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Submitted:
03 March 2023
Posted:
06 March 2023
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Organ/Tissue System | irAEs | Approx. Onset Frequency (%) |
---|---|---|
Gastrointestinal | Oral mucositis | < 5 |
Xerostomia | < 6 | |
Gastritis | > 50 (PD-1), < 5 (PD-L1) | |
Colitis | > 10 | |
Ileitis | > 10 | |
Hepatitis | 5 – 10 | |
Pancreatitis | < 5 | |
Dermatologic | Dermatitis | > 20 |
Pruritus | 10 – 50 | |
Stevens Johnson | < 5 | |
Psoriasis | < 5 | |
Vitiligo | 5 – 10 | |
DRESS syndrome | < 4 | |
Endocrine | Hypohysitis | 5 – 10 |
Hyper-/hypothyroidism | < 10 | |
Diabetes Mellitus | < 3 | |
Addison’s disease | 5 – 10 | |
Pulmonary | Pleuritis | < 1 |
Pneumonitis | < 5 | |
Sarcoid-like granulomatosis | 5 – 7 (CTLA-4), < 0.5 (PD-L1) | |
Neurologic | Encephalitis | < 5 |
Meningitis | < 5 | |
Guillain Barré | < 5 | |
Neuropathy | < 5 | |
Myasthenia gravis | < 5 | |
Myelopathy | < 1 | |
Optic neuritis | < 1 | |
Cardiovascular | Myocarditis | < 5 |
Pericarditis | < 3 | |
Vasculitis | < 1 | |
Hematologic | Thrombocytopenia | < 2 |
Neutropenia | < 1 | |
Hemolytic anemia | < 5 (CTLA-4), < 10 (PD-1) | |
Pancytopenia | < 1 | |
Renal | Acute interstitial nephritis | < 5 |
Acute tubular injury | < 1 | |
Glomerulonephritis | < 2 | |
Musculoskeletal | Dermatomyositis | < 1 |
Arthritis | < 4 | |
Ocular | Retinitis | < 3 |
Conjunctivitis | < 1 | |
Uveitis | < 5 | |
Scleritis | < 1 | |
irAEs: Immune related adverse events CTLA-4: Cytotoxic T lymphocyte associated protein 4 PD-1: Programmed cell death protein 1 PD-L1: Programmed cell death ligand 1 DRESS: Drug reaction with eosinophilia and systemic symptoms |
ICIT | irAEs | Onset Time (week) |
CTCAE Peak (week) |
Damping Time (week) |
---|---|---|---|---|
CTLA-4 | Colitis | 4 – 5 | 6 | 10 |
Hepatitis | 6 – 7 | 8 – 13 | 15 | |
Pancreatitis | 3 – 9 | N/A | N/A | |
Pruritus | ≈ 4 | ≈ 5 | ≈ 6 | |
Hypohysitis | 6 – 7 | 8 | ∞ | |
Addison’s disease | 6 – 7 | 8 | ∞ | |
Myasthenia gravis | 2 – 6 | 1 – 4 | N/A | |
Acute interstitial nephritis | 2 – 12 | N/A | N/A | |
PD-1 or PD-L1 | Colitis | 4 – 5 | 6 | 10 |
Hepatitis | 6 – 7 | 8 – 14 | 15 | |
Pancreatitis | 3 – 30 | N/A | N/A | |
Pruritus | ≈ 4 | ≈ 5 | ≈ 6 | |
Hypohysitis | 6 – 7 | 8 | ∞ | |
Addison’s disease | 6 – 7 | 8 | ∞ | |
Pneumonitis | 10 – 11 | 12 | 22 | |
Myasthenia gravis | 4 – 5 | N/A | N/A | |
Acute interstitial nephritis | 12 – 72 | N/A | N/A | |
CTLA-4 and PD-1 | Colitis | 3 – 4 | 5 | 10 |
Hepatitis | 5 – 6 | 7 – 13 | 15 | |
Pruritus | ≈ 2 | ≈ 4 | ≈ 5 | |
Hypohysitis | ≈ 2 | 4 | ∞ | |
Addison’s disease | ≈ 2 | 4 | ∞ | |
Pneumonitis | ≈ 5 | ≈ 7 | ≈ 11 | |
Myasthenia gravis | 2 | N/A | N/A | |
ICIT: Immune checkpoint inhibition therapy irAEs: Immune related adverse events CTCAE: Common terminology criteria for adverse events CTLA-4: Cytotoxic T lymphocyte associated protein 4 PD-1: Programmed cell death protein 1 PD-L1: Programmed cell death ligand 1 N/A: Not available |
ICIT | irAEs | Onset Time (week) |
Frequency Peak (week and %) |
Damping Time (week) |
|
---|---|---|---|---|---|
CTLA-4 and PD-1 | Gastrointestinal | 0 – 1 | ≈ 5 | ≈ 46 | 6 – 8 |
Dermatologic | 0 | ≈ 2 | ≈ 52 | 4 – 5 | |
Endocrine | 2 – 3 | ≈ 10 | ≈ 9 | ≈ 18 | |
Pulmonary | ≈ 1 | 5 – 6 | 25 | ≈ 10 | |
Hepatic | 0 | 4 – 5 | 39 | ≈ 8 | |
Renal | 1 | 5 – 6 | ≈ 5 | 10 | |
Other | 2 | 10 | ≈ 2 | 18 | |
ICIT: Immune checkpoint inhibition therapy irAEs: Immune related adverse events CTLA-4: Cytotoxic T lymphocyte associated protein 4 PD-1: Programmed cell death protein 1 |
Diagnosis | TSH | fT4 |
---|---|---|
Primary hypothyroidism | High | Low |
Subclinical hypothyroidism | High | Normal |
Secondary hypothyroidism | Normal | Low |
Primary hyperthyroidism | Low | High |
Subclinical hyperthyroidism | Low | Normal |
TSH: Thyroid stimulating hormone, fT4: Free thyroxine |
Class | Type | Examples | Notes |
---|---|---|---|
Nonopioids | NSAIDs | Ibuprofen, aspirin, diflunisal, piroxicam, naproxen | Risk of renal failure in chronic use, not recommended in hemostatic disorders, risk of gastrointestinal bleeding |
Acetaminophen | Paracetamol | Risk of hepatotoxicity in overdosage | |
Weak opioids | Codeine | Oxycodone, hydrocodone, propoxyphene | Mostly in combination with NSAIDs or acetaminophen |
Potent opioids with short half-life | Morphine Fentanyl |
Oxymorphone, hydromorphone, meperidine, pentazocine, butorphanol | Meperidine not recommended in patients with renal disease |
Potent opioids with long half-life | Methadone Levorphanol |
Risk of withdrawal symptoms in physically dependent patients |
Parameter | Definition of scoring |
---|---|
Score with 100, if regression starts after the first initial infusion | |
Score with 100 – 5x, if regression starts after the xth infusion where x=2,...,6 | |
Score with 100 – 7y, if regression starts after the yth infusion where y=7,...,11 | |
Score with 10, if regression starts beyond the 12th infusion | |
Score with 0, if no regression is observed at the assessment stage | |
Score with x, where x denotes tumor volume shrinkage in % at the assessment stage | |
Score with the average for multiple tumors, i.e. number of tumors | |
Score with 100, if remission starts latest after the 3rd infusion | |
Score with 100 – 10(x – 3), if remission starts after the xth infusion where x=4,...,11 | |
Score with 10, if remission starts beyond the 12th infusion | |
Score with 0, if no remission is observed at the assessment stage | |
Score between 75 – 100, if there is no preexisting comorbidity and autoimmune disorder | |
Score between 50 – 74, if there is only one preexisting comorbidity or autoimmune disorder | |
Score between 0 – 49, if there is more than one preexisting comorbidity or autoimmune disorder | |
Score with 100, if all of the baseline biomarkers in Figure 4 present compatibility with ICIT | |
Score with 100 – 14(7 – x), if x of the baseline biomarkers in Figure 4 present compatibility with ICIT where x=1,...,6 | |
Score with 0, if none of the baseline biomarkers in Figure 4 present compatibility with ICIT | |
Score with 5, if there is no irAE after the first initial infusion | |
Score with 5x, if there is no irAE after the xth infusion where x=2,...,20 | |
Score with 0 when any irAE is observed at the assessment stage | |
Increment each w with whose corresponding parameter scored between 60 – 100 in the previous assessment stage where denotes number of weightings to be incremented | |
Decrement each w with whose corresponding parameter scored between 0 – 40 in the previous assessment stage where denotes number of weightings to be decremented | |
ICIT: Immune checkpoint inhibition therapy : Timing of regression start : Regression rate : Timing of remission start : Personal immune strength score : Baseline biomarker compatibility : Time without toxicity or irAEs : Person-specific dynamic weightings |
score range | Optimum ICIT duration |
---|---|
90 – 100 | Exit after 9th infusion |
75 – 89 | Exit after 12th infusion |
60 – 74 | Exit after 16th infusion |
50 – 59 | Exit after 22th infusion |
25 – 49 | Exit after 30th infusion |
0 – 24 | Exit after 35th infusion |
ICIT: Immune checkpoint inhibition therapy : ICIT success rate |
Step# | Description of step |
---|---|
1 | ICIT continues |
2 | Check whether the patient is psychologically doing well and GO TO step 3 if YES, otherwise WITHHOLD ICIT until improvement |
3 | Check whether the patient is symptomatically doing well and GO TO step 4 if YES, otherwise WITHHOLD ICIT until improvement |
4 | Check whether the patient has developed any irAE or toxicity and GO TO step 5 if NO, otherwise REFER to management algorithms presented in the previous section |
5 | Check whether MRNn+1 > MRNn (n є ℕ) and GO TO step 6 if NO, otherwise DISCONTINUE ICIT permanently |
6 | Check whether NTn+1 > NTn+2 (n є ℕ) and GO TO step 7 if NO, otherwise DISCONTINUE ICIT permanently |
7 | Check whether VTn+1 > 1.15xVTn (n є ℕ) and GO TO step 8 if NO, otherwise DISCONTINUE ICIT permanently |
8 | CONTINUE ICIT |
9 | GO TO step 1 and MAKE n=n+1 |
ICIT: Immune checkpoint inhibition therapy irAE: Immune related adverse event MRNn: Number of metastatic regions at analysis stage n NTn: Number of existing tumors at analysis stage n VTn: Existing tumor volumes at analysis stage n ℕ: Natural numbers |
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