Common adverse reactions of sorafenib and countermeasures for management
Sorafenib (trade name: Nexavar, doxorubicin) is an orally administered multi-kinase inhibitor that targets serine/threonine kinases and receptor tyrosine kinases on tumor cells and tumor vessels, 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 glial cell line-derived pro-neurophilic factor receptor (RET). Thus, on the one hand, it inhibits 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 inhibits tumor angiogenesis by inhibiting receptor tyrosine kinases VEGFR and PDGFR upstream and serine/threonine kinases in the Raf/MEK/ERK pathway downstream, thus It can play a dual role of anti-angiogenesis and anti-tumor cell proliferation at the same time. Due to the remarkable effect of treating advanced kidney cancer, it has been approved by the US FDA in December 2005, becoming the first FDA-approved targeted therapy drug for advanced renal cell carcinoma; on October 30, 2007 and November 19, 2007, sorafenib has been approved by EU EAMA and US FDA for the treatment of inoperable advanced HCC, which is the first It is the first and only drug approved for the systemic treatment of hepatocellular carcinoma. Hao Mingzhi, Department of Interventional Therapy, Fujian Cancer Hospital Guo Zhifeng, Department of Medical Oncology, Chifeng Hospital
The results of safety analysis showed that the incidence of serious adverse events (SAEs) in the sorafenib (doxorubicin) and placebo groups were similar, 52% and 54%, respectively. Major adverse events included diarrhea, hand-foot skin reactions, and bleeding, but were usually easily controlled, with the major Grade 3/4 adverse events being diarrhea (52% hesitant 54%), hand-foot syndrome (8%’US.1%), malaise (10%’US.15%), and bleeding (6%’US.9%). In conclusion, sorafenib (doxorubicin) significantly prolonged median OS (by 44%) and TTP (by 73%) in patients with advanced HCC compared with placebo, with easily controlled and well-tolerated adverse effects. This article describes the common adverse reactions of this drug and countermeasures for their management.
Adverse skin reactions
The 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 desquamation; skin discoloration or hair discoloration, and hair loss. It has also been noted that sometimes skin toxicities correlate with efficacy, suggesting that skin reactions may serve as a marker of drug efficacy.
1 Hand-foot syndrome
Symmetrical erythema, pain, swelling, and often abnormal sensation (pins and needles or heat sensitivity) in the palmoplantar area after 2 to 4 weeks of drug administration, which is aggravated 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.
Response: Treatment for hand-foot syndrome is now focused on maintaining skin integrity at the lesion site and preventing the occurrence 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 re-dosing. Treatment is mainly symptomatic: apply emollient cream to protect the lesioned skin, wear soft clothes and shoes to reduce friction and extrusion on 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 1 to 2 weeks and then reapplied or the dose reduced.
2 Facial erythema rash
Red rash may appear on the T-shaped area of the face and scalp after 1 to 2 weeks of drug use, 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.
Countermeasures: The majority of patients with facial erythema rash do not need any treatment. For some patients with grade 2 to 3 toxic side effects, topical application of 2% ketoconazole cream or lotion can be applied.
3 Rash, pruritus
It often occurs on the patient’s face, neck, upper limbs, etc. The mechanism of occurrence is unclear.
Countermeasures: It is recommended to wash the affected skin with non-allergenic drugs, apply emollient cream to protect the lesioned skin, do not apply hormonal drugs locally to the lesion, 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 local rash is infected, antibiotics can be applied. Itching can be treated by applying glycine lotion, zinc oxide and other drugs.
4 Hair loss, dry skin discoloration or hair discoloration, etc.
Anti-vascular treatment may cause hair loss, skin depigmentation or hair discoloration, etc., which usually appear at 5-6 weeks of treatment and recover after 2-3 weeks of stopping treatment. The mechanism may be related to the blocking of the hair follicle melanin stem cells or c-KIT signaling pathway, which affects the activity of tyrosinase (TYR) and its protein, which are closely related to melanogenesis.
Countermeasures: Before starting treatment, cut hair short, comb it naturally and avoid forceful combing; wash hair gently, use soft shampoo containing protein, and dry hair naturally after washing; avoid perming, especially chemical perming and hair dyeing; wear ice caps during treatment to reduce scalp temperature, so that scalp blood flow decreases and hair follicle cell metabolism decreases to reduce hair loss; take vitamin E and other free radical scavengers orally; try hair scavengers. 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.
Elevated blood pressure
Elevated blood pressure is one of the most common toxic side effects during sorafenib treatment, with an incidence of 12% to 75%_2-12l, usually occurring 3 to 4 weeks after the start of treatment, and drug-related hypertension is mostly mild to moderate. The exact mechanism causing the increase in blood pressure is unknown. 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. 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. It is 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.
Countermeasure.
Patients with elevated blood pressure during treatment will have a decrease in blood pressure after discontinuation and generally do not require treatment, but patients with markedly 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 for the treatment of sorafenib-induced hypertension to prevent the accumulation of sorafenib in the body to increase the incidence of adverse effects. Therefore, it is best to use angiotensin-converting enzyme inhibitors (such as captopril, enalapril, benazepril and cilazapril) for antihypertensive treatment; 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 guidance of a cardiologist and considered for permanent discontinuation of sorafenib therapy.
Inferior nail line hemorrhage
After treatment with sorafenib, some patients may experience painless subxiphoid linear bleeding in the fingertips and, less frequently, in the toes. This symptom is often seen in patients with infectious myocarditis or 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.
Countermeasure.
Linear bleeding under the nail may disappear gradually with nail growth and requires no special treatment.
Cardiovascular accidents, thrombophilia, etc.
Inhibition of angiogenesis is the main effect of sorafenib and therefore may cause cardiovascular accidents and thrombotic disorders. 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%). Theoretically, it could cause thrombotic disease, but current clinical trials have not found evidence of thrombotic disease.
Countermeasures.
Treatment with sorafenib should be temporarily or permanently discontinued when such adverse reactions occur.
Gastrointestinal reactions
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, pancreatitis, etc. .
1 Diarrhea
It is usually mild to moderate diarrhea. 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 acidity and alkalinity of the drug changes during the metabolism process, which can directly stimulate the mucosa of the gastrointestinal tract causing diarrhea and other symptoms.
Countermeasures: Generally, it can be relieved by consuming a diet with less residue, low fiber and easy to digest, without adjusting the dose of therapeutic drugs. In case of frequent diarrhea, opioid treatment can be considered, such as oral loperamide hydrochloride, 4mg for the first time and no more than 16mg per day, given in divided doses. If conventional treatment is ineffective, treatment with drugs such as colistin, lidamidine or some adsorbents may be considered. Mucosal protective agents such as Simethicone can be used along with antidiarrhea. Patients with frequent diarrhea and severe dehydration should promptly replenish water and electrolytes, maintain water and electrolyte balance, and supplement with adequate nutrition.
2 Nausea, vomiting and loss of appetite
The occurrence and mechanism are similar to those of diarrhea.
Countermeasures: 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. For mild to moderate symptoms, the combination of metoclopramide and dexamethasone can be considered to improve the antiemetic effect.
3 Oral mucositis, oral ulcers and gastritis
The mechanism of occurrence is not clear, but 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: Brush and rinse your teeth before meals and bedtime every day to maintain oral hygiene; try to eat soft food, a small number of 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. For mild oral ulcers, chlorhexidine oral ulcer patch can be used; for moderate or severe oral pain, topical 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
Common hematopoietic side effects include: anemia, neutropenia, lymphopenia, thrombocytopenia, and increased risk of bleeding. Sorafenib has been reported to cause myelosuppression (e.g. neutropenia and thrombocytopenia) and anemia, but the exact mechanism is not known.
The exact mechanism is unknown. Countermeasures: Patients who have undergone previous myelosuppressive therapy (including radiotherapy and chemotherapy) should be cautious when applying these drugs, and should be monitored closely. In case of fever and co-infection, broad-spectrum antibiotics should be given, and colony-stimulating factors such as granulocyte/monocyte colony-stimulating factor (GM-CSF) and granulocyte colony-stimulating factor (G-CSF) can be considered. Corticosteroids or hemostatic minerals to prevent bleeding. If platelets are less than 20×10/L or there is bleeding, transfusion of platelets, 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. Because sorafenib may increase the risk of bleeding, patients treated with concomitant anticoagulant drugs (e.g., warfarin) should be examined regularly; caution should be exercised in patients with a tendency for active bleeding (e.g., gastrointestinal bleeding). In case of severe bleeding, Sorafenib treatment should be stopped permanently.
Abnormalities of the hepatobiliary system
Transient increase in transaminases (22%), lipase, amylase, alkaline phosphatase, bilirubin, etc. Because it can aggravate the damage to liver and kidney function and cause transient increase in transaminases, increase in lipases, increase in amylase, and increase in bilirubin, there is no experience of safe use in patients with Child-pugh class C liver function, and caution is needed.
Systemic reactions
Influenza-like symptoms 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, etc., may occur during the course of treatment with sorafenib. Encourage patients to rest, and give symptomatic and supportive treatment if necessary. Endocrine abnormalities (hypothyroidism) Closely monitor thyroid function and provide appropriate thyroid hormone supplementation in severe cases.
Patients with active infections (including fungal or viral infections) should be treated with Sorafenib prior to its use.
Birth defects, miscarriage
Based on the results of animal studies of (doxorubicin) sorafenib and its mechanism of action, women should use contraception during treatment with sorafenib; if they become pregnant while taking the drug, inform the patient of the risks of the drug to the fetus.
Abnormalities in nutritional metabolism
Hypophosphatemia (15%), dehydration, and hyponatremia may occur during sorafenib administration. Wound healing complications have not been specifically studied in relation to the effects of sorafenib on wound healing.