Adverse reactions to targeted drugs Experts from around the world have described various emerging adverse reactions to targeted therapies separately.
They are briefly described as follows.
Cardiotoxicity
Dr. Siu of the Royal Margaret Cancer Centre provided a general 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, with cytotoxic anthracyclines producing type I injury and molecularly targeted drugs such as trastuzumab producing type II injury, for example.
Angiogenesis inhibitors and MEK inhibitors induce hypertension, and vascular endothelial growth factor (VEGF) inhibitors induce hypertension in a dose-dependent manner, and increased blood pressure should be treated with angiotensin-converting enzyme inhibitors and/ or calcium channel blockers, maintaining the VEGF inhibitor dose as much as possible.
Prolonged QTc interval is a side effect of histone deacetylase inhibitors, ABL inhibitors, MET inhibitors, and multi-target tyrosine kinase inhibitors, and predisposing factors include genetic factors such as congenital long QT syndrome, or acquired causes, as follows.
Cardiac: decreased left ventricular ejection, left ventricular hypertrophy, cardiac ischemia, atrioventricular node block, mitral valve prolapse, sinus node insufficiency.
Metabolic: electrolyte disturbances such as low potassium, low magnesium, low calcium, malnutrition, hypothyroidism.
Drug induction: antiarrhythmics such as quinidine, methylsulfamethazine, amiodarone, psychiatric drugs such as amitriptyline, venlafaxine, antibiotics such as azithromycin, moxifloxacin, antihistamines such as astemizole, 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 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 ameliorated by taking the drug on an empty stomach. QTc prolongation is less common with dasatinib than with bosutinib and ponatinib. The 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
Immunonodal inhibitors are promising cancer immunotherapies. siu said cardiotoxicity is rare among immunonodal inhibitors, with eprilimus having low cardiotoxicity among FDA-approved drugs and pembrolizumab having no risk of cardiotoxicity when used at the recommended dose.
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 is recommended.
Summary
Dr. Siu said cardiovascular toxicity such as LV failure, QTc prolongation and hypertension can be observed with 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 effusion, 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.
Gefitinib, incidence 1%, 30% lethality. Risk factors include advanced age, poor PS scores, smoking, short time to cancer diagnosis, reduced normal lung volume on CT, history of previous interstitial lung disease, and concurrent cardiac disease.
Erlotinib, incidence 0.6%, 30% lethality.
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 with characteristic dyspnea, 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 has provided a precise summary of the skin toxicity of targeted therapy. 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 mainly 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 can occur at 4-8 weeks of treatment; curly and soft hair, balding of the forehead, and eyelash growth at 4-8 weeks of treatment.
BRAF inhibitors
BRAF inhibitors such as verofinib and darafenib have a therapeutic effect in patients with BRAF mutations. The BRAF v600E mutation is present in half of cutaneous melanomas and is also seen in non-small cell lung cancer, colorectal cancer, and papillary thyroid cancer.
The effectiveness of verofinib has been demonstrated in metastatic melanoma, with 25% of keratoacanthomas and squamous cells being effective. Darafenib, a next-generation V600E mutant BRAF inhibitor, is effective in the treatment of metastatic melanoma and is less toxic than verofenib.
Single-agent targeted therapy fails over time, and some studies have combined two targeted agents with safe results and some increased side effects. The literature reports that the use of verofenib immediately after radiotherapy can lead to severe skin toxicity, so it is recommended that verofenib should not be used within 1 week before or after radiotherapy.
Patients should be informed of cutaneous side effects before starting treatment, most of which are manageable. Cutaneous side effects have a significant impact on quality of life and treatment depends on the indications such as systemic symptoms, eosinophilia, maculopathy, epidermal peeling and mucosal damage. Infection or other drug effects need to be excluded.
Severe signs include DRESS – drug rash with eosinophilia and systemic symptoms: diffuse rash, eosinophilia >1500, systemic symptoms such as fever, lymph node enlargement, hepatitis, nephritis and neurological symptoms, toxic epidermolysis bullosa and Stevens-Johnson syndrome.
The symptoms requiring treatment are summarized below (Table 1). Symptoms that did not require treatment or had no effective treatment included sublingual bleeding, hair changes, asymptomatic nail changes, early facial rash, and yellow rash.
Table 1. Skin manifestations and treatment
Endocrine toxicity
Roila summarized most of the important endocrine toxicities of targeted therapy, including hypothyroidism, hypogonadism, hypopituitarism, and secondary hyperparathyroidism.
Hypothyroidism
Abnormal thyroid function is primarily hypothyroidism and is common in patients treated with tyrosine kinase inhibitors. Symptoms of hypothyroidism such as fatigue, weakness, constipation, depression and coldness can be attributed to cancer or other chemotherapy drugs, and in some cases the dose of chemotherapy drugs needs to be reduced or discontinued because hypothyroidism can alter pharmacokinetics and clearance, leading to unpredictable side effects that affect quality of life.
Recurrent hypothyroidism
Imatinib, sorafenib and motesanib can cause recurrent hypothyroidism on stable doses of eugenol, characterized by an increase in TSH within 2 weeks of treatment. Screening includes TSH testing before treatment, every 4 weeks, and every 2 months when TSH and eugenol are stable. Doubling of the eugenol dose at the start of treatment should be considered with imatinib therapy.
New onset hypothyroidism
Sunitinib, sorafenib and axitinib can cause hypothyroidism. It is recommended that patients be monitored for baseline TSH and T4 levels at the time of treatment, every 4 weeks and then every 2-3 months.
Hypogonadism
Hypogonadism occurs in 80%-100% of male patients treated with the ALK inhibitor crizotinib for 2-3 weeks. Symptoms include erectile dysfunction, decreased libido, fatigue, muscle loss, and decreased axillary and pubic hair. Patients should be asked if they have any symptoms and testosterone levels should be checked. Hypogonadism is diagnosed when total testosterone, free testosterone, FSH and LH are low. Interruption and replacement therapy may restore gonadal function or improve symptoms.
Pituitary Inflammation and / Hypopituitarism
Eprilimus can cause pituitary inflammation and hyperalgesia, and the dose of the drug correlates with the incidence of pituitary inflammation. Headache, nausea, vertigo, behavioral changes, visual abnormalities, and weakness occur at 6 weeks post-treatment. Differentiation from new brain metastases is required, and MRI-enhanced scans are of diagnostic interest. Cortisol, ACTH, free T3, T4 and TSH, testosterone and FSH, LH and prolactin should be measured.
In the presence of symptomatic pituitary insufficiency or any grade 3-4 endocrinopathy, discontinue eprilimus and taper to IV methylprednisolone (1-2 mg/kg) followed by prednisone (1-2 mg/kg/day) for more than 4 weeks with concomitant replacement therapy. Symptoms usually improve after a few days, and imaging shows a reduction in pituitary swelling and heterogeneity.
Severe dehydration, hypotension or shock are signs of adrenal crisis, and glucocorticoids are given intravenously.
Secondary hyperparathyroidism
Secondary hyperparathyroidism can occur with sorafenib, sunitinib, imatinib, and nilotinib therapy and is characterized by decreased serum phosphorus, decreased urinary calcium concentrations, increased PTH, and normal or decreased serum calcium concentrations. Routine biochemical monitoring is not necessary, but hypovitaminosis D synergistically contributes to sorafenib-induced sarcopenia, causing osteochondrosis. Vitamin D supplementation can be helpful in improving hypophosphatemia and PTH concentrations.
Hypophosphatemia occurs frequently with everolimus therapy and has been reported with HDAC, MEK, and ALK inhibitors. dr. Roila believes that regular monitoring is necessary and that phosphorus supplementation should be given, with only severe cases requiring interruption of drug therapy.
In summary
Endocrine toxicity induced by targeted therapy negatively affects quality of life. Fatigue and headaches may be attributed to chemotherapy, but are actually caused by endocrine toxicity. It is helpful to treat patients in concert with an endocrinologist.
Gastrointestinal toxicity
Patients often experience lactose intolerance, small intestinal bacterial overgrowth (SIBO) and abnormal bile acid metabolism after chemotherapy. Dr. Andreyev says that GI symptoms are not adequately recognized and that some GI toxicity makes patients extremely weak, but this is not usually considered very important by physicians.
Diarrhea
Dr. Andreyev cites a quote from Professor Ferry: 75,000 patients in the UK are treated with 5-FU, and at least 15% of patients develop grade 3 diarrhea, with a mortality rate of 1-5%. The mechanism of diarrhea remains unclear.
Dr. Andreyev believes that symptoms are of little diagnostic significance. He cites the example of a 32-year-old cord blood transplant woman with 35 weeks of continuous diarrhea treated with tacrolimus, hormones, ciprofloxacin, doxycycline, valganciclovir, fluconazole, and amphotericin for a diagnosis of GvHD, SIBO, and cytomegalovirus infection. While eventually reviewing the medical history, the etiology could be lansoprazole. So the etiology of diarrhea may be diverse.
Gastrointestinal damage may result in abnormal carbohydrate absorption, abnormal intestinal motility, abnormal fat metabolism, abnormal vitamin and bile salt absorption, and altered sphincter function. However, few studies have attempted to identify the causes of cancer treatment-induced gastrointestinal symptoms, resulting in less attention and treatment of GI symptoms.
Easily manageable conditions
SIBO accounts for 39% of the GI symptoms induced by cancer treatment. Symptoms associated with SIBO are shown in Table 2. The diagnosis of SIBO includes a blow test and 12-finger intestinal aspirate. If >1 × 103 clonogenic units are detected, antibiotic therapy, such as rifamycin, ciprofloxacin, doxycycline, or metronidazole, should be given empirically.
Table 2. Symptoms of SIBO
Dr. Andreyev believes that abnormal bile acid absorption (BAM) can misdiagnose irritable bowel syndrome (IBS) in 1% of the population. The diagnosis includes a SeHCAT scan with 98% sensitivity and specificity, and Dr. Andreyev believes that kolevulan has shown improvement in GI symptoms.
The SeHCAT scan is diagnostically relevant. A low-fat diet and treatment with celebrex improved the symptoms, and half of the patients returned to normal bowel movements without any adjustment in the dose of ranadolamide.
Summary
Cancer therapy-induced nausea and vomiting can be successfully treated, but gastrointestinal symptoms are often overlooked and oncologists should actively evaluate and treat gastrointestinal symptoms in patients treated for cancer. Patients and physicians need to be aware of the risks of chemotherapy-induced diarrhea and its treatment. Good control of diarrhea and chemotherapy dosing need not be reduced or discontinued, indirectly improving treatment outcomes.