Cutaneous side effects of EGFR and protein kinase inhibitors

Author: Dr Nick Turnbull, Dermatology Registrar, London, United Kingdom, 2011.


What are EGFR inhibitors?

Epidermal growth factor receptor (EGFR) inhibitors are a new group of medicines developed to treat a wide range of cancers. Overexpression of EGFR by about 30% of cancers is one reason for their excessive cell proliferation and tumour growth.

Although effective in the treatment of many cancers, EGFR inhibitors often result in adverse reactions in the skin, which occur in at least half of treated patients.

The side effects are helping scientists to learn more about skin disorders. In some cases, the presence of an adverse skin reaction indicates the medicine is effective in treating the tumour.

People may be treated with these medicines for long periods of time and will have to weigh up the benefits versus the side effects.

What are protein kinase inhibitors?

Protein kinases are enzymes within the cell that result in cellular proliferation. Protein kinase inhibitors reduce cell proliferation. They target the amino acids tyrosine, threonine and serine. Some EGFR inhibitors are also protein kinase inhibitors.

How do these inhibitors work?

EGFR inhibitors are targeted specifically against EGFR on the outside of the cell. Protein kinase inhibitors target protein kinases on the inside of the cell. The specific receptors found on the cancer determine which drug is likely to be of benefit.

  • EGFR are located in the cell membrane. On binding with an epidermal growth factor ligand outside the cell, they activate a protein kinase inside the cell.
  • They prevent the phosphorylation of the specific amino acid, e.g. tyrosine

EGFR and kinase inhibitors may be particularly useful in cancer therapy as they they are less toxic than more traditional chemotherapies. Specific drugs target different types of cell and may be monclonal antibodies with the suffix -mab or small molecules with the suffix -nib.

Drug nameMolecular targetIndication
Monoclonal antibody
Retuximab CD20+ Non-Hodgkin lymphoma
Cetuximab KRAS Colorectal cancer
Squamous cell carcinomas of head and neck
Panitumumab KRAS Colorectal cancer
Small molecule
Imatinib BCR-ABL, PDGFR, and c-KIT Chronic Myeloid Leukaemia (CML)
Gastrointestinal stromal tumour.
Gefitinib EGFR, Her1 Non Small Cell Lung Cancer (NSCLC).
Erlotinib EGFR Metastatic NSCLC
Pancreatic cancer.
Lapatinib EGFR, HER2/neu Breast cancer
Osimertinib EGFR, T790M/neu Non-small cell lung cancer
Vandetanib EGFR, VEGFR, RET tyrosine kinase Thyroid tumour
Sorafenib VEGFR, PDGFR, RAF Renal cell carcinoma
Hepatocellular carcinoma
Sunitunib PDGFR, VEGFR, KIT and others Renal cell carcinoma
Gastrointestinal stromal tumours
Neuroendocrine pancreatic tumours
Some of the available EGFR inhibitors

EGFR = epidermal growth factor receptor; PDGFR = platelet derived growth factor receptor; VEGFR = vascular endothelial growth factor receptor

There is currently great interest in small molecule mutated B-RAF inhibitors, vemurafenib and dabrafenib, that are effective in the treatment of B-RAF positive metastatic melanoma. B-RAF is a specific threonine kinase protein.

Many more EGFR and protein kinase inhibitors are under development.

What are the cutaneous side effects of monoclonal antibody EGFR inhibitors?

The most common cutaneous side effects of the monoclonal antibody EGFR inhibitors are:

Folliculitis

Folliculitis (inflamed hair follicles) occurs in up to 40-85% of patients. It is any early event, seen usually within the first ten days of treatment. Sterile inflammatory papules and pustules are seen predominantly on the T-zone of the face but they can be more widespread involving the chest and back. Occasionally the scalp and pubic regions are involved or rarely the entire body.

Folliculitis is especially common and often severe with cetuximab. The intensity of the folliculitis can fluctuate even when continuing to take the drug.

The folliculitis can often be managed with:

If folliculitis is severe, the drug may need to be stopped and it will resolve.  The incidence and severity of the EGFR inhibitor-induced follicular reactions is reduced by half by pre-treating with doxycycline or minocycline. These tetracycline medications can also be prescribed once the rash has occurred allowing continued treatment with the EGFR inhibitor drug.

Folliculitis due to protein kinase inhibitor

Alopecia and trichomegaly

Drug induced alopecia (hair loss) is less common than folliculitis and tends to occur later, usually at 2-3 months. Patients may find their hair become fine and brittle. They may experience frontal temporal hair loss similar to male pattern balding. This may or may not improve if the drug is stopped.

Alopecia due to protein kinase inhibitor

In contrast, patients often experience excessive facial hair and eyelash growth (hypertrichosis, trichomegaly).

Dry skin (xerosis, pulpitis)

Dry skin is very common and is managed with emollients. These drugs can even cause pulpitis with painful fissures on fingertips.

The dry skin sometimes resembles seborrhoeic dermatitis.

Dry skin and keratoderma due to protein kinase inhibitor

Paronychia

Paronychia refers to painful inflammation of the nail folds. Fingers are more frequently affected than toes. Paronychia can sometimes resolve spontaneously even with continued use of the drug but it clears quickly on stopping it.

Treatment involves avoiding trauma such as from tight shoes, avoiding excessive trimming or biting, and wearing appropriate footwear. Topical steroids and antiseptics may help. It is important to treat secondary bacterial and fungal infection.

Skin cancer

Squamous cell carcinoma and multiple keratoacanthomas have been reported to arise in patients on sorafenib and other EGFR inhibitors.

What are the side effects of small-molecule tyrosine kinase inhibitors?

The small molecule kinase inhibitors often block multiple enzymes meaning means there is some cross over in the actions and side effects of these drugs.

The most common side effects are:

  • Nonspecific rashes
  • Periocular oedema
  • Acral erythema
  • Splinter haemorrhages
  • Pigmentation changes
  • Photosensitivity

In addition, the same side effects listed above due to monoclonal antibodies may also arise.

Nonspecific rashes

Imatinib induces a rash in a third of patients who start taking it, but this rash is generally self-limited. Imatinib has rarely been associated with vasculitis, Steven Johnson syndrome/TEN, and acute generalised exanthematous pustulosis (AGEP).

A red facial rash is frequently seen within the first two weeks of treatment with sorafenib. It can appear very much like seborrhoeic dermatitis and usually settles without treatment. It can be associated with scalp tingling or dysaesthesia.

Nonspecific rash due to protein kinase inhibitor

Facial swelling

Swelling (oedema) of eyelids and face is common with imatinib and sunitinib. Oedema may also affect lower legs, lungs (pleural effusions) and brain (cerebral oedema).

Acral erythema

Acral erythema (red hands and feet) is commonly seen with sorafenib and sunitanib. It presents as painful symmetrical red, swollen palms and soles. These drugs may also cause keratoderma / hyperkeratosis (excessive scale) and desquamation (peeling). Acral erythema tends to occur two to four weeks after starting treatment and is dose dependent. It rapidly improves on stopping the drug and may not recur on restarting it.

The small molecule kinase inhibitors tend to cause less extensive but more scaly acral erythema than that induced by standard chemotherapy (hand-foot syndrome or palmar plantar erythrodysathesia).

Preventative measures include appropriate footwear to prevent injury to pressure areas. Discomfort may necessitate brief interruption of treatment.

Painful red, callused palms due to protein kinase inhibitor

Splinter haemorrhages

Painless distal splinter haemorrhages are common, particularly affecting fingernails. It has been suggested that they are due to inhibition of vascular endothelial growth factor receptor (VEGFR). VEGFR is thought involved in the repair of the delicate spiral capillaries under the nail, which are subject to frequent injury.

Pigmentation changes of hair and skin

Depigmented or white hair is usually noticed after a month of treatment with sunitinib. It is reversible with restoration of hair colour two to three weeks after treatment is stopped.

Kinase inhibitors may lead to local or diffuse hypopigmentation (white skin or leucoderma) and hyperpigmentation (dark patches).

Leucoderma due to protein kinase inhibitor

Photosensitivity

Protein kinase inhibitors may lead to sunburn after minimal exposure to the sun (drug-induced photosensitivity).

Sunburned earlobe following minimal sun exposure due to protein kinase inhibitor

 

Related Information

References

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  • M. E. Lacouture; B. L. Melosky. Cutaneous Reactions to Anticancer Agents Targeting the Epidermal Growth Factor Receptor: A Dermatology-Oncology Perspective. Skin therapy letter.com. Volume 12,No. 6, July-August 2007.PubMed.
  • Tasi et al. Hand-Foot Syndrome and Seborrheic Dermatitis-Like Rash Induced by Sunitinib in a Patient With Advanced Renal Cell Carcinoma. Journal of clinical Oncology 2006 5786-5788. PubMed.
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  • Mario E. et al. Evolving Strategies for the Management of Hand–Foot Skin Reaction Associated with the Multitargeted Kinase Inhibitors Sorafenib and Sunitinib. The Oncologist 2008;13:1001–1011. PubMed.
  • Dummer R, Tsae H, Robert C. How cutaneous eruptions help to understand the mode of action of kinase inhibitors. Br J Dermatol 2012:167;965-967. PubMed.
  • Bracarda S, Ruggeri EM, Monti M, Merlano M, D'Angelo A, Ferraù F, Cortesi E, Santoro A; Sorafenib Working Group.. Early detection, prevention and management of cutaneous adverse events due to sorafenib: recommendations from the Sorafenib
    Working Group. Crit Rev Oncol Hematol. 2012 Jun;82(3):378-86. doi: 10.1016/j.critrevonc.2011.08.005. Review. PubMed PMID: 21944842. PubMed.

  • Epidermal Growth Factor Receptor Inhibitor-associated Rash Prevented by Oral Tetracyclines. Medscape report.

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