Sorafenib (Sorafenib, trade name: Nexavar, doxorubicin) is an oral multikinase inhibitor that targets serine/threonine kinases and receptor tyrosine kinases on tumor cells and tumor vasculature, including RAF kinase, VEGFR-2, VEGFR.3, platelet-derived growth factor receptor B (PDGFR-B), stem cell factor receptor (KIT), Fms-like tyrosine kinase 3 (FLT3) and pro-neurotrophin receptor of glial cell line origin (RET). Thus, on the one hand, it can inhibit tumor cell proliferation by inhibiting receptor tyrosine kinases KIT and FLT3 and serine/threonine kinases in the Raf/MEK/ERK pathway; on the other hand, it can inhibit tumor angiogenesis by upstream inhibition of the receptor tyrosine kinases VEGFR and PDGFR and downstream inhibition of the serine/threonine kinases in the Raf/MEK/ERK pathway, thus Therefore, it can simultaneously play the dual role of anti-angiogenesis and anti-tumor cell proliferation. Due to the significant effect of treating advanced renal cancer, it has been approved by the U.S. FDA for marketing in December 2005, becoming the first targeted therapy drug for advanced renal cell carcinoma approved by the FDA; on October 30, 2007 and November 19, 2007, sorafenib has been successively approved by the European Union EAMA and the U.S. FDA for the treatment of inoperable advanced HCC, which is currently the first and only drug approved for the systemic treatment of hepatocellular carcinoma. Results of the safety analysis showed that the incidence of serious adverse events (SAEs) was similar in the sorafenib (doxorubicin) group and the placebo group, at 52% and 54%, respectively. Major adverse events included diarrhea, hand-foot skin reactions, and bleeding, but were usually easily controlled, with the major 3/4-degree adverse events being diarrhea (52% hesitant to 54%), hand-foot syndrome (8%’US.1%), malaise (10%’US.15%), and bleeding (6%’US.9%). In conclusion, sorafenib (doxorubicin) significantly prolonged median OS (44% prolongation) and TTP (73% prolongation) in patients with advanced HCC compared to placebo, and adverse effects were easily controlled and well tolerated. This article describes the common adverse reactions of this drug and treatment countermeasures. Skin adverse reactions Skin toxicities caused by sorafenib are relatively common, and 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, and dandruff; skin depigmentation or hair discoloration and alopecia. Some scholars have also noted that sometimes skin toxicity and efficacy have a correlation, suggesting that skin reactions may be used as a sign of drug efficacy. 1, hand and foot syndrome 2 ~ 4 weeks after the drug palm and plantar areas of symmetrical erythema, pain, swelling, often accompanied by sensory abnormalities (pins and needles or heat sensitivity), exacerbated in warm environments. In severe foot lesions, the patient may develop a limp. Sometimes the erythema is also present on the tips of the fingers and around the nails. The lesions are often associated with hyperkeratosis and desquamation, which distinguishes it from the hand-foot syndrome caused by chemotherapeutic agents such as cytarabine, fluorouracil, and epothilone. The pathogenesis is not clear. Since skin keratinocytes do not express VEGF and FLT3 receptors, it is hypothesized that the mechanism of lesion development may be related to a direct toxic response to (doxorubicin) sorafenib. RESPONSE: Treatment of hand-foot syndrome now focuses on maintaining the integrity of the skin at the site of the lesion and preventing the development of skin infections. Rash is often dose-dependent and subsides rapidly after discontinuation of the drug, and in some patients the rash no longer occurs after the drug is reduced and re-administered. Treatment is mainly symptomatic: such as the application of moisturizing cream to protect the lesion skin, wear soft clothes and shoes to reduce the friction on the skin lesions, squeeze, and avoid contact with chemicals on hands and feet. If the patient can not tolerate, can first stop 1 ~ 2 weeks after the drug or reduce the dose of the drug, serious patients need to terminate the drug. 2, facial erythema rash 1 ~ 2 weeks after the drug patients face T-shaped area and scalp parts can appear red rash, often accompanied by scalp sensory numbness. Rash with the increase in temperature and aggravated, generally in the drug a few weeks will subside or disappear. The mechanism of its occurrence is unclear. Countermeasures: the vast majority of patients with facial erythema do not need any treatment, for some patients with 2 to 3 toxic side effects can be applied locally 2% ketoconazole cream or lotion. 3, rash, itching often occurs in the patient’s face, neck, upper limbs and so on. The mechanism of its occurrence is not clear. Countermeasures: It is recommended to apply non-sensitizing drugs to clean the affected skin, apply emollient cream to protect the lesion skin, do not apply hormonal drugs to the lesion, avoid applying items that cause skin dryness, avoid sun exposure, wear loose-fitting clothes to reduce friction lesions. Antihistamines can be taken orally or applied topically. Antibiotics can be applied if the localized rash is infected. Itching can be applied glycolite lotion, zinc oxide and other medications. 4, alopecia, dry skin discoloration or hair discoloration, etc. Antivascular therapy may cause alopecia, skin discoloration or hair discoloration, etc., usually appearing in 5 to 6 weeks of treatment, and recovering after stopping treatment for 2 to 3 weeks. The mechanism may be related to the blockage of follicular melanin stem cells or c-KIT signaling pathway, affecting the activity of tyrosinase (TYR) and its proteins, which are closely related to melanogenesis. Countermeasures: before the start of treatment, cut hair short, combing should be natural, avoid combing hard; shampooing action to be gentle, to use protein-containing soft shampoo, wash the hair should be naturally air-dried; to avoid perming, especially chemical perming and hair coloring; treatment process can wear an ice cap to reduce the temperature of the scalp, so that the scalp blood flow is reduced, the metabolism of the follicle cells to reduce the decline in hair loss; can be orally consumed free radical scavengers, such as vitamin E; trial of free radical scavengers; the use of oral vitamins E and so on Free radical scavengers; trial hair nutrients evenly coated on the head to reach the scalp, can reduce the incidence of hair loss. Patients avoid sun exposure and wear wigs if necessary. Elevated blood pressure Elevated blood pressure is one of the most common toxic side effects during sorafenib therapy, with an incidence of 12% to 75% _2-12l, usually occurring 3 to 4 weeks after the start of treatment, and most drug-related hypertension is mild to moderate. The exact mechanism causing the increase in blood pressure is not clear. Veronese et al. examined the levels of VEGF, catecholamines, renin and aldosterone in the blood of patients after treatment, and did not find any significant correlation between changes in the levels of these factors or hormones and the increase in blood pressure. The aortic index of increase (CAIx) and aortic pulse conduction velocity (APWV) were increased compared with pre-treatment, but there was no correlation with increased systolic blood pressure. The arterial vessel walls stiffened and became less elastic during treatment, but this change could not be determined to be a cause or a consequence of the elevated blood pressure. It is hypothesized that the mechanism of the patients’ increased blood pressure may have been caused by sorafenib’s direct reduction in the number of blood vessel formations, disruption of endothelial cell function, and alteration of nitric oxide metabolism. Patients treated with sorafenib should be closely monitored for changes in blood pressure, especially during the first 6 weeks of treatment. Countermeasures: Patients with elevated blood pressure during treatment will experience a decrease in blood pressure after discontinuation of the drug and generally do not require treatment, but antihypertensive therapy is required for patients with markedly elevated blood pressure (patient’s blood pressure ≥160/100 mmHg) and/or appropriate symptoms. Since sorafenib is mainly decomposed in the liver by cytochrome oxidase CYP3A4-mediated oxidation, some scholars have suggested that calcium antagonists that inhibit the CYP3A4 metabolic pathway (e.g., diltiazem, verapamil, nifedipine, etc.) should be avoided for the treatment of sorafenib-induced hypertension to prevent the accumulation of sorafenib in vivo and increase the incidence of adverse reactions. Sorafenib treatment may eventually activate the renin-angiotensin-aldosterone system, therefore, antihypertensive treatment is best to use angiotensin-converting enzyme inhibitors (such as captopril, enalapril, benazepril and cilazapril, etc.); some patients who are allergic to or intolerant of angiotensin-converting enzyme inhibitors can be applied to the treatment of angiotensin Ⅱ receptors blockers (such as chlorosartan potassium, valsartan, irbesartan and timosartan). The patients who are allergic or intolerant to angiotensin converting enzyme inhibitors can be treated with angiotensin II receptor blockers (e.g., chlorosartan potassium, valsartan, irbesartan, and timosartan). Patients with severe or persistent hypertension despite antihypertensive medications or hypertensive crises should be referred to a cardiologist for guidance and consideration of permanent discontinuation of sorafenib therapy. After sorafenib treatment, some patients may develop painless subnail linear hemorrhage at the fingertips and, less frequently, at the toes. This symptom is often seen in patients with infectious myocarditis and rheumatoid arthritis, and is often regarded as a precursor to thrombosis or embolism. Similar symptoms may occur in healthy individuals with trauma to the digits. The mechanism of occurrence may be related to the action of drugs on VEGFR. The blockage of VEGFR impairs the physiologic repair of capillaries in the nail bed. However, some researchers have suggested that the efficacy of antiangiogenic drugs can be monitored by measuring capillary function in the nail bed. Countermeasures: Subungual linear hemorrhage can disappear gradually with nail growth and does not require special treatment. Cardiovascular and cerebrovascular accidents, thrombotic diseases, etc. Inhibition of angiogenesis is the main effect of sorafenib, so it may cause cardiovascular and cerebrovascular accidents and thrombotic diseases. The incidence of myocardial ischemia/infarction associated with treatment was found to be higher in the sorafenib group (2.9%) than in the placebo group (0.4%). Theoretically, it could cause thrombophilia, but current clinical trials have not found evidence of thrombophilia. Countermeasures: Sorafenib treatment should be discontinued temporarily or permanently in the event of such adverse reactions. Gastrointestinal reactions Gastrointestinal toxic reactions may occur during sorafenib treatment, and the incidence is not completely consistent among reports. Gastrointestinal reactions (95%): diarrhea (58%), nausea (30%), vomiting (24%), gastritis and oral mucositis (35%, including dry mouth and tongue pain, dysphagia), dyspepsia, loss of appetite (47%), constipation (32%), gastroesophageal reflux The symptoms of diarrhea are as follows 1, diarrhea is generally mild to moderate diarrhea. The exact mechanism of gastrointestinal toxic side effects is not clear, may be related to sorafenib into the gastrointestinal tract after absorption of a long time, the drug in the process of metabolism with the change in pH, this change can directly stimulate the gastrointestinal mucosa caused by diarrhea and other symptoms. Countermeasure: Generally, it can be relieved by consuming a diet with less residue, low fiber and easy to digest, and there is no need to adjust the dosage of therapeutic drugs. When the frequency of diarrhea is high, the application of opioids can be considered, such as oral loperamide hydrochloride, the first oral dose of 4mg, the daily dose does not exceed 16mg, given in divided doses. Treatment with drugs such as colistin, ritamidine or some adsorbents may be considered if conventional treatment fails. Stopping diarrhea can be accompanied by mucosal protectants such as Simethicone. Patients with frequent diarrhea and severe dehydration should supplement water and electrolytes in time to maintain water and electrolyte balance and supplement nutrition. 2.Nausea, vomiting, loss of appetite Its occurrence and mechanism are similar to the occurrence of diarrhea. Countermeasures: Symptoms can be alleviated through dietary modification, such as drugs not taken with food (it is advisable to take drugs one hour before or two hours after eating); it is recommended to eat high protein, high calorie and light food, small amount of food several times. Mild to moderate symptoms can be considered metoclopramide (gastroenterology), dexamethasone benadryl to improve the effect of antiemetic; if necessary, once a day chlorpromazine treatment can also be effective in controlling the symptoms of nausea and vomiting; the need for severe symptoms of the application of the 5-HT3 receptor antagonist (entacinone, ketorolac, ou bibidazole, etc.), the dehydration is serious to be appropriate to replenish the fluids and electrolytes. 3, oral mucositis, oral ulcers and gastritis The mechanism of occurrence is not clear, it may be related to the abnormal formation of normal blood vessels after treatment, which in turn leads to physiological repair disorders of the oral mucosa. Countermeasures: daily brushing and rinsing before meals and bedtime to maintain oral hygiene; try to eat soft food, small meals, avoid eating too hard, too cold, too hot and spicy food. Use non-irritating oral cleansers such as hydrogen peroxide and saline 1:1 mixture for oral disinfection. Mouth ulcers are mild, can be chlorhexidine mouth ulcer film treatment; for moderate or severe oral pain, can be used locally, such as 2% lidocaine, aluminum thiosulfate, phenylephrine and so on. Mycobacterial infection can be mycobacteria 1O million U / ml to rinse the oral cavity, and 3% of the soda saline gargle. 4, hematopoietic system adverse reactions The common toxic side effects of hematopoietic system mainly include: anemia, neutropenia, lymphocytopenia, thrombocytopenia, increased risk of bleeding and so on. Sorafenib has been reported to cause bone marrow suppression (e.g. neutropenia and thrombocytopenia) and anemia, but the exact mechanism is not clear. Countermeasures: Patients who have previously undergone myelosuppressive therapy (including radiotherapy and chemotherapy) should be cautious when applying these drugs, and should closely monitor the changes in blood picture, and consider applying antibiotics to prevent infection when the white blood cells are less than 1×10/L and the neutrophils are less than 0.5×1O/L, and need to be protected from isolation and discontinue the drug. If fever symptoms and co-infection should be given broad-spectrum antibiotic treatment, can consider the application of colony-stimulating factors such as granulocyte/monocyte colony-stimulating factor (GM-CSF) and granulocyte colony-stimulating factor (G-CSF), etc.; transient thrombocytopenia (platelets less than 50 × 10/L) can be considered to apply a small-dose sugar In transient thrombocytopenia (platelets less than 50×10/L), small-dose glucocorticoids or hemostatic sensitizers can be considered to prevent bleeding. Platelet transfusion, high-dose hemostasis and hormones (prednisone, etc.) should be considered when platelets are less than 20×10/L or there is bleeding. If necessary, apply colony-stimulating factor or interleukin I11 to stimulate the growth and differentiation of megakaryocytes. Because sorafenib may increase the risk of bleeding, therefore, patients co-treated with anticoagulant drugs (e.g., warfarin) should undergo regular checkups; it should be used with caution in patients with a tendency to active bleeding (e.g., gastrointestinal bleeding). If bleeding occurs, it should be treated aggressively, and sorafenib treatment should be permanently discontinued in cases of severe bleeding. Hepatobiliary system abnormalities: transient increase in aminotransferases (22%), lipase, amylase, alkaline phosphatase, bilirubin. Because of its ability to exacerbate the damage to hepatic and renal function, causing transient increases in transaminases, lipase, amylase, and bilirubin, there is no experience in the safe use of the drug in patients with hepatic function Child-pugh class C. Caution should be exercised. Systemic reactions Sorafenib in the course of treatment may occur such as fatigue (73%), weakness, pain (78%): including headache (19%), abdominal pain (19%), mouth pain, bone pain, joint (12%) and muscle pain (11%), weight loss (33%), fever, hoarseness and other influenza-like symptoms, explain to the patient that this is a common reaction does not mean that the treatment is ineffective, encourage the patient to rest appropriately, and if necessary, give the patient the right treatment. Encourage patients to rest appropriately and give symptomatic and supportive treatment if necessary. Endocrine abnormalities (hypothyroidism) Monitor thyroid function closely, and supplemental thyroid hormone is needed for severe cases. Infections Patients with active infections (including fungal or viral infections) should be treated prior to the administration of sorafenib. Birth defects, abortion According to the results of animal experiments on sorafenib and its mechanism of action, women should use contraception during sorafenib treatment; if pregnancy occurs while taking the drug, patients should be informed of the hazards of the drug to the fetus. Nutritional abnormalities Hypophosphatemia (15%), dehydration, and hyponatremia may occur with sorafenib. Wound Healing Complications The effect of sorafenib on wound healing has not been specifically studied.