Lung cancer is the most common cancer worldwide in terms of incidence and mortality, and is a major threat to human health. At the time of diagnosis, more than 70% of them are locally advanced and late stage, losing the opportunity of surgical treatment, and medical treatment or combined radiotherapy is the main treatment modality. In the last decade, molecularly targeted therapy represented by epidermal growth factor receptor tyrosine kinase inhibitors gefitinib and erlotinib has become an indispensable treatment for advanced non-small cell lung cancer.
Due to their high efficacy, rapid remission, low toxicity and good tolerability in sensitive populations, they have brought new hope for survival to many patients with advanced lung cancer in clinical applications. However, there are some safety-related problems in the clinical use of these drugs in recent years, mainly related to the following aspects.
Indications
Epidermal growth factor receptor tyrosine kinase inhibitors are mainly indicated for patients with advanced non-small cell lung cancer with EGFR-sensitive mutations, and can also be used as salvage therapy (but with low efficacy) after chemotherapy for EGFR wild-type patients. There is no evidence for preoperative or postoperative treatment of patients with early-stage lung cancer.
Significance of genetic testing for efficacy prediction
Numerous clinical studies have shown that the efficiency of gefitinib in EGFR mutation-positive patients is 70%-90%, while the efficiency of wild-type patients is only 1%-10%, so it is significant to screen for possible beneficiaries.
Dosing Precautions
For oral administration, note that combination with CYP3A4 inducers (e.g., rifampin, phenytoin, carbamazepine, barbiturates, or St. John’s wort) may reduce efficacy. Nursing mothers should be advised to discontinue breastfeeding during treatment with this product. There is no information on the safety and efficacy of this product in pediatric or adolescent patients, so it is not recommended.
Targeted therapy for lung cancer has always been an alternation of old and new drugs. Androgel and semetinib, which are currently under development, are promising in this regard. The safety and efficacy of Androgel in phase I clinical trials have been well established for RAS mutations in lung cancer.
Common Toxicity and Related Management
EGFR tyrosine kinase inhibitors have a similar spectrum of cutaneous adverse reactions, with common manifestations including dryness (dry skin), pruritus, desquamation, nail/perineal changes (usually nail fungus), abnormal hair growth (usually manifested as alopecia, thick eyelashes, or facial hypertrichosis), and capillary dilation (usually manifested as swelling of small blood vessels and hyperpigmentation), while papulopustular lesions (i.e. acne or acne-like rash) is the most common skin adverse reaction, with an incidence of 60% to 80%.
Some patients experience loss of appetite and abnormal liver function, and only 1 to 3 percent of patients develop drug-induced interstitial pneumonia, which may be life-threatening.
Expert advice on dose reduction or discontinuation of EGFR-TKIs
1. EGFR-TKIs should be reduced or discontinued as a last resort after failure of treatment for grade III skin reactions, with erlotinib reduced to 100 mg/day and gefitinib to 250 mg every other day, and treatment interrupted only if skin reactions persist for 2-4 weeks and do not clear.
2. Treatment of rash cannot be stopped during discontinuation of EGFR-TKIs. Because the rash may last for a long time.
3.Some patients only need to stop the drug temporarily, and can continue the drug after the rash improves.
Preventive measures
1. Ask the patient to reduce the time of sun exposure and pay attention to avoiding light. The rash caused by small-molecule tyrosine kinase inhibitors is mostly photosensitive and can cause a more severe rash when exposed to sunlight.
2. Keep the body clean and dry parts of the skin moist every day. Do not touch alkaline and irritating toiletries, and apply mild moisturizer or silicone cream or vitamin E ointment after bathing to prevent dry skin.
3.It is recommended to use a broad-spectrum sunscreen with SPF>18.
4.Patients with ingrown toenail (reverse peeling) may develop nail fungus and local hyperplasia reaction during the medication process. During the treatment of EGFR-TKIs, it is necessary to change foot stress habits and wear loose, breathable shoes; EGFR-TKIs treatment one week before that hot warm water foot soak (continue in medication) or edible salt + water + white radish slices (or pepper) (boil) after foot soak and apply skin care products or silicone cream can prevent foot rash from occurring. Actively treat tinea pedis.
Treatment of rash, dry skin and scratching
1. Mild toxicity: Patients may not require any form of intervention, but can also use topical dermaplanin, hydrocortisone (10% or 25% ointment) or chlorambucil (10% gel), or erythromycin ointment. For dry skin with itching, thin phenol glycerin lotion twice daily or benadryl ointment can be applied to the itchy area. The dose of EGFR-TKIs should not be changed due to mild toxicity. 2 weeks later, the degree of rash should be re-evaluated, and if the condition worsens or does not improve significantly, the patient will be treated for moderate toxicity.
2. Moderate toxicity: apply 2.5% hydrocortisone ointment or erythromycin ointment topically, and take Keratan orally. For dry skin with itching, apply Benadryl ointment or compound benzoic acid ointment to the itching area 1-2 times daily. The rash should be re-evaluated after 2 weeks; if the situation worsens or does not improve significantly, proceed to the next level of treatment.
3. Severe rash: interventions are basically the same as for moderate rash, but the drug dose can be increased appropriately. If necessary, shock dose of methylprednisolone can be given, and the dose of EGFR-TKIs can be reduced; if combined with infection, choose the appropriate antimicrobial agent for treatment, such as cefuroxime 250 mg bid, and consider suspending the drug or discontinuing treatment if the adverse effects are not fully relieved after 2-4 weeks.