Sorafenib, a multi-kinase inhibitor targeting VEGF and its receptors, is the first targeted therapy approved by the FDA for the treatment of metastatic kidney cancer and was officially launched in China at the end of November 2006. In order to reduce some problems or confusion in the process of using the new drug.
The toxic side effects found in the course of sorafenib administration, their occurrence mechanism and their treatment methods are reviewed as follows for your reference.
1.Circulatory system side effects
Elevated blood pressure Elevated blood pressure is one of the most common toxic side effects of (doxorubicin) sorafenib treatment.
The incidence is 12% to 75%_2-12l, and it usually appears 3-4 weeks after the start of treatment, and the drug-related hypertension is mostly mild to moderate. The exact mechanism of the increase in blood pressure is unknown, but Veronese et al. did not find any significant correlation between changes in VEGF, catecholamines, renin and aldosterone levels in the blood of patients after treatment. Aortic increase index (CAIx) and aortic pulse conduction velocity (APWV) were increased compared to pre-treatment, but did not correlate with increased systolic blood pressure. The arterial vessel wall stiffened and became less elastic during treatment, but this change could not be determined as a cause or a consequence of the increased blood pressure.
He speculated that the mechanism of the increase in blood pressure may be due to a direct reduction in angiogenesis, disruption of endothelial cell function, and alteration of nitric oxide metabolism by sorafenib. Patients receiving sorafenib should be monitored closely for changes in blood pressure, especially during the first 6 weeks of treatment. Patients with elevated blood pressure during treatment will decrease after discontinuation of the drug and generally do not require treatment, but patients with significantly elevated blood pressure (patient’s blood pressure ≥ 160/100 mmHg) and/or appropriate symptoms require antihypertensive therapy.
Since sorafenib is broken down mainly in the liver by cytochrome oxidase CYP3A4-mediated oxidation, it has been suggested that calcium antagonists that inhibit the CYP3A4 metabolic pathway (e.g., diltiazem, verapamil, nizendipine, etc.) should be avoided in the treatment of sorafenib-induced hypertension to prevent the accumulation of sorafenib drug in patients to increase the incidence of adverse effects. The treatment of sorafenib may eventually activate the renin-angiotensin-aldosterone system, therefore, antihypertensive treatment is best with angiotensin-converting enzyme inhibitors (such as captopril, enalapril, benazepril and silazepril); some patients who are allergic to or cannot tolerate angiotensin-converting enzyme inhibitors can be treated with angiotensin II receptor blockers (such as corsartan potassium, valsartan, irbesartan and temisartan). (e.g., crosartan potassium, valsartan, irbesartan, and telmisartan). Patients with severe or persistent hypertension or hypertensive crisis despite the use of antihypertensive drugs should be treated under the supervision of a cardiologist and considered for permanent discontinuation of sorafenib therapy.
Some patients may experience painless subxiphoid hemorrhage on the fingertips after treatment with (doxorubicin) sorafenib.
It is less common in the toes. This symptom is often seen in patients with infectious myocarditis and rheumatoid arthritis, and is often considered a precursor to thrombosis or embolism. Similar symptoms can occur in healthy individuals with trauma to the fingertips. The mechanism of occurrence may be related to the action of drugs on VEGFR. The blockade of VEGFR impairs the physiological repair of the capillaries in the nail bed. However, some investigators have proposed to monitor the efficacy of anti-angiogenic drugs by testing the capillary function of the nail bed. The subxiphoid hemorrhage may disappear gradually with nail growth and requires no special treatment.
Cardiovascular accidents, thrombophilia, etc.
Inhibition of angiogenesis is the main effect of (doxorubicin) sorafenib, so it may cause cardiovascular accidents, thrombotic diseases, etc. The incidence of treatment-related myocardial ischemia/myocardial infarction was found to be higher in the sorafenib group (2.9%) than in the placebo group (0.4%), and sorafenib treatment should be temporarily or long-term discontinued when such adverse reactions occur.
2, skin adverse reactions
(Doxorubicin) Sorafenib caused by the skin toxic side effects are relatively common, some skin symptoms affect the quality of survival of patients. Common skin reactions include pruritus, hand-foot syndrome, dry skin, erythema multiforme, exfoliative dermatitis, acne, folliculitis, rash, eczema, urticaria, desquamation, etc.; skin discoloration or hair discoloration, hair loss. It has also been noted that sometimes there is a correlation between skin toxicities and efficacy, suggesting that skin reactions may serve as a marker of drug efficacy.
(1) Hand-foot syndrome
Symmetrical erythema, pain and swelling in the palmoplantar area, often accompanied by sensory abnormalities (pins and needles or heat sensitivity), may appear after 2-4 weeks of drug administration and may worsen in warm environments. Patients with severe lesions on the feet may develop a limp. Sometimes erythema may also appear on the ends of the fingers and around the nails. The lesions are often accompanied by hyperkeratosis and desquamation, thus distinguishing it from the hand-foot syndrome caused by chemotherapeutic agents such as cytarabine, fluorouracil, and epi-amycin.
The pathogenesis is unclear. Since skin keratin-forming cells do not express VEGF and FLT3 receptors, it is speculated that the mechanism of lesion development may be related to the direct toxic response to (doxorubicin) sorafenib. Treatment of hand-foot syndrome is now focused on maintaining the skin integrity of the lesion and preventing the development of skin infections. The rash is often dose-dependent and subsides rapidly after discontinuation of the drug, and in some patients, the rash no longer appears after drug reduction and reintroduction.
Treatment is mainly symptomatic: apply emollient creams to protect the lesioned skin, wear soft clothes and shoes to reduce friction and compression of the lesion, and avoid contact with chemical substances on the hands and feet. If the patient cannot tolerate it, the medication can be stopped for one to two weeks and then reapplied or the dose reduced.
(2) Facial erythema rash
After 1 to 2 weeks of use, a red rash may appear on the T-shaped area of the face and scalp, often accompanied by numbness of the scalp. The rash worsens with increasing temperature and usually subsides or disappears after a few weeks of medication. The mechanism of its occurrence is unclear. The vast majority of patients with facial erythema rash do not require any treatment, and some patients with grade 2 to 3 toxic side effects can be treated with topical application of 2% ketoconazole cream or lotion.
(3) Rash and pruritus
It often occurs on the patient’s face, neck, upper limbs, etc. The mechanism of occurrence is unclear. It is recommended to wash the affected skin with non-allergenic drugs, apply emollient creams to protect the lesioned skin, do not apply hormonal drugs locally, avoid applying items that cause dry skin, avoid sun exposure, and wear loose fitting clothes to reduce friction on the lesion. Antihistamines can be taken orally or applied topically. If the rash is infected, antibiotics can be applied. Itching can be treated with glycolic lotion, zinc oxide and other drugs.
(4) Hair loss, dry skin discoloration or hair discoloration Anti-vascular treatment may cause hair loss, skin discoloration or hair discoloration, which usually occurs in 5-6 weeks of treatment and recovers 2-3 weeks after stopping treatment. The mechanism may be related to the blocking of melanocytes or c-KIT signaling pathway, which affects the activity of tyrosinase (TYR) and its protein, which are closely related to melanogenesis.
The following measures can be used to reduce the occurrence of hair loss: before starting treatment, cut the hair short, comb it naturally and avoid forceful combing; wash the hair gently, use a soft shampoo containing protein, and dry the hair naturally after washing; avoid perming, especially chemical perming and hair dyeing; wear an ice cap during treatment to reduce the scalp temperature, so that blood flow to the scalp is reduced and the metabolism of hair follicle cells decreases. Reduce hair loss;
Free radical scavengers such as vitamin E can be taken orally; a trial of hair nutrients applied evenly to the head to reach the scalp can reduce the incidence of hair loss. Patients avoid sun exposure and wear wigs if necessary.
3.Gastrointestinal reactions
Gastrointestinal reactions (95%): diarrhea (58%), nausea (30%), vomiting (24%), gastritis and oral mucositis (35%, including dry mouth and tongue pain, swallowing difficulties), indigestion, loss of appetite (47%), constipation (32%), gastroesophageal reflux, pancreatitis, etc. .
(1) Diarrhea is usually mild to moderate. The exact mechanism of gastrointestinal side effects is not clear, but it may be related to the long absorption time after sorafenib enters the gastrointestinal tract and the change of its acidity and alkalinity during the metabolism of the drug, which can directly stimulate the mucosa of the gastrointestinal tract and cause diarrhea and other symptoms. Generally, it can be relieved by consuming less residue, low-fiber and easy-to-digest diet, and there is no need to adjust the dose of therapeutic drugs.
(2) When diarrhea is frequent, opioid treatment can be considered, such as oral loperamide hydrochloride, the first oral dose is 4mg, and the daily dose does not exceed 16mg, given in divided doses. If conventional treatment is ineffective, consider treatment with drugs such as colistin, lidamidine or some adsorbents. Mucosal protective agents such as Simethicone can be used along with antidiarrhea. Patients with frequent diarrhea and severe dehydration should be given water and electrolytes in a timely manner to maintain water and electrolyte balance and adequate nutrition.
(3) Nausea, vomiting and loss of appetite The occurrence and mechanism are similar to those of diarrhea. Symptoms can be reduced by dietary modification, such as not taking medication with food (it is advisable to take medication 1 hour before or 2 hours after eating); it is recommended to eat high-protein, high-calorie, light food, and eat small amounts several times. Mild to moderate symptoms can be considered metoclopramide (gastric receptor), dexamethasone benadryl combined application to improve the antiemetic effect; if necessary, once a day chlorpromazine treatment can also be effective in controlling nausea and vomiting symptoms; severe symptoms need to apply 5 a HT3 receptor antagonists (Endoxifen, Ketorol, Obituary, etc.) treatment, dehydration in severe cases, appropriate supplementation of fluids and electrolytes.
(3) The mechanism of oral mucositis, oral ulcers and gastritis is not clear, but may be related to the abnormal formation of normal blood vessels after treatment, which may lead to physiological repair of oral mucosa. Brush your teeth and rinse your mouth before meals and bedtime daily to maintain oral hygiene; eat soft foods as much as possible, small and frequent meals, and avoid eating hard, cold, hot and spicy foods.
Use non-irritating oral cleansers such as hydrogen peroxide and saline 1:1 mixture for oral disinfection. For mild oral ulcers, chlorhexidine oral ulcer patch can be used; for moderate or severe oral pain, local medications such as 2% lidocaine, aluminum thioglycollate, benadryl, etc. can be used. Mycobacterial infections can be treated with mycobacterium 1.0 million U/ml rinse and 3% soda saline rinse.
4, hematopoietic system adverse reactions
The common toxic side effects of hematopoietic system include: anemia, neutropenia, lymphopenia, thrombocytopenia, increased risk of bleeding, etc. Sorafenib has been reported to cause myelosuppression (such as neutropenia and thrombocytopenia) and anemia, but the exact mechanism is not known. Therefore, patients who have had previous myelosuppressive therapy (including radiotherapy and chemotherapy) should be cautious when administering these drugs and should be closely monitored for blood changes and, if necessary, treated with blood transfusions.
(1) Lymphocytosis and neutropenia: Closely monitor changes in white blood cells. Consider applying antibiotics to prevent infection when leukocytes are less than 1×10/L and neutrophils are less than 0.5×1O/L. Protective isolation and discontinuation of medication are required. In case of fever and co-infection, broad-spectrum antibiotics should be given, and leukocyte concentrate infusion and colony-stimulating factors such as GM-CSF and G-CSF can be considered.
(2) Thrombocytopenia: closely monitor changes in platelet count and pay attention to the bleeding symptoms of the patient. In case of transient thrombocytopenia (platelets less than 50×10/L), consider applying low-dose glucocorticoid or hemostat to prevent bleeding. If platelets are less than 20×10/L or if there is bleeding, platelet transfusion, high-dose hemostatin and hormones (prednisone, etc.) should be considered. Apply colony-stimulating factor or interleukin I-11 if necessary to stimulate the growth and differentiation of megakaryocytes.
(3) Increased risk of bleeding The exact mechanism is unclear. Because sorafenib increases the risk of bleeding, patients treated with concomitant anticoagulant drugs (e.g., warfarin) should be examined regularly; patients with a tendency for active bleeding (e.g., gastrointestinal bleeding) should be treated with caution. Once bleeding has occurred, active treatment is required, and sorafenib therapy should be permanently discontinued in cases of severe bleeding.
(4) Anemia Monitor Hgb and HCT levels. Supplement with iron-containing foods as appropriate.
（Transient increase in transaminases (22%), lipase, amylase, alkaline phosphatase, and bilirubin. Because it can aggravate the damage to liver and kidney function and cause transient increase of transaminase, lipase, amylase and bilirubin, it should be used with caution in patients with liver disease, jaundice (hepatitis cirrhosis, etc.) or kidney disease (nephritis, etc.).
5.Summary
The majority of patients reported in the literature have good tolerance and compliance with (doxorubicin) sorafenib treatment. The overall incidence of common adverse reactions: rash (31%-34%), diarrhea (30%-43%), hand-foot syndrome (19%-30%), weakness (18-37%), increased blood pressure (12%-75%), etc. Most of the toxic reactions found were grade 1 or 2. The results of the randomized controlled study showed that grade III and IV toxic reactions occurred most frequently with (doxorubicin) sorafenib for advanced kidney cancer were skin symptoms, other gastrointestinal symptoms, fatigue, and hypertension, the incidence of which was 8%, 4%, 2%, and 3%, respectively, compared with 1%, 3%, 1%, and 1%, respectively, in the placebo control group, and statistical analysis Statistical analysis showed that the incidence of grade III or IV adverse reactions was comparable between the treatment and placebo groups. The proportion of patients who discontinued treatment due to serious adverse reactions was 10% in the treatment group and 8% in the placebo group. Most of the adverse reactions could be resolved by reducing the drug dosage or discontinuing the drug.