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*For medical professionals only to read the summary: Immunotherapy early diagnosis, stratified treatment key points
In recent years, immunotherapy has attracted much attention due to its significant efficacy in patients with advanced tumors, although the efficacy of immunotherapy is certain, but the immune system involves many organs, which will lead to life-threatening immune-related adverse reactions (irAEs).
For oncologists, the treatment of irAE is a clinical must be
mastered.
"Medical Oncology Channel" specially invited Professor Hong Qunying of Zhongshan Hospital affiliated to Fudan University to summarize the treatment strategy of irAE!
Early diagnosis is important Immunotherapy differs from conventional chemotherapy and targeted therapy in order to relieve the suppressed state of the immune system and produce efficacy
by enhancing the function of the immune system.
At present, most of the drugs used in immunotherapy are immune checkpoint inhibitors, mainly targeting PD-1/PD-L1 and CTLA-4 targets
.
According to relevant statistics, the incidence of irAE is 8%-27% in patients using PD-1/PD-L1 inhibitors, and the incidence of irAE in patients with CTLA-4 inhibitors is 54%.
The clinical manifestations of adverse reactions caused by immunotherapy are complex, which can cause serious adverse reactions
in multiple systems and organs of the patient's body.
First of all, it is clinically necessary to improve the understanding of adverse immune reactions, and early identification is very important
.
In addition, the occurrence time of irAE in various systems in the human body is different, and when irAE is encountered clinically, it is recommended to use multidisciplinary team (MDT) collaboration
.
Take irAE common adverse reaction pneumonia
.
When imaging shows inflammation, it cannot be diagnosed as irAE alone, but also needs to be diagnosed and differentiated from
other diseases.
First, determine whether it is caused by the progression of the tumor, such as cancerous lymphangitis
.
Second, identify whether pneumonia
is caused by bacterial and viral infections in the lungs.
Third, identify whether drug-induced pneumonia
is caused by combination drugs such as chemotherapy.
Multidisciplinary collaboration between oncology, respiratory, imaging, and pathology is important
in this process.
Second, we also need to raise awareness
of irAE among patients and their families.
Patients and their families are the first perceivers of irAE, and only when they perceive discomfort and communicate with doctors in time can they better diagnose irAE and treat
it in time.
Stratified treatment Most irAEs can be controlled and reversible by suspending dosing or adding corticosteroids, and treatment of irAEs with drug tapering is not recommended, and the current treatment of irAEs is based on CTCAE grading
.
It is divided into four levels through clinical manifestations, laboratory tests and auxiliary examinations, and the treatment plans for different levels are shown in
Figure 1 below.
Figure 1.
Principles for the treatment of immune-related adverse reactions
Specific coping methods of common irAEs When clinical encounters irAEs involving different organs, the clinical manifestations are different, and the treatment principles are also different
.
▌ Pneumonia: grade 1: asymptomatic, only radiographic changes, lesions limited to 1 lobe or < 25% of lung involvement
:
postpone immunotherapy as appropriate, Close follow-up, if it worsens, treat grade 2 or 3/4 grade
2: mild to moderate new symptoms (dyspnea, cough, chest pain), lesions involving more than 1 lung lobe or 25%~50% of lung involvement
Management mode: suspension of immunotherapy, active oxygen therapy and symptomatic supportive therapy, Glucocorticoid therapy: intravenous administration first, improvement followed by oral administration, such as methylprednisolone 1~2mg/kg/d
.
Gradually reduce the amount
after improvement.
If co-infection cannot be ruled out, the addition of anti-infective therapy
is recommended.
Grade 3/4: severe new-onset symptoms (new or worsening hypoxia; life-threatening; Dyspnea; ARDS)
treatment: stop immunotherapy, active oxygen therapy and symptomatic supportive therapy, use intravenous methylprednisolone 2-4mg/kg/d, and reduce the dose for at least 8w
.
▌Skin toxicity: rash treatment - graded treatment
level 1: rash < 10% of body surface area, with or without symptoms<b20>.
Treatment: avoid skin irritation and exposure, it is recommended to use topical emollients, topical hormonal ointment (weak effect) 1 time per day, oral antihistamines as appropriate, continue immunotherapy
.
Grade 2: The rash covers 10%~30% of the body surface area
.
Treatment: avoid skin irritation and exposure, topical hormone ointment (medium strength) 1~2 times a day, oral antihistamines as appropriate, continue immunotherapy
.
Grade 3: The rash covers > 30% of the body surface area or grade 2 with a large number of symptoms
.
Treatment: stop immunotherapy, topical strong hormone ointment, start hormone therapy (mild: 0.
5~1mg/kg prednisolone once a day oral use for 3 days, and then gradually reduce the dose; Severe: 0.
5~1mg/kg methylprednisolone IV, changed to oral after symptom improvement, and then gradually reduced), after recovering to grade 1-2, immunotherapy
can be restarted.
Grade 4: Rash demolting> 30% of the body surface area, accompanied by erythema, purpura, papules, etc
.
Treatment: 1~2mg/kg methylprednisolone IV, coordinated specialist treatment, termination of immunotherapy
.
▌Treatment of hypothyroidism with abnormal thyroid function: thyroxine 0.
5-1.
5μg/kg, continue immunotherapy
.
Treatment of hyperthyroidism: propranolol or atenolol to control symptoms, painful thyroiditis to prednisolone 0.
5mg/kg to relieve symptoms and then reduce the dose, if you still feel unwell, suspend immunotherapy, wait for symptoms to control and restart
again.
▌All patients with hypophysitis
need to be sent for pituitary axis function blood test and MRI to rule out brain metastases
.
Mild symptoms: mild fatigue, anorexia, no headache
.
Management: Continue immunotherapy with appropriate hormone replacement therapy
.
Moderate symptoms: headache without visual disturbances; or fatigue with mood changes but hemodynamically stable without electrolyte abnormalities
.
Treatment: suspend immunotherapy, followed by oral therapy
with prednisolone 0.
5-1mg/kg.
Severe symptoms: symptoms of severe mass compression, such as severe headache, visual disturbances, or severe adrenal insufficiency
.
Treatment: suspend immunotherapy, followed by methylprednisolone 1mg/kg intravenous therapy, and if necessary, use nonsteroidal anti-inflammatory drugs to relieve pain
.
▌Hepatotoxicity
grade 1: ALT or AST>1-3×ULN
treatment: Continue immunotherapy and repeat liver function
within 1 week.
Grade 2: ALT or AST3-5×ULN
treatment: immunotherapy is suspended and serum aminotransferase and bilirubin levels
are measured twice weekly.
The increase lasts for more than 1~2 weeks, after eliminating other causative factors, use 1mg/kg/d prednisolone, reduce the dose after improvement, and continue to use immune drugs
.
If there is no improvement, increase to 2 mg/kg/day prednisolone and stop the immunization drug
permanently.
Grade 3: ALT or AST5-20×ULN
treatment: permanent discontinuation of immune drugs, and use hormone therapy, the initial dose of 1~2mg/kg/d prednisolone or other equivalent drugs
.
Grade 4: ALT or AST > 20×ULN
treatment: permanent discontinuation of immunology and use of hormone therapy at an initial dose of 2 mg/kg/day prednisolone or other equivalent
.
▌Patients with gastrointestinal toxicity
not accompanied by severe diarrhea receive anti-diarrhea therapy, rehydration and electrolyte replacement, and can continue to use immunotherapy
.
If you continue to diarrhea and watery stools > 4-6 times a day, or accompanied by abdominal pain and bloody stools, immunotherapy should be suspended, immunotherapy should be stopped, and systemic glucocorticoid therapy (intravenous methylprednisolone 1~2mg/kg/d).
Expert profiles
In recent years, immunotherapy has attracted much attention due to its significant efficacy in patients with advanced tumors, although the efficacy of immunotherapy is certain, but the immune system involves many organs, which will lead to life-threatening immune-related adverse reactions (irAEs).
For oncologists, the treatment of irAE is a clinical must be
mastered.
"Medical Oncology Channel" specially invited Professor Hong Qunying of Zhongshan Hospital affiliated to Fudan University to summarize the treatment strategy of irAE!
Scan the QR code above to get the latest tumor information
Early diagnosis is important Immunotherapy differs from conventional chemotherapy and targeted therapy in order to relieve the suppressed state of the immune system and produce efficacy
by enhancing the function of the immune system.
At present, most of the drugs used in immunotherapy are immune checkpoint inhibitors, mainly targeting PD-1/PD-L1 and CTLA-4 targets
.
According to relevant statistics, the incidence of irAE is 8%-27% in patients using PD-1/PD-L1 inhibitors, and the incidence of irAE in patients with CTLA-4 inhibitors is 54%.
Professor Hong said, "As the so-called success is also Xiao He, defeat is also Xiao He
.
It is immunotherapy that enhances the activity of lymphocytes and thus improves immune efficacy, which will lead to the possibility of irAEs
in all parts of the body.
”
The clinical manifestations of adverse reactions caused by immunotherapy are complex, which can cause serious adverse reactions
in multiple systems and organs of the patient's body.
First of all, it is clinically necessary to improve the understanding of adverse immune reactions, and early identification is very important
.
In addition, the occurrence time of irAE in various systems in the human body is different, and when irAE is encountered clinically, it is recommended to use multidisciplinary team (MDT) collaboration
.
Take irAE common adverse reaction pneumonia
.
When imaging shows inflammation, it cannot be diagnosed as irAE alone, but also needs to be diagnosed and differentiated from
other diseases.
First, determine whether it is caused by the progression of the tumor, such as cancerous lymphangitis
.
Second, identify whether pneumonia
is caused by bacterial and viral infections in the lungs.
Third, identify whether drug-induced pneumonia
is caused by combination drugs such as chemotherapy.
Multidisciplinary collaboration between oncology, respiratory, imaging, and pathology is important
in this process.
Second, we also need to raise awareness
of irAE among patients and their families.
Patients and their families are the first perceivers of irAE, and only when they perceive discomfort and communicate with doctors in time can they better diagnose irAE and treat
it in time.
Stratified treatment Most irAEs can be controlled and reversible by suspending dosing or adding corticosteroids, and treatment of irAEs with drug tapering is not recommended, and the current treatment of irAEs is based on CTCAE grading
.
It is divided into four levels through clinical manifestations, laboratory tests and auxiliary examinations, and the treatment plans for different levels are shown in
Figure 1 below.
Figure 1.
Principles for the treatment of immune-related adverse reactions
At the same time, Professor Hong Qunying emphasized: "After the occurrence of irAE, it is necessary to consider whether it is necessary for patients to undergo immunotherapy again, and restart immunotherapy needs to be judged
according to the severity of the patient's irAE.
" When the irAE is grade 1 to 2, immunotherapy can be continued under close observation; When the irAE is grade 3, a temporary discontinuation of immunotherapy may be considered, and the decision to restart immunotherapy
may be discussed later based on the patient's risk/benefit ratio.
When the irAE is level 4, immunotherapy is immediately discontinued, and subsequent immune re-challenges
are no longer considered.
”
Specific coping methods of common irAEs When clinical encounters irAEs involving different organs, the clinical manifestations are different, and the treatment principles are also different
.
▌ Pneumonia: grade 1: asymptomatic, only radiographic changes, lesions limited to 1 lobe or < 25% of lung involvement
:
postpone immunotherapy as appropriate, Close follow-up, if it worsens, treat grade 2 or 3/4 grade
2: mild to moderate new symptoms (dyspnea, cough, chest pain), lesions involving more than 1 lung lobe or 25%~50% of lung involvement
Management mode: suspension of immunotherapy, active oxygen therapy and symptomatic supportive therapy, Glucocorticoid therapy: intravenous administration first, improvement followed by oral administration, such as methylprednisolone 1~2mg/kg/d
.
Gradually reduce the amount
after improvement.
If co-infection cannot be ruled out, the addition of anti-infective therapy
is recommended.
Grade 3/4: severe new-onset symptoms (new or worsening hypoxia; life-threatening; Dyspnea; ARDS)
treatment: stop immunotherapy, active oxygen therapy and symptomatic supportive therapy, use intravenous methylprednisolone 2-4mg/kg/d, and reduce the dose for at least 8w
.
▌Skin toxicity: rash treatment - graded treatment
level 1: rash < 10% of body surface area, with or without symptoms<b20>.
Treatment: avoid skin irritation and exposure, it is recommended to use topical emollients, topical hormonal ointment (weak effect) 1 time per day, oral antihistamines as appropriate, continue immunotherapy
.
Grade 2: The rash covers 10%~30% of the body surface area
.
Treatment: avoid skin irritation and exposure, topical hormone ointment (medium strength) 1~2 times a day, oral antihistamines as appropriate, continue immunotherapy
.
Grade 3: The rash covers > 30% of the body surface area or grade 2 with a large number of symptoms
.
Treatment: stop immunotherapy, topical strong hormone ointment, start hormone therapy (mild: 0.
5~1mg/kg prednisolone once a day oral use for 3 days, and then gradually reduce the dose; Severe: 0.
5~1mg/kg methylprednisolone IV, changed to oral after symptom improvement, and then gradually reduced), after recovering to grade 1-2, immunotherapy
can be restarted.
Grade 4: Rash demolting> 30% of the body surface area, accompanied by erythema, purpura, papules, etc
.
Treatment: 1~2mg/kg methylprednisolone IV, coordinated specialist treatment, termination of immunotherapy
.
▌Treatment of hypothyroidism with abnormal thyroid function: thyroxine 0.
5-1.
5μg/kg, continue immunotherapy
.
Treatment of hyperthyroidism: propranolol or atenolol to control symptoms, painful thyroiditis to prednisolone 0.
5mg/kg to relieve symptoms and then reduce the dose, if you still feel unwell, suspend immunotherapy, wait for symptoms to control and restart
again.
▌All patients with hypophysitis
need to be sent for pituitary axis function blood test and MRI to rule out brain metastases
.
Mild symptoms: mild fatigue, anorexia, no headache
.
Management: Continue immunotherapy with appropriate hormone replacement therapy
.
Moderate symptoms: headache without visual disturbances; or fatigue with mood changes but hemodynamically stable without electrolyte abnormalities
.
Treatment: suspend immunotherapy, followed by oral therapy
with prednisolone 0.
5-1mg/kg.
Severe symptoms: symptoms of severe mass compression, such as severe headache, visual disturbances, or severe adrenal insufficiency
.
Treatment: suspend immunotherapy, followed by methylprednisolone 1mg/kg intravenous therapy, and if necessary, use nonsteroidal anti-inflammatory drugs to relieve pain
.
▌Hepatotoxicity
grade 1: ALT or AST>1-3×ULN
treatment: Continue immunotherapy and repeat liver function
within 1 week.
Grade 2: ALT or AST3-5×ULN
treatment: immunotherapy is suspended and serum aminotransferase and bilirubin levels
are measured twice weekly.
The increase lasts for more than 1~2 weeks, after eliminating other causative factors, use 1mg/kg/d prednisolone, reduce the dose after improvement, and continue to use immune drugs
.
If there is no improvement, increase to 2 mg/kg/day prednisolone and stop the immunization drug
permanently.
Grade 3: ALT or AST5-20×ULN
treatment: permanent discontinuation of immune drugs, and use hormone therapy, the initial dose of 1~2mg/kg/d prednisolone or other equivalent drugs
.
Grade 4: ALT or AST > 20×ULN
treatment: permanent discontinuation of immunology and use of hormone therapy at an initial dose of 2 mg/kg/day prednisolone or other equivalent
.
▌Patients with gastrointestinal toxicity
not accompanied by severe diarrhea receive anti-diarrhea therapy, rehydration and electrolyte replacement, and can continue to use immunotherapy
.
If you continue to diarrhea and watery stools > 4-6 times a day, or accompanied by abdominal pain and bloody stools, immunotherapy should be suspended, immunotherapy should be stopped, and systemic glucocorticoid therapy (intravenous methylprednisolone 1~2mg/kg/d).
Expert profiles
Prof.
Qunying Hong
- Chief physician and associate professor of Zhongshan Hospital affiliated to Fudan University
- Deputy Director of the Department of Respiratory Affairs, Zhongshan Hospital affiliated to Fudan University
- Member of the Lung Cancer Group of the Respiratory Disease Branch of the Chinese Medical Association
- Member of the Lung Cancer Working Committee of the Respiratory Physician Branch of the Chinese Medical Doctor Association
- Member of the Respiratory Endoscopy Professional Committee of the Endoscopist Branch of the Chinese Medical Doctor Association
- Member of the Standing Committee of the Tumor Metastasis Professional Committee of the Chinese Medical Education Association
- Member of the Standing Committee of the Pulmonary Oncology Professional Committee of the Chinese Medical Education Association
- Member of the Pulmonary Oncology Academic Working Committee of the Respiratory Branch of the Chinese Geriatrics Society
- Member of the Standing Committee of the Lung Cancer Special Committee of Shanghai Anti-Cancer Association
- Member of Respiratory Physician Branch of Shanghai Medical Association
- Member of the Internal Medicine Branch of Shanghai Medical Association
- Member and deputy leader of the Pulmonary Interstitial Disease Group of the Pulmonary Society of Shanghai Medical Association
