Endocrine Adverse Events of Nivolumab in Non-Small Cell Lung Cancer Patients—Literature Review
Abstract
:1. Introduction
- Activating molecules (CD28, CD27, OX40, CD137 and GITR (glucocorticoid-induced tumor necrosis factor receptor)), whose stimulation increases the proliferation, differentiation and activation of lymphocytes, positively stimulating the immune response;
- Inhibitory molecules (CTLA-4 (cytotoxic T-limphocyte-associated protein 4), PD-1 (programmed cell death-1), ICOS (inducible T-cell co-stimulator) and LAG-3 (lymphocyte activation gene-3)), the stimulation of which causes the functional depletion of lymphocytes, thus limiting T lymphocyte activity and causing immunosuppression [1].
2. Inhibitory Molecules and Their Use in Oncology
3. Adverse Events Associated with Anti-PD-1 and Anti-PD-L1 Immunotherapy
4. Endocrine Adverse Effects Associated with Nivolumab Treatment
5. Pituitary Gland Disorders
5.1. Epidemiology
5.2. Mechanisms
5.3. Clinical Manifestations
5.4. Diagnostics
5.5. Treatment, Prognosis
6. Thyroid Gland Disorders
6.1. Epidemiology
6.2. Clinical Manifestations
6.3. Mechanisms
6.4. Diagnostics
6.5. Treatment, Prognosis
7. Disorders of Adrenal Glands
7.1. Epidemiology
7.2. Clinical Manifestations
7.3. Diagnostics
7.4. Treatment, Prognosis
8. Diabetes
8.1. Epidemiology
8.2. Clinical Manifestations
8.3. Mechanisms
8.4. Diagnostics
8.5. Treatment, Prognosis
9. Management of Adverse Events during Nivolumab Treatment
10. IrAE and Efficacy of Immunotherapy
11. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
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Adverse Event | Occurrence Rate (%) [30] | Median Time of Occurrence of Adverse Event [30] (Months) | Frequency of Occurrence Observed in Other Studies |
---|---|---|---|
Hypophysitis | 0.6 | 4.9 (range 1.4 to 11 months) | 0.5–0.9 [31,32,33,34] |
Adrenal Insufficiency | 1 | 4.3 (range 15 days to 21 months) | 0.85–1.9 [35,36,37] |
Type 1 Diabetes Mellitus | 0.9 1 | 4.4 (range 15 days to 22 months) | 0.1–1.5 [32,37,38,39] |
Hypothyroidism/Thyroiditis | 9 | 2.9 (range 1 day to 16.6 months) | 2.6–10.1 [33,34,35,36,40,41,42] |
Hyperthyroidism | 2.7 | 1.5 (range 1 day to 14.2 months) | 0.8–15.3 [34,35,37,40,41,42] |
Adverse Events | Intensity [14,68] | Recommended Nivolumab Dosage Modification | Monitoring/Treatment |
---|---|---|---|
Hypophysitis | Grade 1—asymptomatic or mild symptoms, e.g., fatigue, weakness, loss of appetite of mild intensity, no headache | Continued treatment | -Hormonal evaluation -Pituitary MRI -Clinical and hormonal evaluation every 1–3 weeks -Repeat MRI after one month if the symptoms remain and the hormonal tests and/or MRI are normal -Hormonal substitution if necessary (e.g., hydrocortisone 10 to 20 mg orally in the morning, 5 to 10 mg orally in early afternoon; levothyroxine by weight, testosterone or estrogen therapy as needed in those without contraindications. Always start corticosteroids several days before thyroid hormone to prevent precipitating adrenal crisis. Follow FT4 for thyroid hormone replacement titration (TSH is not accurate). ≥Grade 2: 1 mg/kg/day prednisone/prednisone equivalents -Substitution treatment if necessary -Analgesic treatment in case of headaches -In case of clinical improvement (with or without substitution treatment continuation), taper steroids over at least 1 month before resuming treatment -Return to treatment in case of return of AE to level 0–1 |
Grade 2—moderate symptoms, e.g., headaches without vision disturbances, fatigue, worse well-being, hemodynamically stable, no electrolyte abnormalities | Withhold dose, temporary drug interruption | ||
Grade 3—serious mass-effect symptoms, e.g., headaches, vision disturbances or severe symptoms of adrenal insufficiency | Withhold dose, temporary drug interruption | ||
Grade 4 | Permanently discontinue | ||
Adrenal insufficiency | Grade 1 Asymptomatic; | Clinical or diagnostic observations only; no intervention in terms of nivolumab treatment | -Clinical and hormonal evaluation repeated every 1–3 weeks -Glucocorticoids administered in the substitutional doses (hydrocortisone: 10 to 20 mg orally in the morning, 5 to 10 mg orally in early afternoon or prednisone: 5 to 10 mg daily, fludrocortisone (0.1 mg/d) for mineralocorticoid replacement in primary adrenal insufficiency -Grades 3–4: 1 to 2 mg/kg/day prednisone equivalents followed by corticosteroid taper over at least 1 month -Return to treatment in case of return of AE to level 0–1 |
Grade 2 Moderate symptoms; | Consider withholding dose | ||
Grade 3 Severe symptoms; | Discontinuation of treatment/hospitalization | ||
Grade 4 Life-threatening symptoms | |||
Type 1 diabetes | Grade 1 Asymptomatic or mild symptoms; fasting glucose value >ULN-160 mg/dl (>ULN-8.9 mmol/L), no evidence of ketosis | Clinical or diagnostic observations only; no intervention in terms of nivolumab treatment | -Monitoring and treatment of hyperglycemia -In case of AE returning to level 0–1, return to treatment |
Grade 2 Moderate symptoms, fasting glucose value >160–250 mg/dl (>8.9–13.9 mmol/L) | |||
Grade 3 Fasting glucose value >250–500 mg/dl (>13.9–27.8 mmol/l) | Withhold dose, hospitalization indicated | ||
Grade 4 Fasting glucose value >500 mg/dl (>27.8 mmol/L) | Discontinuation of treatment, hospitalization indicated | ||
Thyroid disorders-Hypothyroidism | Grade 1 Asymptomatic or few symptoms TSH elevated (<10 mUL/L), FT3, FT4-normal aTPO and anti-TG usually high | There are no recommended modifications of dosage of nivolumab. In severe cases, (Grade ≥ 3) consider withholding ICI | -Monitor thyroid function prior to and periodically during treatment (before each cycle) -Levothyroxine in case of hypothyroidism -Grade ≥ 3: Hospitalization Supportive therapy for severe cardio-respiratory symptoms Return to Grade 2—consider return to immunotherapy |
Grade 2 Mild symptoms (fatigue, weight gain, constipations, dry skin, eyelid edema, puffy face) Low FT3 and/or FT4, TSH > 10 mUI/L aTPO/antiTg usually high | |||
Grade 3–4 Moderate–severe symptoms (bradycardia, hypotension, pericardial effusion, depression, hypoventilation, stupor, lethargy to myxedema coma) -Very low FT4, FT3 -TSH very high -aTPO and antiTG usually high | |||
Thyroid disorders Hyperthyroidism | Grade 1 Asymptomatic -FT3, FT4 normal -TSH suppressed (<0.1 mUI/L), antiTPO/aTG normal or high | There are no recommended modifications of dosage of nivolumab. In severe cases (Grade ≥ 3), consider withholding ICI | -TSH, FT4, FT3 before each cycle -Close monitoring of thyroid function to catch transition to hypothyroidism in patients with thyroiditis and hyperthyroidism -Overt hyperthyroidism: introduce beta-blocker (propranolol/atenolol/metoprolol) -Consider glucocorticoid therapy—prednisone 1 to 2 mg/kg/d or equivalent tapered over 1 to 2 weeks (not routinely) -Anti-thyroid drug (thiamazol/PTU) in case of Graves’ disease -Grade ≥ 3: Hospitalization -In case of destructive thyroiditis, consider treatment with oral glucocorticoid (prednisone equivalent 0.5–1 mg/kg/day followed by dose reduction) -In case of withholding ICI treatment, consider restarting when symptoms controlled |
Grade 2 Mild symptoms: weight loss, increased appetite, anxiety and irritability, muscle weakness -TSH suppressed (<0.1 mUI/L) -FT4, FT4 high -aTPO/aTG normal or high -TSAbs high in case of Graves’ disease | |||
Grade 3–4 Moderate to severe symptoms: arrhythmia, atrial fibrillation, tremor -TSH suppressed (<0.1 mUI/L) -FT4, FT4 high -aTPO/aTG normal or high -TSAbs high in case of Graves’ disease |
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Dudzińska, M.; Szczyrek, M.; Wojas-Krawczyk, K.; Świrska, J.; Chmielewska, I.; Zwolak, A. Endocrine Adverse Events of Nivolumab in Non-Small Cell Lung Cancer Patients—Literature Review. Cancers 2020, 12, 2314. https://doi.org/10.3390/cancers12082314
Dudzińska M, Szczyrek M, Wojas-Krawczyk K, Świrska J, Chmielewska I, Zwolak A. Endocrine Adverse Events of Nivolumab in Non-Small Cell Lung Cancer Patients—Literature Review. Cancers. 2020; 12(8):2314. https://doi.org/10.3390/cancers12082314
Chicago/Turabian StyleDudzińska, Marta, Michał Szczyrek, Kamila Wojas-Krawczyk, Joanna Świrska, Izabela Chmielewska, and Agnieszka Zwolak. 2020. "Endocrine Adverse Events of Nivolumab in Non-Small Cell Lung Cancer Patients—Literature Review" Cancers 12, no. 8: 2314. https://doi.org/10.3390/cancers12082314