Research ArticleClinical Studies

Adrenal Insufficiency Related to Anti-Programmed Death-1 Therapy

RYO ARIYASU, ATSUSHI HORIIKE, TAKAHIRO YOSHIZAWA, YOSUKE DOTSU, JUNJI KOYAMA, MASAFUMI SAIKI, TOMOAKI SONODA, SHINGO NISHIKAWA, SATORU KITAZONO, NORIKO YANAGITANI and MAKOTO NISHIO
Anticancer Research August 2017, 37 (8) 4229-4232;

Abstract

Background/Aim: Adrenal insufficiency is one of the adverse events (AEs) associated with anti-programmed death-1 (PD1) therapy. Delaying diagnoses can lead to serious conditions. It is necessary to elucidate detailed clinical features of these AEs. Patients and Methods: Patients treated with anti-PD-1 monotherapy or in combination with anti-cytotoxic T cell lymphocyte-4 therapy at our hospital from January 2013 to December 2016 were identified. The patients' clinical characteristics and laboratory and radiologic findings were collected. Results: Adrenal insufficiency occurred in 3% of the patients. All patients were male. At the onset of symptoms, eosinophilia (>500/μl) was observed in four cases. Eosinophilia was observed more than a month before onset of symptoms in three cases. Other pituitary hormones remained relatively stable. Radiological evidence of pituitary inflammation was detected only in one case. Conclusion: Most anti-PD1-related adrenal insufficiency cases involved an isolated ACTH deficiency. Eosinophilia may be an early indicator before the onset of symptoms.

Anti-programmed death-1 (PD1) monoclonal antibodies (mAbs), including nivolumab and pembrolizumab, exhibit anti-tumor effects and produce durable responses in various types of cancers and are listed as a standard treatment for non–small-cell lung cancer (1-3). In addition to their efficacy, anti-PD1 mAbs also generate immune-related adverse events (irAEs). irAEs are less common compared to conventional anticancer drug toxicities and patients occasionally develop severe, life-threatening, grade 3-4 toxicities.

Adrenal insufficiency is one of the adverse events (AEs) that occur following anti-PD1 mAb therapy and may manifest with non-specific symptoms. Therefore, delaying diagnosis and adequate care can lead to serious conditions. Although it is necessary to elucidate the detailed clinical features of this AE for early detection, the clinical and radiological features of anti-PD1 therapy-induced adrenal insufficiency remain poorly described.

Here, we describe five cases of secondary adrenal insufficiency attributed to anti-PD1 therapy at the Department of Thoracic Medical Oncology, Cancer Institute Hospital of Japanese Foundation of Cancer Research.

Patients and Methods

Patients treated with anti-PD-1 mAb monotherapy or combined with anti-cytotoxic T-cell lymphocyte-4 mAb (anti-CTLA-4) were identified at the Department of Thoracic Medical Oncology, Cancer Institute Hospital of Japanese Foundation of Cancer Research from January 2013 to December 2016. Anti-PD-1 monotherapy alone or in combination with anti-CTLA-4 were delivered as part of therapeutic study or for practical clinical usage. Adrenal insufficiency was diagnosed by the treating investigator and confirmed by an endocrinologist.

For all patients, the received treatment regimen was recorded. For the patients with adrenal insufficiency, data regarding the clinical characteristics and laboratory and radiologic findings were retrospectively collected. In addition, the early signs of adrenal insufficiency were explored.

Results

A total of 168 patients received anti-PD-1 therapy alone or in combination with anti-CTLA-4. Adrenal insufficiency occurred in five patients (3.0%) (non–small-cell lung cancer [3/158] and small-cell lung cancer [2/10]) (Table I). Three patients received monotherapy and the other two patients received either monotherapy or combination treatment.

All patients were male with a mean age of 65.4 years (range=58-72 years). The initial symptoms consisted of fatigue and anorexia. The median time of symptom onset was 140 days (range=30-154 days). At the onset of symptoms, eosinophilia (>500/μl) was observed in four cases (Cases 1, 2, 4, and 5), which was identified more than a month before the onset of symptoms in three cases (112, 49, and 56 days before symptom onset) (Figure 1). Hyponatremia (<135 mEq/l) was observed in only two cases and hypoglycemia was not observed in any cases at the onset of symptoms. Hypotension was observed in only one case at the time of admission.

View this table:
Table I.

Cases with adrenal insufficiency.

All cases were suspected to be a secondary adrenal insufficiency due to low plasma ACTH and low plasma cortisol. A gonadotroph deficiency was suspected in Case 4 (LH 0.5 mlU/ml, FSH 3.0 mlU/ml, and testosterone 0.01 ng/mL) and in Case 5 (LH 4.4 mlU/ml, FSH 3.8 mlU/ml, and testosterone 1.67 ng/ml). Other pituitary hormones remained relatively stable in all cases.

All patients underwent magnetic resonance imaging (MRI) of the pituitary or brain 10-31 days after the onset of symptoms. Only one patient (Case 4) presented abnormalities via MRI, suspected to be inflammation or apoplexy of the pituitary; however, none of the other patients exhibited abnormalities of the pituitary as seen by MRI.

One patient (Case 3) experienced an additional immune-related toxicity (type 1 diabetes mellitus) and another patient (Case 4) suffered thyroiditis, interstitial pneumonitis, and skin rash. All patients received a physiological replacement dose of corticosteroids, following which symptoms (e.g. fatigue and appetite loss) rapidly resolved.

Discussion

In the present study, we describe five cases of adrenal insufficiency attributed to anti-PD1 therapy. In addition, there are 10 previously reported cases of secondary adrenal insufficiency related to anti-PD1 treatment (Table II) (4-9).

Each of the five cases described in this study were male. Moreover, in the 10 previously reported cases, eight patients were male. Therefore, sex differences associated with the pituitary may influence the anti-PD1 effects in this region.

In patients with an adrenal insufficiency, there are various associated abnormal findings, including hypotension, hypoglycemia, hyponatremia and eosinophilia (10). Although most of our cases exhibited eosinophilia, hypotension and hyponatremia were less evident and no cases presented with hypoglycemia. Similar to these findings, 10 previously reported cases exhibited similar results. One possible explanation is that patients treated with anti-PD1 are regularly examined and the physician may notice the necessity of examination before disease progression. Another explanation is that all our cases had secondary adrenal insufficiency. In patients with a secondary adrenal insufficiency, the secretion of aldosterone and adrenal androgens are preserved, resulting in different symptoms from primary adrenal insufficiency (10).

Figure 1.
Figure 1.

Change in eosinophil count. A: onset of sympotms. B: on admission.

View this table:
Table II.

Ten previously reported cases of adrenal insufficiency.

Three out of five cases (Cases 1, 2, and 3, which were treated with anti-PD1 monotherapy) presented with an isolated ACTH deficiency. Because we did not perform a stimulation test, we cannot deny the possibility of subclinical hypopituitarism; however, in the 10 previously reported cases, 8 were diagnosed with an isolated ACTH deficiency, with the remaining two cases exhibiting no abnormalities in the other pituitary hormones, which would indicate an isolated ACTH deficiency. Anti-CTLA4 therapy also causes secondary adrenal insufficiency with hypophysitis. Moreover, in cases of anti-CTLA4, most patients have at least two pituitary deficiencies (11). Also, it has been reported that there is a relationship between CTLA-4 and several types of hormone secreting cells (12). Therefore, an isolated ACTH deficiency may be an exclusive adverse event associated with anti-PD1 therapy and PD1 and ACTH secretion might be related.

In patients with hypophysitis caused by anti-CTLA-4 therapy, an MRI of the pituitary often shows abnormality (e.g. diffuse enlargement and abnormal enhancement) (13); however, most of our cases did not exhibit any abnormalities according to the MRI. In addition, the abnormal MRI findings resolved completely after the discontinuation of treatment (13). Thus, there is a possibility that the timing of the imaging affected the results; however, in the 10 previously reported cases, only one case was found to have a pituitary abnormality observed on MRI. Thus, the MRI may have a low sensitivity to hypophysitis in relation to anti-PD1 therapy.

As mentioned above, no specific symptoms or examinations exist for adrenal insufficiency that lead to a delayed diagnosis and adequate care. Although examining the levels of ACTH and cortisol is one method of obtaining a diagnosis, this cannot be routinely achieved in daily clinical practice. Here, we showed that eosinophilia appeared prior to the onset of symptoms, and thus, may be an early predictive marker of adrenal insufficiency. Furthermore, we can routinely examine eosinophil counts in a clinical setting. Therefore, if patients present with eosinophilia, we should closely examine the symptoms and laboratory findings in suspicion of a subclinical adrenal insufficiency. In addition, hyponatremia has also been reported to be a predictor of secondary adrenal insufficiency in association with anti-PD1 therapy (9); however, in our patients, hyponatremia displays fewer characteristics. Moreover, patients with lung cancer often exhibit hyponatremia with SIADH. Therefore, hyponatremia may be an inappropriate predictive marker for the diagnosis of adrenal insufficiency.

Conclusion

Most anti-PD1-related adrenal insufficiency cases involve a secondary adrenal insufficiency with an isolated ACTH deficiency. Moreover, cases of panhypopituitarism were rare. Furthermore, eosinophilia may be an early indicator, before the onset of symptoms.

  • Received June 15, 2017.
  • Revision received July 1, 2017.
  • Accepted July 3, 2017.

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Adrenal Insufficiency Related to Anti-Programmed Death-1 Therapy
RYO ARIYASU, ATSUSHI HORIIKE, TAKAHIRO YOSHIZAWA, YOSUKE DOTSU, JUNJI KOYAMA, MASAFUMI SAIKI, TOMOAKI SONODA, SHINGO NISHIKAWA, SATORU KITAZONO, NORIKO YANAGITANI, MAKOTO NISHIO
Anticancer Research Aug 2017, 37 (8) 4229-4232;
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