Background
Nasopharyngeal carcinoma (NPC) is especially endemic in Southern China and Southeast Asia, where the age-standardized incidence is as high as 21 per 100,000 person-years [
1,
2]. In recent decades, the adoption of intensity-modulated radiotherapy (IMRT) and the widespread use of concurrent chemotherapy have substantially improved the prognosis of NPC [
3]. Nevertheless, NPC remains an important cause of cancer-related death, with a global incidence of approximately 50,000 deaths annually [
4].
Immune evasion is a well-researched mechanism of carcinogenesis, and anti-PD-1 monoclonal antibodies have shown efficacy in improving the survival of recurrent or metastatic NPC [
5‐
7]. In studies involving anti-PD-1 immunotherapy, one of the most common immune-related adverse events (irAEs) was thyroid dysfunction [
8‐
13]. And the onset of immune-related thyroid dysfunction is found to be associated with significant improvement in clinical outcomes in lung cancer and melanoma [
14‐
16]. Early-phase clinical studies using anti-PD-1 immune checkpoint inhibitors in recurrent or metastatic NPC have reported incidence rates of hypothyroidism during immunotherapy, which were 18.5% for pembrolizumab [
5], 6.7% for nivolumab [
6], and 32% for camrelizumab [
7]. Cuzzocrea et al. reported that a metastatic NPC patient had hypothyroidism and a concomitant rise in anti-thyroid peroxidase (A-TPO) antibody after treatment with nivolumab and chemoradiotherapy [
17]. Currently, anti-PD-1 monoclonal antibodies are also used in clinical practice to improve the prognosis of newly diagnosed, nonmetastatic NPC. And the performance status, clinical characteristics, combined therapeutic protocol, and clinical outcome of newly diagnosed, nonmetastatic NPC patients are very different from those of recurrent or metastatic NPC patients. Considering the increasing use of anti-PD-1 immunotherapy in nonmetastatic NPC patients, this study aims to illustrate the incidence and clinical course of immune-related thyroid dysfunction and its role as a predictor of survival in nonmetastatic NPC.
Methods
Patients
The medical records of 4003 nonmetastatic NPC patients diagnosed between January 1, 2019, and December 31, 2021, were extracted from the Big Data Intelligence Framework at the Sun Yat-sen University Cancer Centre. The following inclusion criteria were applied: histologically diagnosed NPC based on the World Health Organization criteria and completed chemoradiotherapy (CCRT) or radiotherapy (RT). Among the patients, 786 received at least one dose of PD-1 antibody (i.e., camrelizumab, nivolumab, pembrolizumab, sintilimab, tislelizumab, or toripalimab) during treatment with induction chemotherapy (IC), concurrent chemoradiotherapy (CCRT) or radiotherapy, and 3217 received only IC+CCRT, CCRT or IC+RT. The following exclusion criteria were applied: no normal thyroid function tests within 1 month before treatment; no available thyroid function tests within 2 months after the completion of CCRT or RT; thyroid disease history before treatment; and other malignancies. After review, 165 patients with immunotherapy and 642 patients without immunotherapy were selected. Propensity score matching (PSM) was then used to match the patients who received immunotherapy and the patients who did not receive immunotherapy. Finally, we included 165 patients in the immunotherapy group and 165 patients in the control group. All covariates between the two groups achieved an adequate balance by PSM (Table
1). Additional file
1: Figure S1 shows the patient selection process.
Table 1
Distribution of demographic and clinical characteristics of patients in the control and immunotherapy groups
n | 330 | 165 | 165 | |
Gender, no. (%) | | | | 0.899 |
Male | 246 (74.545) | 124 (75.152) | 122 (73.939) | |
Female | 84 (25.455) | 41 (24.848) | 43 (26.061) | |
Age (median (range)) | 45 (13–71) | 45 (13–71) | 44 (14–71) | 1 |
WHO histology, no. (%) | | | | 1 |
II | 3 (0.909) | 1 (0.606) | 2 (1.212) | |
III | 327 (99.091) | 164 (99.394) | 163 (98.788) | |
T stagea, no. (%) | | | | 0.678 |
T1 | 13 (3.939) | 5 (3.030) | 8 (4.849) | |
T2 | 31 (9.395) | 17 (10.303) | 14 (8.485) | |
T3 | 178 (53.939) | 92 (55.758) | 86 (52.121) | |
T4 | 108 (32.727) | 51 (30.909) | 57 (34.545) | |
N stagea, no. (%) | | | | 0.492 |
N0 | 10 (3.030) | 3 (1.818) | 7 (4.242) | |
N1 | 88 (26.667) | 48 (29.091) | 40 (24.243) | |
N2 | 103 (31.212) | 51 (30.909) | 52 (31.515) | |
N3 | 129 (39.091) | 63 (38.182) | 66 (40.000) | |
TNM stagea, no. (%) | | | | 0.595 |
I | 1 (0.303) | 0 (0.000) | 1 (0.606) | |
II | 9 (2.727) | 4 (2.424) | 5 (3.030) | |
III | 104 (31.515) | 56 (33.939) | 48 (29.091) | |
IVa | 216 (65.455) | 105 (63.637) | 111 (67.273) | |
Pretreatment cfEBV DNA (copies/ml) (median (range)) | 935 (0–395000) | 825 (0–395000) | 940 (0–249000) | 0.507 |
Family historyb, no. (%) | | | | 1 |
Yes | 13 (3.939) | 6 (3.636) | 7 (4.242) | |
No | 317 (96.061) | 159 (96.364) | 158 (95.758) | |
Treatment, no. (%) | | | | 0.1 |
IC+CCRT | 308 (93.333) | 153 (92.727) | 155 (93.940) | |
CCRT | 12 (3.637) | 9 (5.455) | 3 (1.818) | |
IC+RT | 10 (3.030) | 3 (1.818) | 7 (4.242) | |
Treatment
All patients received radical radiotherapy using an intensity-modulated technique. Target volumes were delineated according to the institutional guidelines that complies with
International Commission on Radiation Units and Measurements Reports 50 and 62 [
18,
19]. The prescribed doses were 66–72 grays (Gy)/28–33 fractions to the planning target volume (PTV) of the primary gross tumor volume, 64–70 Gy/28–33 fractions to the PTV of the gross tumor volume of the involved lymph nodes, 60–63 Gy/28–33 fractions to the PTV of the high-risk clinical target volume, and 54–56 Gy/28–33 fractions to the PTV of the low-risk CTV. In this study, of the 330 patients, 308 (93.3%) received IC and CCRT, 12 (3.6%) received IC and RT, and 10 (3.0%) received only CCRT.
The IC regimens comprised one to four cycles of 3-weekly GP, PF, TP, or TPF. The CCRT regimens comprised one to three cycles of 3-weekly cisplatin or nedaplatin. The immunotherapy regimens comprised one to six cycles of 3-weekly camrelizumab, toripalimab, tislelizumab, nivolumab, sintilimab or pembrolizumab. The GP regimen comprised 80 mg/m2 cisplatin on day 1 and 1000 mg/m2 gemcitabine on day 1 and day 8. The PF regimen comprised 75 mg/m2 cisplatin on day 1 and 5-FU 500 mg/m2/day continuously from day 1 to day 5. The TP regimen consisted of 75 mg/m2 docetaxel on day 1 and 75 mg/m2 cisplatin on day 1. The TPF regimen consisted of 60 mg/m2 docetaxel on day 1, 60 mg/m2 cisplatin on day 1, and 500 mg/m2/day 5-FU continuously from day 1 to day 5. The regimens were repeated every 3 weeks for 1–4 cycles. The concurrent chemotherapy regimen consisted of 80–100 mg/m2 cisplatin/nedaplatin administered every 3 weeks for a maximum of three cycles, beginning on the first day of RT. The dose of each cycle of immunotherapy was 200 mg for camrelizumab, tislelizumab, sintilimab, and pembrolizumab; 240 mg for toripalimab; and 360 mg for nivolumab.
Study variables
Thyroid function tests, including thyroid-stimulating hormone (TSH), free T4 (FT4), free T3 (FT3), A-TPO, and thyroglobulin (TG), were measured at the following time points: within 1 month before treatment (before IC), followed every immunotherapy cycle, within 1 month before radiotherapy (before RT), and within 2 months upon radiotherapy completion (after RT).
Thyroid outcomes during treatment were characterized as either (i) normal—normal TSH level and FT4 level within our institutional reference range (TSH: 0.270–4.200 μIU/mL; FT4: 12.000–22.000 pmol/L) throughout treatment—or (ii) thyroid dysfunction—includes hypothyroidism, hyperthyroidism, and biphasic thyroid dysfunction. Hypothyroidism and hyperthyroidism includes clinical type and subclinical type. The clinical hypothyroidism was defined by TSH levels above the upper reference limit with concomitant FT4 levels below the lower reference interval. The subclinical hypothyroidism was defined by TSH levels above the upper reference limit with normal FT4 levels. Clinical hyperthyroidism was defined by TSH levels below the lower reference interval with concomitant FT4 levels above the upper reference interval. Subclinical hyperthyroidism was defined by TSH levels below the lower reference interval with normal FT4 levels. Biphasic thyroid dysfunction was defined by transient hyperthyroidism followed by hypothyroidism. In addition, our institutional reference range for A-TPO is 0–35 U/mL. Patients were considered to have positive A-TPO if their A-TPO was higher than 35 U/mL at any point during surveillance.
Patient demographic and clinical characteristics included gender, age, WHO histology, T stage, N stage, TNM Stage, pretreatment cfEBV DNA, treatment, IC cycles, IC regimens, CCRT cycles, immunotherapy regimens, and immunotherapy cycles. The stage was according to the 8th edition of the American Joint Commission on Cancer (AJCC) staging system. The cfEBV DNA were measured using a real-time quantitative polymerase chain reaction assay amplifying the
BamHI-W region of the EBV genome, as previously described [
20,
21]. The pretreatment cfEBV was examined within 1 month before treatment and the posttreatment cfEBV was examined within 3 months after radiotherapy.
Statistical analysis
The data are summarized as frequencies and percentages for categorical variables and as medians and ranges for continuous variables. The chi-square test or Fisher’s exact test was used to compare categorical variables, and the Kruskal–Wallis test was used for continuous variables. Median levels of TSH and anti-thyroid antibody levels were characterized over time. Univariable and multivariable tests of association between thyroid dysfunction and the complete biological response (cBR; defined as undetectable cfEBV DNA) posttreatment were performed using Logistic regression. Patient demographic and clinical characteristics (gender, age, WHO histology, T stage, N stage, TNM Stage, pretreatment EBV DNA, treatment, IC cycles, IC regimens, CCRT cycles, immunotherapy regimens, and immunotherapy cycles) were included as covariates in the multivariable Logistic regression. Tests were two-sided, and
P values < 0.05 were considered significant. All analyses were performed with R version 3.4.4 (
http://www.r-project.org).
Discussion
This is the first study to explore the incidence and clinical features of thyroid dysfunction and its role as a survival predictor in newly diagnosed, nonmetastatic NPC patients treated with anti-PD-1 immunotherapy. In this study, we found patients in the immunotherapy group developed more hypothyroidism, less hyperthyroidism, and a distinct pattern, biphasic thyroid dysfunction. Immunotherapy also accelerates the development of hypothyroidism. The early elevation of A-TPO without aberrant TSH and FT4 may be a predictive marker for biphasic thyroid dysfunction, a distinct pattern only observed in patients receiving immunotherapy. It is notable that there is an association between the development of thyroid dysfunction and cBR in the immunotherapy group but not in the control group. Therefore, immune-related thyroid dysfunction could be an indicator for better survival but non-immune-related thyroid dysfunction could not.
Our study reported a higher incidence rate of thyroid dysfunction than most other studies. In retrospective studies assessing antibody-mediated thyroid dysfunction, the reported incidence rates were 14.290%, 21%, and 28.380% in non-small-cell lung carcinoma (NSCLC) and 17.780%, 18.180%, and 27.450% in metastatic melanoma. In anti-PD-1 clinical trials for recurrent or metastatic NPC, the range of incidence rates of hypothyroidism during immunotherapy was wide, from 6.700 to 32%. Only one case of hyperthyroidism was reported in the camrelizumab clinical trial for recurrent or metastatic NPC. In anti-PD-1 clinical trials for NSCLC, melanoma, and renal cell carcinoma, the incidence rates of thyroid dysfunction range from 2.500 to 14%, with a mean rate of 5.900% for hypothyroidism and 3.300% for hyperthyroidism [
24‐
29]. The relatively high incidence of thyroid dysfunction in newly diagnosed, nonmetastatic NPC was likely the result of unavoidable irradiation of the thyroid gland during radiotherapy, which may render the thyroid gland more susceptible to autoimmunity [
30,
31]. Compared with the control group, the incidence of hyperthyroidism is lower in the immunotherapy group (23.636% vs. 10.909%,
P = 0.002). As three quarters of hyperthyroidism in the control group was subclinical, the hyperthyroidic effect of radiation during treatment was not strong. The incidences of clinical hyperthyroidism were similar between the two groups (4.242% vs. 4.848%,
P = 0.792). In the immunotherapy group, thyroid glands suffer damages from both radiation and PD-1 blockade. The incidence of clinical thyroid dysfunction was higher in the immunotherapy group (14.545% vs. 7.273%,
P = 0.034), which indicates strong damage from PD-1 blockade. Since hypothyroidism is the main form of immune-related thyroid dysfunction, the strong hypothyroidic effect from PD-1 blockade in the immunotherapy group may overwhelm the hyperthyroidic effect of radiation and induce the occurrence of hypothyroidism in vulnerable thyroid glands. Therefore, the immunotherapy group has lower incidence of hyperthyroidism than the control group.
Of note, 3.03% of patients in the immunotherapy group developed a distinct pattern of thyroid dysfunction and transient hyperthyroidism followed by hypothyroidism, which was not observed in the control group. This pattern of thyroid dysfunction resembles thyroiditis and was also reported in patients with other cancers who received anti-PD-1 immunotherapy [
13,
15,
32‐
34]. In this study, we found that all of these patients had positive A-TPO and overt hypothyroidism. In biphasic thyroid dysfunction, the onset of A-TPO was earlier than that of transient hyperthyroidism; however, in hypothyroidism and hyperthyroidism, the onset of A-TPO coincided with thyroid dysfunction. The median number of immunotherapy cycles between the introduction of immunotherapy and the presence of A-TPO in biphasic thyroid dysfunction was 2, earlier than that in normal thyroid function (4 cycles), hypothyroidism (4 cycles), and hyperthyroidism (3 cycles). Therefore, we hypothesized that the early elevation of A-TPO without aberrant TSH and FT4 may be a predictive marker for biphasic thyroid dysfunction.
One of the shortcomings of our study is the limited total duration of follow-up. On the one hand, the relatively short follow-up time hindered the exploration of the relationship between immune-related thyroid dysfunction and survival outcome. Instead, we used cBR, a widely recognized survival marker for NPC, to indirectly explore the relationship between thyroid dysfunction and survival. On the other hand, the incidence rates of thyroid dysfunction and positive rates of A-TPO may be underestimated. In particular, the occurrence of hypothyroidism after hyperthyroidism may be missed since the long-term pattern of thyroid function was not observed. Therefore, in our future study, we will extend the follow-up time to address these questions. Another limitation is that the 3-week interval of surveillance of thyroid function may be too long, and some abnormalities may be missed, especially when the sample size is small. Nevertheless, in our study, the overall changes in thyroid function can still be reflected due to the relatively large sample size. A notable advantage of our study over previous studies is our relatively large sample size [
13,
15,
32,
34]. In addition, previous studies have focused on NSCLC and melanoma, in which anti-PD-1 immunotherapy has been extensively used; this is the first study to focus on nonmetastatic NPC, in which anti-PD-1 immunotherapy is still in the clinical trial stage.
Conclusions
In conclusion, in newly diagnosed, nonmetastatic NPC patients, thyroid dysfunction is common during treatment. Compared with conventional treatment, anti-PD-1 immunotherapy changed the spectrum of thyroid dysfunction and accelerates the onset of hypothyroidism. Acquired thyroid dysfunction is a predictor for better response to immunotherapy but not for routine treatment. Therefore, as a potential predictor for survival, thyroid function should be under regular and intensive surveillance in clinical practice of anti-PD-1 immunotherapy in nonmetastatic NPC patients.
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