Cardiotoxicity
Dr. Siu of the Royal Margaret Cancer Center provides an overview of the cardiotoxicity of molecularly targeted drugs, including left heart failure, hypertension and QT interval (QTc) prolongation. The mechanisms of drug-induced left heart failure vary, for example cytotoxic anthracyclines produce type I injury, while molecularly targeted drugs such as trastuzumab produce type II injury.
Angiogenesis inhibitors and MEK inhibitors induce hypertension, and vascular endothelial growth factor (VEGF) inhibitors induce hypertension in a dose-dependent manner, and angiotensin-converting enzyme inhibitors and/calcium channel blockers should be used to treat increased blood pressure, maintaining the VEGF inhibitor dose whenever possible.
Prolonged QTc interval is a side effect of histone deacetylase inhibitors, ABL inhibitors, MET inhibitors, and multi-target tyrosine kinase inhibitors. Predisposing factors include genetic factors such as congenital long QT syndrome, or acquired causes, as follows.
1, heart: decreased left ventricular ejection function, left ventricular hypertrophy, cardiac ischemia, atrioventricular node block, mitral valve prolapse, sinus node insufficiency.
2, metabolism: electrolyte disorders such as low potassium, low magnesium, low calcium, malnutrition, hypothyroidism.
3, drug induction: antiarrhythmics such as quinidine, methylsulfamethazine, amiodarone, psychiatric drugs such as amitriptyline, venlafaxine, antibiotics such as azithromycin, moxifloxacin, antihistamines such as acepromazole, terfenazol, other drugs such as domperidone and cardiofloxacin.
New drugs targeting HER2
Dr. Siu summarized the cardiotoxicity of new drugs targeting HER2. Lapatinib reduced left ventricular ejection fraction (LVEF) less than trastuzumab; combination of patuximab and trastuzumab did not increase cardiotoxicity; TDM1 reduced LVEF less than trastuzumab.
Angiogenesis inhibitors
Angiogenesis inhibitors can also reduce LVEF, leading to CHF and hypertension, with a rare risk of reversible posterior encephalopathy syndrome and thrombotic microangiopathy. Multi-target tyrosine kinase inhibitors prolong QTc and can also cause diarrhea with secondary electrolyte disturbances and arterial thrombotic events.
ABL inhibitors
Drugs include imatinib, nilotinib, dasatinib, bosutinib, and ponatinib. Imatinib and nilotinib may reduce LVEF leading to CHF; imatinib >600 mg/day may cause edema without a decrease in LVEF and QTc prolongation in up to 4% of patients.
These side effects are more frequent with nilotinib and can be improved by taking the drug on an empty stomach. QTc prolongation occurs less frequently with dasatinib than with bosutinib and ponatinib. The US FDA cancelled the approval of ponatinib due to severe atherosclerosis.
Other drugs
Trametinib (MEK inhibitor) causes decreased LVEF and CHF, peripheral edema and hypertension. Crizotinib (ALK/MET inhibitor) causes QTc prolongation and peripheral edema; histone deacetylation (HDAC) inhibitors such as vorinodi and romidepsin induce QTc prolongation; thalidomide causes bradycardia.
Nodal inhibitors
Immune nodal inhibitors are promising cancer immunotherapy. siu said cardiotoxicity is rare in immune nodal inhibitors, with low cardiotoxicity among FDA-approved such drugs eprilimus and no risk of cardiotoxicity when pembrolizumab is used at the recommended dose according to the instructions.
ESMO Guidelines
ESMO has published guidelines for managing cardiac risk in cancer therapy, and targeted therapies are generally less cardiotoxic, although some may have serious comorbidities. A baseline assessment of cardiovascular risk factors, comorbidities, and LVEF is recommended. cardiotoxicity is noted with higher doses, such as standard 12-lead ECG when adriamycin >500 mg/m2 or liposomal adriamycin >900 mg/m2.
Summary
Dr. Siu said cardiovascular toxicity such as LV failure, QTc prolongation and hypertension can be observed in various targeted therapies and is usually treatable and reversible. Risk prevention, detection, reporting and treatment should be part of the plan for the use of these drugs.
Pulmonary Toxicity
Dr. Meyer discussed the pulmonary toxicity of targeted therapies, including acute and subacute pneumonia, alveolar hemorrhage, hemoptysis, pleural exudate, pulmonary arterial hypertension (PAH), and pulmonary embolism. He highlighted acute and subacute pneumonia and PAH.
It is difficult to determine whether the pathological changes in the lung are due to drug complications, infectious disease or cancer itself. Manifestations of infection, left heart failure and cancer invasion can be ruled out by chest CT, bronchoscopy and bronchial biopsy, microbiological testing and bronchoalveolar lavage (BAL). Drug toxicity is then confirmed by clinical and imaging changes, occasionally by BAL or lung biopsy.
Acute or subacute pneumonia has been reported in several targeted therapies. In summary, the following are.
1. gefitinib, incidence 1%, 30% lethality. Risk factors include advanced age, poor PS score, smoking, short time to cancer diagnosis, reduced normal lung volume on CT, history of previous interstitial lung disease, and concurrent cardiac disease.
2. Erlotinib, incidence 0.6%, 30% lethality.
3, mTOR inhibitor: 11% incidence, 3% grade 3-4 pneumonia, usually asymptomatic, low lethality.
Acute or subacute pneumonia manifestations include cough, dyspnea and fever. Imaging features include diffuse alveolar damage, hypersensitivity pneumonitis, nonspecific interstitial pneumonia, acute eosinophilic pneumonia, and mechanized pneumonia. Image patterns and pathologic findings lacked correlation.
Treatment included discontinuation, supportive therapy, and corticosteroid use in critically ill patients. Gefitinib and erlotinib are used again after discontinuation, either in reduced doses or with concomitant glucocorticoids, and pneumonia may reappear, and it has been suggested that glucocorticoids may prevent recurrence.
PAH
PAH may progress from asymptomatic to symptomatic, manifested by characteristic dyspnea with clear breath sounds, mostly normal chest radiographs, and mean pulmonary artery pressure > 25 mmHg on cardiac ultrasound and right heart intubation. PAH may improve after discontinuation, but will not be completely reversed.
Skin toxicity
Robert provided a precise summary of the skin toxicity of targeted therapies. Some skin side effects are mild and do not require special treatment, but some particularly severe reactions can reduce quality of life and create safety issues. Skin changes can have a significant impact on patients, and although not life-threatening, they can cause depression due to altered appearance.
EGFR inhibitors
EGFR inhibitors can produce a range of skin toxicity. Folliculitis primarily affects the face and trunk and usually occurs at 1-3 weeks of treatment; gangrene is evident at 2-4 weeks of treatment; nail fungus may occur at 4-8 weeks of treatment; curling and softening of hair, balding of the forehead, and eyelash growth at 4-8 weeks of treatment.