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Department of Internal Medicine, Chonnam National University Medical School, Gwangju, Korea
Copyright © 2021 Korean Endocrine Society
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (https://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
CONFLICTS OF INTEREST
No potential conflict of interest relevant to this article was reported.
AUTHOR CONTRIBUTIONS
Conception or design: J.H.Y., A.R.H. Acquisition, analysis, or interpretation of data: J.H.Y., A.R.H. Drafting the work or revising: J.H.Y. Final approval of the manuscript: J.H.Y., A.R.H., H.K.K., H.C.K.
Characteristic | Normal thyroid function (n=161) | No overt hypothyroidism (n=139) | Overt hypothyroidism (n=25) | P value | P valuea |
---|---|---|---|---|---|
Age, yr | 68.6±9.9 | 66.0±11.3 | 65.5±10.1 | 0.076 | |
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Female sex | 41 (25.5) | 40 (28.8) | 13 (52.0) | 0.025 | |
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PD-1/PD-L1 inhibitor | 0.592 | ||||
Pembrolizumab | 76 (47.2) | 58 (41.7) | 11 (44.0) | ||
Nivolumb | 54 (33.5) | 52 (37.4) | 11 (44.0) | ||
Durvalumab | 10 (6.2) | 6 (4.3) | 2 (8.0) | ||
Atezolizumab | 21 (13.0) | 23 (16.5) | 1 (4.0) | ||
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Duration of PD-1/PD-L1 inhibitor therapy, mo | 3.0 (1.0–7.0) | 5.0 (1.0–10.0) | 11.0 (5.0–17.5) | <0.001 | c, d |
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No. of doses of PD-1/PD-L1 inhibitor | 5.0 (3.0–10.5) | 7.0 (3.0–15.0) | 16.0 (8.5–27.5) | <0.001 | c, d |
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Baseline TSH level | 1.70 (1.13–2.34) | 2.04 (1.29–3.32) | 2.74 (1.83–4.73) | <0.001 | b, c, d |
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Baseline free T4 level | 1.24 (1.15–1.39) | 1.21 (1.10–1.35) | 1.17 (1.07–1.29) | 0.217 | |
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Baseline anti-TPO positivity | 2/45 (4.4) | 2/48 (4.2) | 2/6 (33.3) | 0.015 | |
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Baseline anti-Tg positivity | 1/45 (2.2) | 1/48 (2.1) | 1/6 (16.7) | 0.132 | |
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Follow-up anti-TPO positivity | 2/9 (33.3) | 7/39 (17.9) | 7/18 (38.9) | 0.208 | |
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Follow-up anti-Tg positivity | 1/9 (11.1) | 5/39 (12.8) | 9/18 (50.0) | 0.005 |
Values are expressed as mean±standard deviation, number (%), or median (interquartile range).
PD-1, programmed cell death protein-1; PD-L1, programmed cell death protein-ligand 1; TSH, thyroid stimulating hormone; T4, thyroxine; TPO, thyroid peroxidase; Tg, thyroglobulin.
a Post hoc analysis using Bonferroni correction;
b P<0.05 between normal thyroid function and no overt hypothyroidism;
c P<0.05 between normal thyroid function and overt hypothyroidism;
d P<0.05 between no overt hypothyroidism and overt hypothyroidism.
Characteristic | Value |
---|---|
Age at PD-1/PD-L1 inhibitor initiation, yr | 67.2±10.6 |
| |
Female sex | 94 (28.9) |
| |
PD-1 inhibitor | |
Pembrolizumab | 145 (44.6) |
Nivolumab | 117 (36.0) |
| |
PD-L1 inhibitor | |
Durvalumab | 45 (13.8) |
Atezolizumab | 18 (5.5) |
| |
Type of cancer | |
Lung cancer | 184 (56.6) |
Melanoma | 39 (12.0) |
Renal cell carcinoma | 23 (7.1) |
Biliary cancer | 19 (5.8) |
Hepatocellular carcinoma | 16 (1.9) |
Bladder cancer | 10 (3.1) |
Gastric cancer | 10 (3.1) |
Colorectal cancer | 8 (2.5) |
Oropharyngeal cancer | 6 (1.8) |
Esophageal cancer | 3 (0.9) |
Peritoneal carcinomatosis | 2 (0.6) |
Thymic cancer | 1 (0.3) |
Nasopharygneal cancer | 1 (0.3) |
Pancreas cancer | 1 (0.3) |
Multiple myeloma | 1 (0.3) |
Canthal cancer | 1 (0.3) |
| |
Duration of follow-up, mo | 5.0 (1.0–9.0) |
| |
Duration of PD-1/PD-L1 inhibitor therapy, mo | 4.0 (1.0–9.0) |
| |
No. of doses of PD-1/PD-L1 inhibitor | 6.0 (3.0–12.0) |
| |
Baseline thyroid function status | |
Normal | 309 (95.1) |
Subclinical hypothyroidism | 13 (4.0) |
Subclinical hyperthyroidism | 3 (0.9) |
Characteristic | Normal thyroid function (n=161) | No overt hypothyroidism (n=139) | Overt hypothyroidism (n=25) | P value | P value |
---|---|---|---|---|---|
Age, yr | 68.6±9.9 | 66.0±11.3 | 65.5±10.1 | 0.076 | |
| |||||
Female sex | 41 (25.5) | 40 (28.8) | 13 (52.0) | 0.025 | |
| |||||
PD-1/PD-L1 inhibitor | 0.592 | ||||
Pembrolizumab | 76 (47.2) | 58 (41.7) | 11 (44.0) | ||
Nivolumb | 54 (33.5) | 52 (37.4) | 11 (44.0) | ||
Durvalumab | 10 (6.2) | 6 (4.3) | 2 (8.0) | ||
Atezolizumab | 21 (13.0) | 23 (16.5) | 1 (4.0) | ||
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Duration of PD-1/PD-L1 inhibitor therapy, mo | 3.0 (1.0–7.0) | 5.0 (1.0–10.0) | 11.0 (5.0–17.5) | <0.001 | |
| |||||
No. of doses of PD-1/PD-L1 inhibitor | 5.0 (3.0–10.5) | 7.0 (3.0–15.0) | 16.0 (8.5–27.5) | <0.001 | |
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Baseline TSH level | 1.70 (1.13–2.34) | 2.04 (1.29–3.32) | 2.74 (1.83–4.73) | <0.001 | |
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Baseline free T4 level | 1.24 (1.15–1.39) | 1.21 (1.10–1.35) | 1.17 (1.07–1.29) | 0.217 | |
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Baseline anti-TPO positivity | 2/45 (4.4) | 2/48 (4.2) | 2/6 (33.3) | 0.015 | |
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Baseline anti-Tg positivity | 1/45 (2.2) | 1/48 (2.1) | 1/6 (16.7) | 0.132 | |
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Follow-up anti-TPO positivity | 2/9 (33.3) | 7/39 (17.9) | 7/18 (38.9) | 0.208 | |
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Follow-up anti-Tg positivity | 1/9 (11.1) | 5/39 (12.8) | 9/18 (50.0) | 0.005 |
Thyroid IRAE | Age, yr/Sex | Cancer | PD-1/PD-L1 inhibitor | Baseline TPO antibody titer, IU/mL | Baseline Tg antibody titer, IU/mL | Follow-up TPO antibody titer, IU/mL | Follow-up Tg antibody titer, IU/mL | Change in TPO antibody positivity | Change in Tg antibody positivity |
---|---|---|---|---|---|---|---|---|---|
OH | 68/M | Kidney | Pembrolizumab | 13.2 | 71.1 | 9.6 | 168.2 | (−) → (+) | (−) → (+) |
OH | 45/F | Melanoma | Nivolumab | 219.0 | 86.6 | 191.1 | 385.2 | (+) → (+) | (−) → (+) |
No-OH | 67/F | Biliary | Pembrolizumab | 66.6 | 14.6 | 24.4 | 0 | (+) → (−) | (−) → (−) |
No-OH | 64/F | Kidney | Pembrolizumab | 7.8 | 11.9 | 5.7 | 23.7 | (−) → (−) | (−) → (−) |
No-OH | 67/M | Liver | Nivolumab | 18.4 | 0 | 25.7 | 0 | (−) → (−) | (−) → (−) |
No-OH | 62/M | Lung | Nivolumab | 6.9 | 0 | 9.7 | 0 | (−) → (−) | (−) → (−) |
No-OH | 59/M | Lung | Nivolumab | 52.6 | 93.6 | 13.0 | 12.0 | (+) → (−) | (−) → (−) |
No-OH | 45/F | Lung | Nivolumab | 7.3 | 11.0 | 10.3 | 0 | (−) → (−) | (−) → (−) |
No-OH | 69/M | Lung | Nivolumab | 11.2 | 86.6 | 5.6 | 0 | (−) → (−) | (−) → (−) |
No-OH | 63/M | Lung | Durvalumab | 0 | 0 | 13.9 | 0 | (−) → (−) | (−) → (−) |
No-OH | 78/M | Lung | Durvalumab | 19.5 | 0 | 42.3 | 0 | (−) → (+) | (−) → (−) |
No-OH | 59/M | Lung | Durvalumab | 20.2 | 0 | 16.1 | 28.1 | (−) → (−) | (−) → (−) |
No-OH | 68/M | Lung | Durvalumab | 0 | 0 | 7.3 | 0 | (−) → (−) | (−) → (−) |
No-OH | 71/M | Lung | Durvalumab | 8.3 | 0 | 12.2 | 0 | (−) → (−) | (−) → (−) |
No-OH | 74/M | Lung | Atezolizumab | 32.1 | 0 | 12.5 | 10.4 | (−) → (−) | (−) → (−) |
No-OH | 57/M | Lung | Atezolizumab | 14.0 | 0 | 27.7 | 0 | (−) → (−) | (−) → (−) |
No-OH | 55/M | Lung | Atezolizumab | 13.5 | 0 | 12.4 | 0 | (−) → (−) | (−) → (−) |
No-OH | 69/F | Lung | Atezolizumab | 9.1 | 178.7 | 7.4 | 457.6 | (−) → (−) | (+) → (+) |
No-OH | 37/M | Lung | Atezolizumab | 13.5 | 0 | 15.8 | 0 | (−) → (−) | (−) → (−) |
Normal thyroid function | 79/F | Lung | Pembrolizumab | 15.5 | 0 | 15.7 | 11.8 | (−) → (−) | (−) → (−) |
Variable | Value |
---|---|
Temporal changes in thyroid function during the follow-up | |
Normal→Thyrotoxicosis→Hypothyroidism | 7 (28.0) |
Normal→Hypothyroidism | 8 (32.0) |
Normal→Subclinical hyperthyroidism→Hypothyroidism | 3 (12.0) |
Normal→Subclinical hypothyroidism→Hypothyroidism | 3 (12.0) |
Subclinical hypothyroidism→Hypothyroidism | 3 (12.0) |
Subclinical hypothyroidism→Thyrotoxicosis→Hypothyroidism | 1 (4.0) |
| |
Time to development of overt hypothyroidism, mo | 3.0 (2.0–4.5) |
| |
Levothyroxine replacement dose, μg/day | 100 (88–125) |
| |
Duration of levothyroxine replacement, mo | 11.0 (4.0–25.5) |
| |
Cancer treatment strategy at the last follow-up | |
Maintenance of PD-1/PD-L1 inhibitor | 9 (36.0) |
Cessation of PD-1/PD-L1 inhibitor | 16 (64.0) |
Change to other treatment modalities | 13 (81.3) |
Best supportive care | 3 (18.8) |
Values are expressed as mean±standard deviation, number (%), or median (interquartile range). PD-1, programmed cell death protein-1; PD-L1, programmed cell death protein-ligand 1.
Values are expressed as mean±standard deviation, number (%), or median (interquartile range). PD-1, programmed cell death protein-1; PD-L1, programmed cell death protein-ligand 1; TSH, thyroid stimulating hormone; T4, thyroxine; TPO, thyroid peroxidase; Tg, thyroglobulin.
PD-1, programmed cell death protein-1; PD-L1, programmed cell death protein-ligand 1; IRAE, immune-related adverse event; TPO, thyroid peroxidase; Tg, thyroglobulin; OH, overt hypothyroidism.
Values are expressed as number (%) or median (interquartile range). PD-1, programmed cell death protein-1; PD-L1, programmed cell death protein-ligand 1.