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Effects of cabozantinib on plasma adrenocorticotropic hormone and serum cortisol levels in patients with metastatic renal cell carcinoma: a retrospective study
Yuji Hataya1*, Mayuka Kurata1, Kimiaki Murabe1, Takuro Hakata2, Kanta Fujimoto1, Toshio Iwakura1, Toshinari Yamasaki3 and Naoki Matsuoka1
Abstract
Background Tyrosine kinase inhibitors (TKIs) are widely used to treat various solid tumors; however, adverse events, such as fatigue and anorexia, remain significant concerns. TKI-induced primary adrenal insufficiency (PAI) is a potential cause of these symptoms; however, its pathophysiology remains unclear. To better understand TKI-induced PAI, we conducted a retrospective study to investigate the effects of TKI on adrenocortical function.
Methods We analyzed the plasma adrenocorticotropic hormone (ACTH) and serum cortisol levels in 18 patients with metastatic renal cell carcinoma (mRCC) treated with cabozantinib (CABO). Patients with plasma ACTH levels exceeding 63.3 pg/mL on at least two occasions were classified into the high ACTH group (High group), whereas the remaining patients were assigned to the normal ACTH group (Normal group). The clinical characteristics of the two groups were compared.
Results The High group consisted of eight patients, whereas the Normal group included ten. In the High group, plasma ACTH levels increased after CABO administration, remained elevated during treatment, and decreased after discontinuation, whereas serum cortisol levels remained within the normal range. Plasma ACTH levels in the High group significantly increased from pre-treatment values of 27.6 (16.9-52.1) pg/mL to median values of 91.4 (82.1- 101.1) pg/mL during treatment (p<0.01). Similarly, plasma ACTH levels in the Normal group showed a slight increase from pre-treatment values of 31.1 (25.5-40.9) pg/mL to median values of 46.3 (33.5-50.7) pg/mL during treatment (p <0.05). Fatigue and anorexia were reported in seven and six patients in the High and Normal group, respectively. Three patients in the High group were diagnosed with PAI based on ACTH stimulation tests. These patients experienced prompt symptom improvement following hydrocortisone administration and continued the treatment. No significant differences in the clinical characteristics at CABO initiation were observed between the groups.
Conclusions CABO administration may affect adrenocortical function in patients with mRCC and contribute to symptoms such as fatigue and anorexia. Although TKI-induced PAI represents a mild form, appropriate diagnosis and
*Correspondence:
Yuji Hataya yhataya@kcho.jp
Full list of author information is available at the end of the article
☒ BMC
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hydrocortisone administration alleviate the symptoms and support the continuation of treatment. It is important to monitor adrenocortical function and conduct ACTH stimulation tests for early diagnosis and management of PAI.
Clinical trial number Not applicable.
Keywords Tyrosine kinase inhibitor, Immune checkpoint inhibitor, Cabozantinib, Nivolumab, Primary adrenal insufficiency, Fatigue, Anorexia
Background
Tyrosine kinase inhibitors (TKIs) targeting vascular endothelial growth factor receptors (VEGFRs) are widely used to treat various solid tumors. Although these agents are effective, they can cause adverse events, including fatigue and anorexia, which require dose adjustment or treatment interruption. Recently, TKI-induced pri- mary adrenal insufficiency (PAI) has been reported as a potential cause of these symptoms. A small case series of patients with thyroid cancer treated with TKIs reported that approximately 50% were diagnosed with PAI based on adrenocorticotropic hormone (ACTH) stimulation tests [1-3]. Fatigue was the most common symptom, which improved rapidly with glucocorticoid replacement therapy. These patients tested negative for anti-adrenal cortex antibodies, and no morphological changes in the adrenal glands were observed on follow-up computed tomography (CT) imaging.
Immune checkpoint inhibitors (ICIs) are known to induce adrenal insufficiency (AI) as an immune-related adverse event (irAE) [4]. ICI-related AI typically presents as a secondary AI, whereas ICI-induced PAI is extremely rare, occurring in <0.1% of patients [5]. ICI-induced PAI has been reported to be associated with endocrine irAEs, such as ICI-induced diabetes and thyroid disorders [6], as well as the presence of anti-adrenal cortex antibodies [7]. In these patients, progressive adrenal gland atrophy can be observed on CT imaging, and adrenocortical function can irreversibly decline [4]. During ICI treatment, regular monitoring of plasma ACTH and serum cortisol levels is recommended for early detection of AI [8]. In contrast, the effects of TKIs on altered plasma ACTH and serum cortisol levels have not been fully elucidated, and regular monitoring is not currently recommended.
We encountered a case of PAI in a patient with meta- static renal cell carcinoma (mRCC) undergoing com- bination therapy with nivolumab (NIVO), an ICI, and cabozantinib (CABO), a TKI. Based on the clinical findings and treatment course, CABO was considered the most likely cause of PAI in this patient. To bet- ter understand the pathophysiology of TKI-induced PAI, we conducted a retrospective study to evaluate the effects of CABO on adrenocortical function by assessing the plasma ACTH and serum cortisol levels in similar patients.
Methods
This retrospective study used the medical records of 42 patients with mRCC treated with CABO at Kobe City Medical Center General Hospital, Japan, between 1 April 2020 and 30 April 2024. After excluding 14 patients due to insufficient data, four received steroid treatment, five underwent treatment for AI, one had elevated plasma ACTH levels above the reference range before CABO administration, and 18 patients were included in the final analysis. The patient characteristics at the start of CABO treatment are summarized in Table 1. For compara- tive analysis, we classified patients into two groups: the high ACTH group (High group), consisting of patients whose plasma ACTH levels exceeded the upper normal limit (63.3 pg/mL) at least twice during CABO treatment, and the normal ACTH group (Normal group), which included all remaining patients.
This study was approved by the Research Ethics Com- mittee of Kobe City Medical Center General Hospital (approval no. zn250110) and was conducted in accor- dance with the principles of the Declaration of Helsinki. The requirement for informed consent was waived by the Research Ethics Committee of Kobe City Medical Center General Hospital, given the retrospective nature of this study.
Adrenocortical function was assessed using blood samples collected during morning outpatient visits. Plasma ACTH and serum cortisol levels were measured using electrochemiluminescence immunoassay (ECLu- sys ACTH and cortisol II kit, Roche Diagnostics, Tokyo, Japan). The standard institutional reference ranges for morning plasma ACTH and serum cortisol were 7.2- 63.3 pg/mL and 7.1-19.6 µg/dL, respectively.
The 250-µg ACTH stimulation test, considered the gold standard, was performed for PAI diagnosis. Corti- sol responsiveness was considered sufficient if the peak serum cortisol level at 30 or 60 min after ACTH admin- istration exceeded 18 µg/dL [9]. PAI was diagnosed based on both a reduced cortisol response to the ACTH stimu- lation test and clinical findings. For patients diagnosed with PAI, additional testing for anti-adrenal cortex anti- bodies was performed (Quest Diagnostics, San Capist- rano, CA, USA).
| All patients | High group | Normal group | P | |
|---|---|---|---|---|
| n=18 | n=8 | n=10 | ||
| Age, y | 70.5 (66.3-76.3) | 71.0 (69.8-75.5) | 69.0 (60.8-75.8) | NS |
| Women, n (%) | 5 (27.8) | 3 (37.5) | 2 (20.0) | NS |
| ACTH (pg/mL) | 30.8 (20.7-44.1) | 27.6 (16.9-52.1) | 31.1 (25.5-40.9) | NS |
| cortisol (ug/dL) | 10.9 (9.7-12.9) | 10.0 (9.3-12.7) | 11.4 (10.3-12.9) | NS |
| Metastatic sites, n (%) * | NS | |||
| bone | 9 (50.0) | 5 (62.5) | 4 (40.0) | |
| lung | 11 (61.1) | 5 (62.5) | 6 (60.0) | |
| adrenal | 5 (27.8) | 2 (25.0) | 3 (30.0) | |
| others | 8 (44.4) | 4 (50.0) | 4 (40.0) | |
| Surgical procedure before CABO treatment, n (%) * | NS | |||
| partial nephrectomy | 11 (61.1) | 3 (37.5) | 8 (80.0) | |
| total nephrectomy | 4 (22.2) | 2 (25.0) | 2 (20.0) | |
| adrenalectomy | 1 (5.6) | 1 (12.5) | 0 (0) | |
| no surgery | 3 (16.7) | 3 (37.5) | 0 (0) | |
| Line of CABO Treatment, n (%) | NS | |||
| first-line | 6 (33.3) | 4 (50.0) | 2 (20.0) | |
| second-line and later | 12 (66.7) | 4 (50.0) | 8 (80.0) | |
| Treatment regimen, n (%) | NS | |||
| combination therapy* | 7 (38.9) | 4 (50.0) | 3 (30.0) | |
| monotherapy ** | 11 (61.1) | 4 (50.0) | 7 (70.0) | |
| Medical History | ||||
| ICI, n (%) | 12 (66.7) | 4 (50.0) | 8 (80.0) | NS |
| Nivolmab | 2 (11.1) | 0 (0) | 2 (20.0) | |
| Pembrolizumab | 3 (16.7) | 0 (0) | 3 (30.0) | |
| Ipilimumab+Nivolmab | 2 (11.1) | 2 (25.0) | 0 (0) | |
| Avelumab | 5 (27.8) | 2 (25.0) | 3 (30.0) | |
| TKI, n (%) * | 11 (61.1) | 3 (37.5) | 8 (80.0) | NS |
| Axitinib | 11 (61.1) | 3 (37.5) | 8 (80.0) | |
| Pazopanib | 2 (11.1) | 0 (0) | 2 (20.0) | |
| Thyroid antibody, n (%) | 3/14 (21.4) | 2/6 (33.3) | 1/8 (12.5) | NS |
| Endocrine irAEs, n (%) | 3 (16.7) | 3 (37.5) | 0 (0) | NS |
| thyroid dysfunction | 2 (11.1) | 2 (25.0) | 0 (0) | |
| diabetes mellitus | 1 (5.6) | 1 (12.5) | 0 (0) |
Data are expressed as median (interquartile range) and n (%). P-values are derived by comparing the High and Normal groups. ACTH, adrenocorticotropic hormone; CABO, cabozantinib; ICI, immune checkpoint inhibitor; irAE, immune-related adverse event; n, number of patients; NIVO, nivolumab; NS, not significant; TKI, tyrosine kinase inhibitor. * Including duplicates; # CABO and NIVO; CABO
Statistical analyses
Continuous data were expressed as median values with interquartile ranges (IQR) and categorical data as num- bers. Parameters between the two groups were compared using the Mann-Whitney U test or Pearson’s chi-square tests. Statistical significance was set at p<0.05. Statisti- cal analyses were performed using the Statistical Package for the Social Sciences version 27.0 (IBM SPSS 27.0; IBM Corp., Armonk, NY, USA).
Results Case presentation
A 72-year-old man was initiated on combination ther- apy with NIVO and CABO in January 2022 for RCC with multiple metastases to the bones, lungs, liver, and lymph nodes. He was referred to our department in
January 2024 after routine monitoring for irAE following NIVO treatment revealed thyroid dysfunction. Labora- tory tests showed a serum thyroid-stimulating hormone (TSH) level of 16.00 mIU/L (reference range: 0.61-4.23 mIU/L), a serum-free triiodothyronine level of 2.15 pg/ mL (reference range: 2.30-4.00 pg/mL), and a serum-free thyroxine level of 1.11 ng/dL (reference range: 0.90-1.70 ng/dL). Thyroid autoantibodies were mildly elevated, with a thyroglobulin antibody level of 30 IU/mL (refer- ence range: 0-27 IU/mL) and a thyroid peroxidase anti- body level of<9 IU/mL (reference range: 0-15 IU/mL), whereas thyroid ultrasound findings were normal.
Further interviews revealed that the patient had expe- rienced fatigue, appetite loss, and 10-kg weight loss since January 2023, which coincided with an increase in
nephrectomy
fatigue, anorexia, and weight loss HC (mg)
10
CABO (mg)
20
30
40
30
40
20
NIVO
200
ACTH (pg/mL)
150
100
50
0
30
cortisol (µg/dL)
20
10
0
20
TSH (µU/mL)
10
0
X-2/1
4
7
10
X-1/1
4
7
10
X/
1
4
7
10
| Time (min) | |||||
|---|---|---|---|---|---|
| 0 | 30 | 60 | |||
| Patient 1 | 4 days after CABO | ACTH (pg/mL) | 21.4 | ||
| discontinuation | cortisol (µg/dL) | 11.5 | 15.7 | 15.1 | |
| Patient 2 | Undergoing CABO | ACTH (pg/mL) | 74.8 | ||
| treatment | cortisol (µg/dL) | 8.7 | 12.1 | 12.6 | |
| Patient 3 | Undergoing CABO | ACTH (pg/mL) | 58.5 | ||
| treatment | cortisol (µg/dL) | 8.2 | 12.4 | 13.0 | |
| 4 months after CABO | ACTH (pg/mL) | 27.1 | |||
| discontinuation | cortisol (ug/dL) | 6.3 | 11.8 | 13.5 | |
Patient 1 corresponds to the 72-year-old case referred to our department. ACTH, adrenocorticotropic hormone; CABO, cabozantinib
the CABO dosage. Before CABO treatment, the patient exhibited low plasma ACTH and elevated serum cortisol levels; however, there was no evidence of autonomous cortisol secretion. These findings were most likely due to a transient fluctuation related to sampling conditions. After administration of NIVO and CABO, the plasma ACTH levels of the patient persistently ranged from 80 to 160 pg/mL, whereas serum cortisol levels remained within the normal range (Fig. 1). The patient received denosumab injections and chewable combination tablets containing calcium carbonate, magnesium carbonate, and trisodium citrate hydrate for bone metastases and febuxostat for hyperuricemia. The patient had no history of steroid use. On physical examination, his height was 160.5 cm, weight was 45.5kg, and body mass index was
17.7kg/m2. His blood pressure was 122/85 mmHg, and his pulse rate was 70 beats per minute.
Four days after discontinuing CABO, an ACTH stim- ulation test revealed a reduced cortisol response, with serum cortisol levels increasing only from 11.5 to 15.7 µg/ dL (Table 2). CT imaging revealed no abnormalities in the adrenal glands throughout the course, and anti-adre- nal cortex antibodies remained negative. The symptoms improved promptly following hydrocortisone (HC) 10mg administration. The patient subsequently underwent right nephrectomy. Plasma ACTH levels decreased dur- ing the suspension of NIVO and CABO but increased again upon resumption of therapy. Serum TSH levels were normalized following HC administration. With con- tinued HC administration, the patient’s fatigue and appe- tite loss resolved, allowing continuation of NIVO and CABO combination therapy.
In this case, PAI was diagnosed based on a reduced cor- tisol response in the ACTH stimulation test and prompt symptom improvement following HC administration. Elevated plasma ACTH levels were observed after both NIVO and CABO administration, suggesting poten- tial involvement of both drugs. Typically, ICI-related AI presents as a secondary AI, while ICI-induced PAI is extremely rare [5]. Reported cases of ICI-induced PAI are characterized by progressive adrenal atrophy, irreversible adrenocortical dysfunction, or the presence of anti-adre- nal cortex antibodies [4, 7]. Based on the clinical findings and treatment course, CABO was considered the most
likely cause of PAI in this patient; however, its underlying pathophysiology remains unclear. To further investigate TKI-induced PAI, we conducted a retrospective study to evaluate the effects of CABO on adrenocortical function.
Analysis of changes in adrenocortical function after CABO administration in patients with mRCC
We analyzed 18 patients with mRCC treated with CABO at our institution. After CABO administration, two dis- tinct patterns were observed: one group exhibited per- sistently elevated plasma ACTH levels (High group), whereas the other maintained levels within the normal range (Normal group). The High group consisted of eight patients, whereas the Normal group included ten. In the High group, plasma ACTH levels increased after CABO
administration and remained elevated throughout the treatment, whereas serum cortisol levels remained within the normal range (Fig. 2). Patient 1 corresponds to the 72-year-old case referred to our department.
To identify changes in adrenocortical function before and after CABO administration, we compared the pre- treatment values to the median values observed during treatment (Fig. 3). In the High group, plasma ACTH lev- els significantly increased from 27.6 (16.9-52.1) pg/mL pre-treatment to 91.4 (82.1-101.1) pg/mL during treat- ment (p<0.01), whereas serum cortisol levels remained unchanged from 10.0 (9.3-12.7) µg/dL pre-treatment to 10.8 (10.5-12.9) µg/dL during treatment. In the Normal group, plasma ACTH levels showed a slight but signifi- cant increase from 31.1 (25.5-40.9) pg/mL pre-treatment
High group
Normal group
200
200
150
150
ACTH (pg/mL)
ACTH (pg/mL)
100
100
50
50
0
0
0
12
24
36
48
60
72
84
96
108
120
0
12
24
36
48
60
72
84
96
108
120
weeks
weeks
30
30
25
25
cortisol (ug/dL)
20
cortisol (ug/dL)
20
15
15
10
10
5
5
0
0
0
12
24
36
48
60
72
84
96
108
120
0
12
24
36
48
60
72
84
96
108
120
weeks
weeks
1
2
3
4
1
2
3
4
5
5
6
7
8
6
7
8
9
10
High group
Normal group
ACTH (pg/mL)
cortisol (ug/dL)
ACTH (pg/mL)
cortisol (µg/dL)
200
30
200
30
P < 0.01
25
N.S.
P < 0.05
25
N.S.
1
150
1
150
2
20
2
20
3
3
4
100
15
4
100
15
5
5
6
10
6
10
7
50
7
50
8
5
8
5
9
10
0
0
0
0
pre-treatment
during treatment
pre-treatment
during treatment
pre-treatment
during treatment
pre-treatment
during treatment
200
30
25
150
ACTH (pg/mL)
cortisol (µg/dL)
20
100
15
10
50
5
0
0
0
3
6
9
12
15
18
21
0
3
6
9
12
15
18
21
weeks
weeks
1
3
4
1
3
4
6
7
6
7
to 46.3 (33.5-50.7) pg/mL during treatment (p<0.05), whereas serum cortisol levels remained unchanged from 11.4 (10.3-12.9) µg/dL pre-treatment to 11.4 (9.1-12.3) ug/dL during treatment. Four of the five patients in the High group available for follow-up after CABO discon- tinuation exhibited a decrease in plasma ACTH levels (Fig. 4). The remaining patient (Patient 7) did not show a decrease; however, this patient had received another TKI at the time of measurement.
ACTH stimulation tests were performed in three patients (Patients 1-3) in the High group (Table 2).
Patient 1 was tested 4days after CABO discontinua- tion, whereas patients 2 and 3 were tested during CABO treatment. All three patients exhibited a reduced cortisol response. In patient 3, a repeat ACTH stimulation test was performed 4months after CABO discontinuation due to disease progression, but no improvement in the cortisol response was observed. All three patients expe- rienced prompt symptom improvement following oral HC (5-10mg/day) administration. CT imaging revealed no evidence of adrenal atrophy throughout the course, and anti-adrenal cortex antibodies remained negative.
| All patients | High group | Normal group | P | |
|---|---|---|---|---|
| n=18 | n=8 | n=10 | ||
| Treatment period (weeks) | 56.1 | 59.4 | 55.0 | NS |
| (39.8-92.4) | (47.1- | (35.0- | ||
| 83.5) | 98.6) | |||
| Symptoms of fatigue and anorexia, n (%) | 13 (72.2) | 7 (87.5) | 6 (60.0) | NS |
| Reasons for CABO | NS | |||
| discontinuation | ||||
| progression disease, n (%) | 7 (38.9) | 4 (50.0) | 3 (30.0) | |
| symptom, n (%) | 1 (5.6) | 1 (12.5) | 0 (0) | |
| death due to other causes, n (%) | 1 (5.6) | 0 (0) | 1 (10.0) | |
| continuation of CABO, n (%) | 9 (50.0) | 3 (37.5) | 6 (60.0) |
Data are expressed as median (interquartile range) and n (%). P-values were compared between the high and normal groups. CABO, cabozantinib; n, number of patients; NS, not significant
At the time of PAI diagnosis, all patients had normal serum sodium and potassium levels, and none exhibited hypotension.
We compared the clinical characteristics of the High and Normal groups at the time of CABO initiation (Table 1). No significant differences were observed between the two groups regarding age, sex, plasma ACTH and serum cortisol levels, metastatic sites, prior surgical procedures, presence of adrenal metastasis, or history of adrenalec- tomy. CABO was administered as the first-line therapy in six patients, all in combination with NIVO. Among the 12 patients who received CABO as a second-line or later therapy, 11 were treated with CABO monotherapy. All patients receiving CABO as a second-line or later therapy had prior exposure to ICI, and 11 had prior use of TKI. However, these factors did not differ significantly between the High and Normal groups. Thyroid autoanti- bodies were detected in three patients in the High group but in none of the patients in the Normal group, whereas endocrine irAEs were observed in three and one patient, respectively, with no significant differences between the groups.
Fatigue and anorexia during CABO treatment were more common in the High group, affecting seven patients (87.5%), compared to six patients (60.0%) in the Normal group (Table 3). Of the seven patients in the High group, three patients with a reduced cortisol response to the ACTH stimulation test experienced prompt symptom improvement following HC administration and were able to continue treatment. However, the remaining three patients who did not receive HC continued treatment despite experiencing persistent fatigue and anorexia, whereas one patient had to discontinue CABO due to severe fatigue.
Discussion
In this study, we retrospectively analyzed 18 patients with mRCC treated with CABO and identified two distinct ACTH response patterns. In the High group, plasma ACTH levels considerably increased during treatment, whereas serum cortisol levels remained within the nor- mal range. Furthermore, all three patients who under- went ACTH stimulation testing showed a reduced cortisol response and experienced prompt symptom improvement following oral HC administration, which allowed them to continue CABO treatment.
Stressful conditions, such as fatigue and anorexia during CABO treatment, may have contributed to the observed elevation in plasma ACTH levels. Nevertheless, three patients in the High group were diagnosed with PAI based on a reduced cortisol response to the ACTH stimulation test and prompt symptom improvement following HC administration. Despite elevated plasma ACTH levels, the serum cortisol levels remained within the normal range, suggesting that TKI-induced PAI may be a mild form of AI. These findings are consistent with previously reported cases of TKI-induced PAI in patients with thyroid cancer [1-3]. Additionally, the remaining patients in the High group exhibited persistently elevated plasma ACTH levels despite normal serum cortisol lev- els, suggesting potential adrenal dysfunction. However, as ACTH stimulation tests were not performed in these patients, the presence of PAI remains uncertain.
A previous prospective study investigating TKI- induced PAI reported that approximately half of the patients developed PAI within 12 months, whereas the remaining patients developed PAI after 12months of treatment [3]. In the High group, plasma ACTH levels increased rapidly after CABO administration, remained elevated throughout the treatment, and decreased after discontinuation. In the Normal group, the plasma ACTH levels increased slightly after CABO administration. An increase in ACTH levels during TKI treatment has been reported to be a predictor of future PAI development [3]. Moreover, in the same study, certain patients with nor- mal plasma ACTH and serum cortisol levels were diag- nosed with subclinical PAI based on ACTH stimulation tests [3]. These findings suggest that certain patients in the Normal group may have undetected subclinical PAI or may be at risk of developing overt PAI in the future.
The three patients diagnosed with PAI showed no clini- cal signs of AI apart from fatigue or anorexia. Addition- ally, their normal serum cortisol levels made PAI difficult to detect. However, these patients experienced prompt symptom improvement following HC administration and were able to continue treatment. In contrast, the remain- ing patients in the High group continued treatment despite experiencing persistent fatigue and anorexia, although one patient had to discontinue CABO due to
severe fatigue. Monitoring adrenocortical function is rec- ommended for patients receiving ICIs [8] but not those undergoing TKI treatment. The findings of this study emphasize the need to monitor adrenocortical function and conduct ACTH stimulation tests in patients treated with TKIs.
No significant differences in the clinical character- istics at the start of CABO treatment were observed between the High and Normal groups in this study. However, a study that extracted data from the Food and Drug Administration Adverse Event Reporting System reported a higher incidence of primary or secondary AI attributed to TKIs in patients receiving combination therapy with ICIs [10]. In our study, 11 patients received CABO monotherapy and 7 received ICI combination therapy, with no significant differences in treatment regi- mens between the High and Normal groups. Neverthe- less, due to the limited sample size, further studies are needed to determine whether combination therapy with ICIs increases the risk of TKI-induced PAI.
The primary mechanism underlying TKI-induced PAI involves capillary microvascular damage. VEGFRs are highly expressed in the fenestrated capillaries of endo- crine organs, including adrenal glands. Studies in mice have demonstrated capillary regression and loss of fenes- trated capillary structures in the thyroid after administra- tion of an anti-VEGF inhibitor, with subsequent recovery of the capillary network after treatment discontinuation [11, 12]. Additionally, preclinical studies of sunitinib have reported adrenocortical hypertrophy, inflammation, con- gestion, hemorrhage, and necrosis in rats and monkeys exposed to the drug [13]. A clinical study on lenvatinib in patients with thyroid cancer have documented recov- ery of the cortisol response in ACTH stimulation tests in one patient after drug discontinuation [2]. However, in the current study, no recovery of the cortisol response was observed in any patient after the discontinuation of CABO in the ACTH stimulation test. Further studies involving larger cohorts are needed to clarify the revers- ibility of TKI-induced PAI.
This study has certain limitations. First, the small sam- ple size necessitated cautious interpretation. Second, the study focused exclusively on patients with mRCC receiv- ing CABO, limiting its applicability to other cancer types or TKIs. Third, as a retrospective study, it was subject to inherent bias. Adrenocortical function tests were not routinely performed in all patients receiving TKI mono- therapy, leading to a relatively high number of patients receiving combination therapy with ICI who underwent irAE monitoring. Moreover, only three patients in the High group underwent ACTH stimulation tests, prevent- ing diagnosis of PAI in the remaining patients. Addition- ally, we could not evaluate adrenocortical function using an ACTH stimulation test before TKI treatment, which
limited our ability to determine preexisting AI. Fourth, the CABO dose varied throughout the treatment course, which may have influenced our results. Fifth, in this study, we adopted a cortisol cutoff value of 18 µg/dL for the 250-µg ACTH stimulation test, in accordance with conventional guidelines [9]. However, more sensitive cor- tisol assays have been introduced, and a lower cutoff of approximately 15 µg/dL has been proposed for the diag- nosis of PAI [14]. Future prospective studies with larger cohorts across diverse cancers and TKIs are needed to clarify the diagnosis and clinical features of TKI-induced PAI using these newer cutoff values.
Conclusions
Stressful conditions during CABO treatment may lead to elevated plasma ACTH levels. However, CABO admin- istration itself may also affect adrenocortical function in patients with mRCC and contribute to symptoms such as fatigue and anorexia. HC administration may lead to prompt symptom improvement and allow treatment continuation. It is necessary to monitor adrenocortical function and conduct ACTH stimulation tests for early diagnosis and appropriate management of PAI. Future comprehensive prospective studies are needed to estab- lish more effective strategies for managing TKI-induced PAI and optimizing treatment outcomes.
Abbreviations
| ACTH | Adrenocorticotropic hormone |
| CABO | Cabozantinib |
| CT | Computed tomography |
| HC | Hydrocortisone |
| ICI | Immune checkpoint inhibitor |
| IQR | Interquartile range |
| irAE | Immune-related adverse event |
| mRCC | Metastatic renal cell carcinoma |
| NOVO | Nivolumab |
| PAI | Primary adrenal insufficiency |
| TKI | Tyrosine kinase inhibitor |
| TSH | Thyroid-stimulating hormone |
| VEGFR | Vascular endothelial growth factor receptor |
Acknowledgements
We would like to thank Editage (www.editage.com) for English language editing.
Author contributions
All authors contributed to the conception and design of this study. YH prepared the materials, collected data, and wrote the first draft of the manuscript. YH and MK prepared the figures. All authors commented on the previous versions of the manuscript. All the authors have read and approved the final version of the manuscript.
Funding
This study did not receive any funding.
Data availability
The datasets analyzed in the current study are available from the corresponding author upon request.
Declarations
Ethics approval and consent to participate
This study was performed in accordance with the principles of the Declaration of Helsinki. This study was approved by the Ethics Committee of the Kobe City Medical Center General Hospital (Approval No. zn250110). The requirement for informed consent was waived by the Research Ethics Committee of Kobe City Medical Center General Hospital due to the retrospective nature of this study.
Consent for publication
Not applicable.
Competing interests
The authors declare no competing interests.
Author details
1Department of Diabetes and Endocrinology, Kobe City Medical Center General Hospital, 2-1-1, Minatojima Minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, Japan 2Department of Diabetes, Endocrinology and Nutrition, Kyoto University Graduate School of Medicine Faculty of Medicine, Kyoto, Japan 3Department of Urology, Kobe City Medical Centre General Hospital, Kobe, Japan
Received: 3 May 2025 / Accepted: 7 October 2025 Published online: 04 November 2025
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