1. Hypertension
is one of the most common toxic reactions to targeted drug therapy and is common to the VEGR/VEGFR inhibitor class of drugs (Table 9). The incidence of hypertension associated with treatment with VEGFR tyrosine kinase inhibitors has been reported in the literature to be 24-40, with 8-16 of patients having grade III or higher hypertension. The incidence reported in China is similar to that reported abroad, with an incidence of 15 to 37 for all grades of hypertension. Baseline blood pressure should be evaluated before starting targeted therapy, and for patients with pre-existing hypertension the target blood pressure should be controlled below 140/90 mmHg during treatment. When hypertension reaches grade II or higher or grade I with symptoms, it must be controlled with medication. The best choice of antihypertensive drug is an angiotensin-converting enzyme inhibitor. Avoid calcium antagonists that inhibit CYP3A4 to avoid drug-drug interactions, and consider adjusting the drug dose if concomitant administration with drugs that affect CYP3A4 is required. Suspend or reduce the dose of antihypertensive drugs and monitor blood pressure closely during the treatment interval. Hand-foot syndrome (HFS) usually presents as a bilateral palmoplantar rash with pain and dullness of sensation and a tendency to hyperkeratosis, erythema, and desquamation at mechanically stretched areas (Table 11). The incidence of Sorafenib-induced HFS is reported to be high in the literature, with an incidence of 51.0 for all grades of HFS and 16.1 for ≥ grade III. Cutaneous reactions to the hands and feet are more common in Chinese patients, with an incidence of 55-68 for all grades of HFS reported in the literature. Clinical manifestations of skin toxicity include dry skin, rash, pruritus, blistering, molting, localized thickening of skin keratin, or seborrheic dermatitis with skin sagging. It usually appears 3 to 8 weeks after the start of treatment. In targeted therapy, the incidence of all graded rashes was 13 to 37 , and grade III or higher symptoms were 0.1 to 4.0 Examine the palms and soles of the hands prior to treatment to exclude pre-existing areas of skin keratinization. Intervention should be immediate at the onset of symptoms, either with an ointment or lotion containing a 10-urea component or, in the case of hyperkeratosis, with an exfoliating treatment using an ointment containing 35 to 40 urea. For grade II or higher symptoms, an ointment containing 0.05 clobetasol may be used; for pain, a topical analgesic such as 2 lidocaine may be used. In case of severe symptoms, a dermatologic consultation is recommended. In the event of grade II or higher HFS, consider interrupting dosing until the severity of symptoms subsides below grade I. Reduce or restart treatment at the same dose. Interstitial lung disease (ILD) is a group of diffuse lung diseases involving primarily the interstitial, alveolar, or fine bronchi, with a high incidence of 19.8 in second-line mTOR inhibitor therapy. mTOR inhibitor therapy should be used with particular attention to co-morbidities of ILD and infection, and should be used with caution for multiple metastases in both lungs, poor lung function, and obstructive lung disease. It should be used with caution in patients with multiple metastases in both lungs, poor lung function, obstructive pneumonia, or other active infections. Prior to initiating therapy, patients with advanced renal cell carcinoma with respiratory symptoms should be evaluated, and lung imaging and lung function should be monitored regularly. In milder ILD, no action is required and close monitoring is sufficient. In severe ILD, targeted drug therapy should be discontinued and shock therapy with hormones (e.g., methylprednisolone) should be administered. The incidence of cardiac adverse events due to VEGFR inhibitors is 2 to 10, as evidenced by decreased left ventricular ejection fraction (1eft ventricular ejection fraction (LVEF) and myocardial ischemia. In patients without cardiac risk factors, baseline LVEF testing should be considered. Patients with cardiac risk factors or recent adverse cardiovascular events should be closely monitored for vital signs and LVEF; if congestive heart failure occurs, targeted therapy should be suspended; if symptomatic congestive heart failure does not occur, but LVEF<50, or a decrease of 20 from baseline LVEF, the targeted drug dose should be reduced or treatment suspended. Patients with a history of long Q-T interval, antiarrhythmic drugs, bradycardia, and electrolyte abnormalities should have regular electrocardiogram and blood potassium and magnesium tests.
Table 9 Grading of hypertension associated with targeted therapies for renal cell carcinoma
2. Hematologic toxicityCommon hematologic toxicities associated with targeted therapy for advanced renal cell carcinoma are neutropenia, thrombocytopenia, and anemia (Table 10). The incidence of hematologic toxicity due to sunitinib is high and is a major cause of dose reduction or discontinuation in Chinese patients. Routine blood monitoring and attention to symptoms of infection are required before and during treatment.
If neutropenia is ≥ grade I, leukocyte-raising drugs should be given until they rise to normal levels. For thrombocytopenia, routine platelet-raising therapy can be given. Patients with dizziness, blurred vision, shortness of breath, or other symptoms of anemia should be taken seriously and given vitamin B12 and iron if necessary. Targeted drug doses should be reduced in cases of grade I or higher hematologic toxicity. Grade III/IV hematologic toxicity should be discontinued until the hematologic toxicity is reduced to baseline levels before restarting therapy. If the patient recovers rapidly from grade III/IV hematologic toxicity during conventional therapy, no dose adjustment is necessary, but close monitoring is required and adjustment of the dosing regimen may be considered.
Table 10 Grade of hematologic toxicity of targeted therapy for renal cell carcinoma
3. Hand-foot syndrome and skin toxicity
Table 11 Grading of hand-foot syndrome and skin toxicity with targeted therapy for renal cell carcinoma
4. Gastrointestinal adverse reactionsDiarrhea, nausea, and vomiting are common (Table 12). Mild diarrhea can be treated with electrolyte supplementation; severe diarrhea should occur with intravenous fluids and electrolyte supplementation, along with loperamide and diphenoxylate. Proton pump inhibitors or H2 receptor antagonists may be beneficial in preventing dyspepsia with symptoms similar to nausea, but should be avoided while patients are on axitinib. Antiemetic treatment with a dopamine antagonist such as metoclopramide or alizapride is recommended. Gastrointestinal adverse reactions are related to dietary habits. Patients are advised to eat small and frequent meals, ensure adequate fluid intake, eat a light diet, avoid spices, avoid laxatives, and avoid hyperosmolar food additives. For grade I and II gastrointestinal adverse reactions, no dose adjustment of the target drug is usually necessary; in the case of grade III and IV adverse reactions, the dose should be reduced or discontinued.
Table 12 Grade of gastrointestinal adverse reactions to targeted therapy for renal cell carcinoma
5. HypothyroidismHypothyroidism of varying degrees occurred in 12-19 of patients with advanced renal cell carcinoma treated with VEGFR inhibitors (Table 13), and the incidence gradually increased with the duration of treatment. Domestic studies have shown a slightly higher incidence of hypothyroidism than in Western populations, ranging from 14.0 to 24.9. Transient hyperthyroidism may occur in some patients, generally without intervention, and most will progress to hypothyroidism during subsequent treatment. The classification of hypothyroidism in renal cell carcinoma targeted therapy is shown in Table 5. thyroid function tests are performed at the beginning of treatment and thyroxine and thyroid stimulating hormone (TSH) are monitored closely during targeted therapy. Patients with mildly elevated TSH without symptoms need only continued monitoring, while patients with TSH>10 mU/L or clinical signs of hypothyroidism require thyroid hormone replacement therapy. In most cases, thyroid hormone replacement therapy is effective in controlling symptoms and does not require suspension of targeted drug therapy or dose adjustment.
Table 13 Grading of hypothyroidism for targeted therapy in renal cell carcinoma
6. HepatotoxicityLiver function should be closely monitored during treatment with pegaptanib. For patients with hepatic impairment, hepatoprotective drugs are recommended, and for patients at risk of liver damage, aggressive treatment for primary liver disease (e.g., hepatitis B, cirrhosis, etc.) is required before starting targeted therapy. During treatment, if a rise in ALT above 8 times the upper limit of normal occurs, the drug should be discontinued promptly and resumed until it returns to baseline levels; if a rise in ALT above 3 times the upper limit of normal occurs again after resumption of treatment, the drug should be permanently discontinued; if a rise in GLT above 3 times the upper limit of normal and a rise in bilirubin above 2 times the upper limit of normal occur concurrently, the drug should be permanently discontinued.
7. Interstitial lung disease
8. Cardiotoxicity