I. Molecularly targeted anti-tumor drugs listed in China
In recent decade, many molecularly targeted antitumor drugs have been marketed in China and widely used in clinical practice. According to the target and nature of drugs, these drugs can be broadly classified into the following categories.
1.Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI), such as Gefitinib, Erlotinib, Afatinib, etc.
2, anti-EGFR monoclonal antibody, such as cetuximab (Cetuximab); anti-vascular endothelial growth factor.
3, (VEGF) monoclonal antibodies, such as bevacizumab (Bevacizumab).
4, anti-HER-2 monoclonal antibody, such as trastuzumab (Trastuzumab).
5, ALK tyrosine kinase inhibitors, such as crizotinib (Crizotinib).
6, anti-CD20 monoclonal antibody, such as rituximab (Rituxan).
7, multi-target inhibitors, such as Sorafenib (Sorafenib), Sunitinib
(Sunitinib), etc.
8, Bcr-Abl tyrosine kinase inhibitors, such as imatinib (lmatinib).
9, mTOR kinase inhibitors, such as CCI-779.
10, Others, Aurora kinase inhibitors, ubiquitin-proteasome inhibitors [such as bortezomib (Bortezomib)], histone deacetylases (HDACs) inhibitors, etc.
In general, the adverse reactions of these drugs are predictable and controllable, and this article only describes the adverse reactions of several widely used drugs and their clinical management principles.
Second, the epidermal growth factor receptor tyrosine kinase inhibitor anti-EGFR monoclonal antibody adverse reactions and treatment
Gefitinib and erlotinib, the most widely used drugs in clinical practice, as well as the second-generation drug afatinib, have played an important role in the treatment of patients with advanced or metastatic non-small cell lung cancer with EGFR-sensitive mutations, with clear efficacy and significant prolongation of progression-free survival. This class of drugs achieves tumor suppression by blocking epidermal growth factor receptor (EGFR) tyrosine kinase domain phosphorylation activation signaling and downstream MAPK and AKT signaling pathways in cancer cells, promoting apoptosis, curbing proliferation, and anti-tumor angiogenesis. Afatinib is a second-generation non-reversible EGFR-TKI with the same high efficacy as the first-generation drugs and efficacy against T790M resistance mutations, but the associated toxicity is also more pronounced than that of the first-generation drugs because its recommended dose is close to its dose-limiting toxicity (DLT).
One of the most common adverse effects of EGFR-TKI drugs is skin toxicity (about 50-85%), which manifests itself in the form of rash (60%-80%), nail fungus and nail fracture (6%-1
2%), hair changes (5%-6%), dry skin (4%-35%), hypersensitivity reactions (2%-3%), and mucositis (2%-36%).
The most prominent one is acne-like rash, which usually appears within two weeks after drug administration, mostly on the scalp, face, neck, chest and back, etc. The mechanism of rash occurrence is not completely clear and may be related to immature glial cell growth and differentiation, upregulation of p27, KRT1, STAT3, and release of inflammatory factors after phosphorylated EGFR signaling is inhibited, which eventually leads to keratinocyte apoptosis and vascular swelling, etc. related. Interestingly, and based on previous studies, rash is a surrogate predictor for the evaluation of EGFR-TKI efficacy regardless of EGFR mutation status, and the extent of rash correlates with cetuximab efficacy. A study by Roman et al. in the USA showed that the majority of rashes secondary to erlotinib
appeared at 2 weeks post-treatment flesh, peaked at 3-5 weeks, and then tapered off, without the need to taper the drug if not necessary. With the MSKCC (Memorial Sloan-Kettering
Cancer Center) led by the MASCC (MultinationalAssociation for Supportive Care in
Cancer) Skin Toxicity Management Collaborative Group recommends the description and follow-up of skin toxicity based on NCI-CTCAE4.0, which combines relevant indicators such as patient health-related quality of life (HQOL), activities of daily living (ADI), and patient-reported prognosis (PROs). According to the current treatment consensus, for mild rashes with limited lesions, mild symptoms, unrestricted daily activities and no recurrent infections, topical dermatological agents can be applied topically while keeping the body clean and the skin moist, which usually provides significant relief.
For moderate rashes with extensive lesions, moderate symptoms, mildly restricted daily activities and no repeated infections, the most important EGFR-TKI agent correction is generally not required, and the dose can be reduced in severe cases; the rash site can be treated topically with hydrocortisone and clindamycin, and moderate rashes can be treated continuously with bimecrolimus combined with doxycycline (doxycycline) or minocycline, etc. Severe patients can also be combined with Moderate rash can be treated with a combination of doxycycline (Doxycycline) or minocycline. The rash needs to be evaluated after 2 weeks of treatment, and in patients with severe rash with extensive lesions, severe symptoms, significant limitations in daily activities, and potentially recurrent infections, dose modification is recommended or treatment needs to be discontinued if efficacy is poor.
In addition, before taking targeted drugs orally, physicians should inform patients of the symptoms associated with possible skin adverse reactions and advise them to practice good lifestyle habits and avoid sun exposure. Similarly, the administration of diphenhydramine or a low dose of hormone prior to the use of elvitazemab can also prevent the development of severe rashes.
Another common adverse effect of EGFR-TKI drugs is gastrointestinal toxicity, the most common of which is diarrhea. The incidence of diarrhea is approximately 55%, with a grade 3/4 toxicity of 6%. Mild diarrhea is relatively easy to control and is relieved by symptomatic treatment or short-term loperamide, with little need for adjustment of TKls drug dose.
The combination of other risk factors, such as diarrhea-inducing foods, gastrointestinal motility drugs, stool softeners, etc., should also be evaluated, and the above triggers should be removed first in treatment. After removal of the triggers, diarrhea that persists despite intravenous rehydration and antibiotics requires TKls dose adjustment, interruption or discontinuation of treatment. In addition, the incidence of nausea and vomiting is approximately 30%, with 3rd degree toxicity at 7%. Symptoms can usually be reduced by dietary modifications, such as not taking the drug with food (1 hour before or 2 hours after eating), suggesting lighter foods, and eating smaller and more frequent meals. Mild to moderate symptoms can be considered metoclopramide, dexamethasone, diphenhydramine combined application to improve the antiemetic effect, if necessary, once a day chlorpromazine treatment can also effectively control nausea and vomiting symptoms, the symptoms of severe need to apply 5-hydroxytryptamine receptor antagonist type of treatment, pay attention to dehydration need to correct the water and salt balance in a timely manner.
For patients with oral mucositis and mouth ulcers, oral hygiene should be maintained, soft food should be eaten as much as possible, less frequent meals, and spicy, hard and hot food should be avoided to control them. In addition, mild hepatic impairment, with an incidence of about 30%, should be treated with a 1-fold increase in total bilirubin and/or a 2-fold increase in transaminases, and EGFR-TKI should be reduced or suspended and liver protection should be given. Combination of drugs and foods that can cause liver injury, such as acetaminophen and ethanol, should be avoided during treatment.
Interstitial pneumonia is a rare but extremely serious complication of EGFR-TKI, with an incidence of 2-3% and a lethality rate of nearly 0.3%. It is characterized by new or worsening episodes of dyspnea, hypoxemia, restrictive ventilation and reduced diffusion function and the appearance of new exudative shadows on chest radiographs without apparent cause. Once pulmonary fibrosis has developed, irreversible pulmonary hypoplasia will occur and patients with pulmonary comorbidities are more likely to develop it. Erlotinib causes a low incidence of interstitial pneumonia.
Interstitial pneumonia occurs within 4 weeks of treatment with gefitinib, and the mechanism by which it occurs is unclear. It has been suggested that EGFR inhibitors inhibit the growth of airway epithelial cells and the repair of their damage while suppressing EGFR in tumor tissues, causing an uncontrolled immune inflammatory response and leading to the development of interstitial pneumonia. Therefore, regular chest X-ray and CT examinations should be performed during the drug administration. The possibility of interstitial pneumonia should be considered when unexplained cough, shortness of breath and other respiratory symptoms occur, and the drug should be discontinued immediately and further examination should be conducted in time: once the diagnosis of interstitial pneumonia caused by EGFR-TKI is confirmed, the drug should be avoided and high-dose glucocorticoid therapy should be actively applied to avoid irreversible lesions in the lung.
Adverse reactions and management of anti-vascular endothelial growth factor (VEGF) monoclonal antibody
Bevacizumab is a recombinant humanized IgC1 monoclonal antibody that reduces microvascular growth and inhibits tumor proliferation by binding to vascular endothelial growth factor (VFGF) and blocking the action of VEGF and its receptor (VEGFR). Clinical studies have shown that the combination of bevacizumab and chemotherapy in the first-line treatment of advanced colorectal cancer significantly improved the efficiency, median progression-free survival and overall survival time; in the treatment of advanced non-squamous non-small cell lung cancer, bevacizumab combined with paclitaxel/carboplatin improved progression-free survival and overall survival time; in the treatment of metastatic breast cancer, the combination of bevacizumab and chemotherapy also obtained the same effect of prolonged progression-free survival. In the treatment of metastatic breast cancer, bevacizumab in combination with chemotherapy also showed good results in terms of prolonged progression-free survival.
Hypertension is a common adverse effect of Vascular Endothelial Growth Factor (VFGF) inhibitors. The incidence of hypertension observed in various clinical research trials was approximately 30%. This is due to the fact that bevacizumab mainly affects vascular endothelial cell survival and proliferation and has a dose-dependent effect on blood pressure, with the incidence of hypertension ranging from 2.7% to 32% at low doses (5 or 7.5 mg/kg) and 17.6% to 36% at high doses (10 or 15 mg/kg). Blood pressure should be monitored regularly before and during treatment.
Patients with a previous history of hypertension and unstable blood pressure control should not receive anti-angiogenic drugs. Patients with new-onset hypertension following the use of antiangiogenic drugs may be treated with a calcium ion antagonist to control their blood pressure; if a patient with stable blood pressure control develops elevated blood pressure after treatment with an antiangiogenic drug, an increase in the dose of the original antihypertensive drug or the addition of another antihypertensive drug should be considered. If oral antihypertensive drugs fail to control hypertension, the use of anti-angiogenic drugs should be discontinued.
The incidence of bleeding events is high in patients receiving bevacizumab, with transient epistaxis being the most common. The incidence is about 35%. These side effects are generally mild and can be recovered without treatment. Bleeding events are mainly tumor-related bleeding and trace mucosal and skin bleeding; patients should be closely monitored for coagulation function and blood pressure during treatment. Bevacizumab therapy should be discontinued immediately for severe central nervous bleeding or other 3rd/4th degree bleeding. In early studies, pulmonary bleeding (approximately 2%) in patients with non-small cell lung cancer was potentially fatal, and all pulmonary bleeding events occurred in patients with central squamous carcinoma; therefore, bevacizumab is not approved for squamous lung cancer.
Patients with malignancy are at high risk for thromboembolism, and anti-VEGF drugs, which primarily affect vascular endothelial cell production and proliferation, can expose substromal procoagulant phospholipids. Thromboembolism includes arterial vascular embolism (ATE) and venous vascular embolism (VTE), and the risk of both ATE and VTE is significantly increased when treated with bevacizumab. ATE mainly includes cerebral infarction, transient ischemic attack, and myocardial infarction. In clinical studies for a variety of relevant indications, the risk of grade 3 or higher ATE was significantly increased in the bevacizumab combination chemotherapy group compared to chemotherapy alone, especially when used in the treatment of colorectal and renal cancers.
VTE mainly includes deep vein thrombosis, pulmonary embolism and thrombophlebitis. In a meta-analysis, the overall incidence of VTE in the bevacizumab combination chemotherapy group was 1
1.9%, and the incidence of grade 3 or higher embolism was 6.3%. To prevent the occurrence of thromboembolism, patients should be encouraged to get out of bed more often during treatment, have regular local massage of the lower extremities, and have their blood pressure and thromboembolism-related symptoms closely monitored, especially in elderly patients older than 65 years of age. If signs and symptoms of thrombosis occur, proper thrombolytic anticoagulation therapy should be given. Once ATE occurs, anti-VEGF drugs should be permanently discontinued.
Proteinuria is a common adverse effect of VEGF inhibitors. VEGF expressed by glomerular podocytes is necessary to maintain normal glomerular endothelial cell structure and function, and inhibition of VEGF can disrupt the glomerular filtration barrier and eventually lead to proteinuria. Clinical studies have suggested that the use of bevacizumab increases the risk of proteinuria by approximately 9%. Proteinuria is usually reversible and mostly asymptomatic. Patients treated with VEGF inhibitors should be closely tested for creatinine, renal function, blood pressure and proteinuria. 24-hour urine protein quantification should be performed in patients with ++ to +++ proteinuria. Once renal injury or nephrotic syndrome has developed, the drug must be permanently discontinued and aggressive symptomatic treatment must be administered.
Gastrointestinal perforation is a rare but potentially life-threatening adverse reaction, with typical symptoms including abdominal pain, nausea, vomiting, constipation, and fever. Gastrointestinal perforation can occur in 2%-4% of patients treated with bevacizumab in combination with chemotherapeutic agents, and a meta-analysis showed that the risk was more pronounced in the high-dose group compared with the low-dose group, and the risk of gastrointestinal perforation was significantly higher in colorectal and renal cell carcinoma. Therefore, patients should undergo risk assessment before treatment. A history of chronic inflammatory disease, peptic ulcer and concomitant use of corticosteroids and NSAIDs predicts the possibility of gastrointestinal perforation; VEGF inhibitors should be avoided in patients within 28 days before and after surgery and in those with postoperative wound dehiscence. Therefore, patients presenting with gastrointestinal perforation should be permanently discontinued and a specialist consultation should be sought.
IV. Adverse reactions and management of anti-HER2 monoclonal antibody
Trastuzumab is a recombinant DNA-derived humanized monoclonal antibody that specifically acts on human epidermal growth factor receptor-2
(HER2) at extracellular sites. HER2 is overexpressed in 25-30% of patients with primary breast cancer, with the result that these tumor cells have increased surface HER2 protein expression, leading to HER2 receptor activation. Trastuzumab inhibits the proliferation of tumor cells by suppressing HER2 overexpression. In addition, trastuzumab achieves tumor cell killing through an antibody-dependent cell-mediated cytotoxic response (ADCC).
Cardiotoxicity is the most significant adverse effect of trastuzumab. Advanced patient age, history of prior cardiac disease, history of chest radiotherapy, and history of anthracycline use all increase the cardiotoxicity of trastuzumab. Its major cardiotoxic events include mainly left ventricular insufficiency, arrhythmias, hypertension, symptomatic heart failure, cardiomyopathy and cardiogenic death, which can also cause symptomatic left ventricular ejection fraction (LVEF) reduction. Therefore, prior to the first trastuzumab, patients should be adequately evaluated for cardiac function, including medical history, physical examination, and determination of LVEF values by echocardiography or radiographic cardiovascular imaging scans.
LVEF is retested every 3 months during treatment, as well as at the end of treatment. Trastuzumab therapy should be discontinued for absolute reductions in LVEF of ≥16% relative to pretreatment or for LVEF below the normal range and absolute reductions of ≥lO% relative to pretreatment. If symptomatic heart failure occurs during trastuzumab therapy, standard therapy with diuretics, cardiac glycosides, and/or angiotensin-converting enzyme inhibitors should be administered. In patients with clinically symptomatic heart failure, discontinuation of trastuzumab is strongly recommended unless the individual patient’s benefit outweighs the risk. Trastuzumab is not recommended for patients with a history of congestive heart failure, high-risk uncontrolled arrhythmias, angina pectoris requiring drug therapy, clinically significant valvular disease, transmural myocardial infarction on electrocardiogram, or poorly controlled hypertension, in addition to which serious infusion reactions and pulmonary toxicity have been reported in the clinical use of trastuzumab and require attention.
V. Adverse reactions and treatment of multi-target drugs
At present, the more widely used small molecule tyrosine kinase multi-target inhibitors include sorafenib and sunitinib. Sorafenib, for example, can simultaneously inhibit the kinase activities of RAF kinase, VEGFR-2, VEGFR-3, platelet-derived growth factor receptor-β, KIT, RET and FLT-3, and is used in the treatment of malignant tumors such as advanced or metastatic stem cell carcinoma, renal cell carcinoma and refractory thyroid cancer.
A more typical adverse effect of this class of drugs is hand-foot syndrome. The incidence of hand-foot syndrome caused by sorafenib and sunitinib has been reported to be 33.8% and 19%, respectively, with the incidence of grade 3-4 hand-foot syndrome caused by sorafenib being 6%, which is characterized by intense pain and loss of skin function. The clinical features of hand-foot syndrome caused by conventional chemotherapeutic drugs such as fluorouracil, doxorubicin, and capecitabine are pain, symmetrical erythema, and erythema and desquamation of the palms and soles of the feet, whereas the hand-foot syndrome caused by multikinase inhibitors shows hyperkeratosis, and this adverse effect is dose-dependent, suggesting that it may be related to the direct toxicity of these drugs.
When Grade 3 hand-foot syndrome occurs, treatment should be interrupted to allow the reaction to resolve to Grade 1, and the drug dose should be reduced appropriately when retreating. If a severe intolerable reaction occurs, treatment should be discontinued. For mild hand-foot syndrome, the following measures can be taken to improve symptoms: avoid prolonged standing; wear cotton socks and soft insoles to reduce pressure on the foot; moisturizing care of the foot, etc.
In patients treated with sorafenib and sunitinib, the incidence of hypertension is about 17% and 15%, respectively, which may be related to the direct reduction of the number of angiogenesis, disruption of endothelial cell function and alteration of nitric oxide metabolism by this class of drugs. Therefore, patients should be closely monitored for changes in blood pressure, especially during the first 6 weeks of treatment. Patients with elevated blood pressure during treatment will have a decrease in blood pressure after discontinuation of the drug and generally do not require treatment, but patients with markedly elevated blood pressure (patients with blood pressure ≥160/l00 mmHg) and/or appropriate symptoms require antihypertensive therapy. Because sotafenib and sunitinib are broken down primarily in the liver by cytochrome oxidase CYP3A4-mediated oxidation, the application of calcium antagonists that inhibit the CYP3A4 metabolic pathway (e.g., diltiazem? , verapamil, nitrendipine, etc.) for the treatment of hypertension caused by this class of drugs to prevent the accumulation of drugs in the patient’s body to increase the incidence of adverse reactions.
Instead, angiotensin-converting enzyme inhibitors (such as captopril, enalapril, benazepril and silazepril, etc.) are preferred; some patients who are allergic to or cannot tolerate angiotensin-converting enzyme inhibitors can be treated with angiotensin II receptor blockers (such as coxsartan potassium, valsartan, irbesartan and tiramisartan, etc.). Patients with severe or persistent hypertension or hypertensive crisis despite the use of antihypertensive drugs should be referred to a cardiologist and considered for permanent discontinuation of sorafenib or sunitinib therapy.
In a phase III clinical trial of sunitinib, hypothyroidism was observed in 85% of patients. Therefore, regular thyroid hormone monitoring during sunitinib treatment is recommended, and hormone replacement therapy with levothyroxine may be given if necessary: In addition, sunitinib has adverse effects including hematologic toxicity similar to that of chemotherapy drugs, mainly neutropenia and thrombocytopenia. Sunitinib is not recommended for use in combination with bevacizumab because of the increased hematologic toxicity when used in combination with other targeted agents. During the treatment period, patients should be advised to take rest, reduce the number of visitors, and reduce the chance of infection. It is also recommended to review the blood picture so that the dose of the drug can be adjusted according to the patient’s condition.
VI. Adverse effects of ALK kinase inhibitors and their management
Recently, the discovery of ALK fusion gene in NSCLC patients is another great leap forward in the treatment of non-small-cell lung cancer. ALK-positive cases in NSCLC account for roughly 3-5% of cases, meaning that globally an estimated 40
For patients with ALK-positive NSCLC, its small molecule tyrosine kinase inhibitor, crizotinib, has shown significant therapeutic activity and prolonged patient survival. More recent studies have shown that crizotinib treatment is also effective in NSCLC with ROS1 fusion gene positivity and C-MET amplification.
The most common adverse effect of crizotinib is visual disturbance (flashes of light, blurred vision, double vision, etc.), which usually occurs shortly after taking crizotinib (on average, it starts to occur in less than 2 weeks of treatment). Most of the visual disturbances are of the first degree; the changes were not evident in previous clinical studies in which the affected patients were tested specifically for vision; and the vast majority of patients did not require drug dose adjustments as a result. The visual disturbance often occurs in the morning or evening, often lasts less than a minute, and has little impact on the patient’s life. In clinical experience abroad, a baseline or routine assessment of vision is not required; however, if visual disturbance is significantly worse, the patient should receive further specialist examination and management. Note that patients should be informed of possible visual problems prior to treatment, and if visual impairment is more pronounced during treatment, patients need to be instructed not to drive motor vehicles until symptoms improve.
Elevations in liver enzymes are also common during crizotinib treatment (most occur within 2 months of treatment). The elevation of liver enzymes is usually reversible, with approximately 5
.3% of patients require temporary discontinuation or dose reduction, and about 1.3% of patients may require permanent discontinuation of therapy. Gastrointestinal reactions to crizotinib treatment include nausea, vomiting, diarrhea, and constipation, most of which are of degree 1 to 2. Often, taking crizotinib with meals will likely help patients with nausea. Antiemetic medications may be considered teabendolam or methotrexate; be careful not to use prochlorperazine or ondansetron 5-HT3 antagonists as this will likely cause prolongation of the QT interval; arepitant, a substrate and inhibitor of CYP3A4, may lead to increased toxicity of crizotinib and is also not recommended.
In addition peripheral edema is also common in patients receiving crizotinib treatment, the specific mechanism of which is not clear, but most of them are 1~2 degrees, which can be controlled by leg elevation, elastic stockings, salt restriction, etc. Diuretic treatment can be considered if necessary.
VII. Adverse effects of other drugs and treatment
Bcr-Abl tyrosine kinase inhibitor Imatinib is mainly used for the treatment of gastrointestinal mesenchymal tumor and chronic granulocytic leukemia, which may cause edema and sodium retention (incidence is about 50%, eyelid edema is the most common) during the drug administration. Nausea (50%-60%),
Vomiting, diarrhea, abdominal pain, malaise, myalgia, myasthenia and erythema are all easily managed.
Painful muscle spasms caused by imatinib treatment often occur in the hands, feet, calf gastrocnemius, and thighs, and tend to show a pattern of recurrent, intense episodes over time, and may appear to resemble tetanic forced contractions; if such symptoms persist without resolution, consider administration of quinidine, calcium/magnesium supplementation, or consideration of treatment with nonsteroidal anti-inflammatory drugs. Bone pain and arthralgia associated with imatinib treatment may be related to clearance of leukocytes from the bone marrow, often occurring during the first month of treatment and is self-limiting, often involving the femur, tibia, hip, and knee, and may be considered for treatment with NSAIDs.
In addition to the above mentioned common toxic events of molecular targeted drugs and their general disposition principles, some special cases should be noted: anti-CD20. monoclonal antibody rituximab in combination with chemotherapy is the standard regimen for the treatment of B-cell lymphoma with very mild adverse effects, but in recent years it has been reported that there has been an increase in the number of cases of acute heavy hepatitis B after combination chemotherapy, and the high rate of hepatitis B virus (HBV) infection in China, in the use of rituximab HBV two-and-a-half and DNA copy number testing is recommended before treatment with rituximab, and the viral count should be closely monitored during treatment. Anti-hepatitis B virus drugs such as lamivudine and entecavir can be applied prophylactically before chemotherapy, which in turn reduces the incidence of HBV reactivation and acute hepatitis.
Summary
We have ushered in the era of individualized targeted therapy for antitumor treatment. The successful application and continuous innovation of a large number of molecularly targeted antitumor drugs have both brought new hope to patients and posed new tests for clinical drug safety. Although most of the toxic events of molecular targeted drugs are predictable and controllable, serious or even life-threatening adverse reactions are still important issues to be prevented in clinical practice. Clinicians should be fully aware of the diversity and severity of the adverse reactions of targeted antitumor drugs, and use the sharp tool in their hands to give patients low-toxicity and high-efficiency antitumor therapy.