Introduction

Immune Checkpoint Inhibitors (ICIs) are a type of treatment that uses antibodies to boost the immune system. These agents have had a significant impact on improving the prognosis for patients with advanced cancers. Hepatocellular Carcinoma (HCC) has become the third leading cause of cancer death worldwide, and the number of patients with HCC continues to rise [1]. Atezolizumab plus bevacizumab have been recommended as the first line in patients with unresectable HCC since 2020 [2]. Based on the positive results of the phase 3 trial of durvalumab plus tremelimumab [3], a combination of anti-PD-L1 and CTLA4 antibodies is also considered as the first line. Thus, immunecombination therapy is the mainstream in systemic therapy for unresectable HCC. ICIs offer significant clinical benefits. However, they can also cause a specific range of side effects called immune-related adverse events (irAEs) [4]. The overall rate of endocrinopathy-related irAEs is about 10% of patients receiving ICI treatments [5]. Endocrinopathy-related irAEs include hypothyroidism, hyperthyroidism, hypophysitis, and adrenal insufficiency, in which thyroid disorders are the most common AEs [5,6]. Hypophysitis and adrenal insufficiency can be fatal even though the number of cases is small [7]. However, there have been few case reports of immune-related Adrenocorticotropic Hormone (ACTH) deficiency in atezolizumab plus bevacizumab therapy for unresectable HCC. This report aims to develop a better understanding of immune-related ACTH deficiency, its management, and the impact on clinical outcomes in patients with unresectable HCC treated with atezolizumab plus bevacizumab.

Case Presentation

Case 1: An 81-year-old man with a history of hepatitis B underwent hepatectomy for HCC 13 years prior and subsequently received Radiofrequency Ablation (RFA) and Transcatheter Arterial Chemoembolization (TACE) twice each. A Gd-EOB-DTPA MRI scan showed multiple hypointense lesions on the hepatobiliary phase in both the right and left hepatic lobes, indicating a recurrence of HCC. As the Child-Pugh score was 5(A) without any distant metastasis, it was classified as intermediate stage (B) HCC according to the Barcelona Clinic Liver Cancer (BCLC) staging system. Since the lesions did not meet the Up-to-seven criteria and with no invasion of the portal vein, first-line chemotherapy was initiated with intravenous administration of atezolizumab at a dose of 1,200 mg/body and bevacizumab at 15 mg/kg of body weight every 3 weeks. After three cycles of atezolizumab plus bevacizumab, the patient achieved Stable Disease (SD) according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria. However, after five cycles of atezolizumab plus bevacizumab (15 weeks from the administration), the patient complained of fatigue and loss of appetite and had low blood pressure; thus, atezolizumab plus bevacizumab was interrupted. Six days after discontinuation, an abnormal endocrinologic finding was detected, and the patient was immediately hospitalized. Blood examinations showed increased values of eosinophils (11.0%) and decreased values of ACTH (1.6 pg/mL) and cortisol (1.0 μg/dL), and the values of the Luteinizing Hormone (LH), thyroid stimulating hormone (TSH), Follicle-Stimulating Hormone (FSH), Prolactin (PRL) and Vasopressin (AVP) were higher than the upper limits of normal, and the Growth Hormone (GH) and Insulin-Like Growth Factor-1 (IGF-Ⅰ)were within the normal range, which suggested secondary adrenal insufficiency (Table 1). The MRI of the pituitary gland showed no obvious abnormalities in the anterior pituitary (Figure 1), indicating atezolizumab-induced Isolated ACTH Deficiency (IAD). Blood tests showed serum TSH, Free Triiodothyronine (FT3), Free Thyroxine (FT4), and Anti-Thyroid Peroxidase Antibody (anti-TPO) levels of 11.6 μIU/mL, 3.60 pg/ mL, 0.86 ng/mL and 3.7 IU/mL, respectively. Thyroid ultrasound sonography showed no morphological abnormalities and antithyroglobulin antibodies were negative, indicating atezolizumabinduced hypothyroidism. After the intravenous administration of hydrocortisone (100mg/body), the fatigue and loss of appetite were promptly improved.

Table 1: The patient’s laboratory findings on hospital admission (Case1).

Figure 1: The Magnetic Resonance Imaging (MRI) of pituitary gland (Case1). a-b The MRI showed no pituitary enlargement.

Following the intravenous administration, oral hydrocortisone at a dose of 60mg/day (0.8mg/kg/day) was started. On the fifth hospital day, the serum cortisol level improved (12.7μg/dL), and the oral dose was reduced to 40 mg/day. After 2 more days, it was reduced to 20 mg/day (Figure 2). After the patient’s symptoms had completely resolved, atezolizumab plus bevacizumab were reintroduced based on the recommendation of the endocrinologists. Gd-EOB-DTPA MRI showed stable disease after seven cycles of treatment (two cycles after the onset of IAD) (Fig.3). Atezolizumab plus bevacizumab was continued for 11 cycles with 20 mg of oral hydrocortisone daily. No recurrence of IAD or other adverse events was observed after the administration of hydrocortisone.

Figure 2: Clinical Course (Case 1).

Figure 3: Changes in Magnetic Resonance Imaging (MRI) with the course of treatment (Case1). a-d Liver Gd-EOB-DTPA MRI. a-b Initial examination. Multiple lesions are seen in S1, S2, S7, S8 and hepatic portal region hilum of liver, with high signal on diffusionweighted imagaing (DWI) and on the arterial phase. c-d After IAD. The size of the lesions did not change.

Case 2: A 65-year-old man with a history of alcoholic cirrhosis was initially diagnosed with HCC in 2013. He had histories of hypertension, diabetes, and a duodenal ulcer and took Esomeprazole Magnesium Hydrate 20mg, Rifaximin 1200mg, Amlodipine Besilate 2.5 mg, Sitagliptin Phosphate Hydrate 25mg and Atenolol 25mg. He reported no relevant family history. He had been a twopack-per-day cigarette smoker for forty years and consumed 70g of alcohol every other day. He received six TACEs, two RFAs, and one cyberknife treatment. Even though he had no extrahepatic metastasis or major portal invasion, he was diagnosed as TACE refractory and started receiving lenvatinib as first-line systemic therapy in November 2018. In April 2019, he underwent Transcatheter Arterial Embolization (TAE), and in June 2020, he underwent TACE. However, a contrast enhancement CT (CECT) performed in October 2020 showed a recurrence of HCC in S8 with adrenal metastasis, which indicated PD, and lenvatinib was discontinued. Since the Child-Pugh score was 6 (A) with an extrahepatic lesion, it was classified as advanced stage (C) according to the BCLC staging system. Second-line chemotherapy with atezolizumab plus bevacizumab was initiated every three weeks. After three cycles of chemotherapy, the patient archived SD according to RECIST criteria. On the day of the fifth cycle of atezolizumab plus bevacizumab (12 weeks from the initial chemotherapy session), the patient complained of fatigue.

Although blood examinations showed decreased values of ACTH (<1.5 pg/mL) and cortisol (0.9 μg/dL), the patient only had fatigue as a symptom (Table 2). As the fatigue was classified as Grade 1 according to Common Terminology Criteria for Adverse Events ver 5.0 (CTCAE ver 5.0), atezolizumab plus bevacizumab was continued based on the recommendation of the endocrinologists. His hormone levels were carefully monitored without any treatment for adrenal deficiency, and blood tests on the day of the sixth cycle showed that the ACTH and cortisol levels had returned to normal (93pg/ml and 9.2 μg/dL, respectably) (Figure 4). Therefore, the sixth cycle was administered without a dose reduction. After six sessions (one cycle after the onset of ACTH deficiency), a CECT performed in March 2021 revealed new multiple HCC lesions in both the right and left hepatic lobes. As a result, atezolizumab plus bevacizumab was discontinued, and the patient was switched to sorafenib as third-line chemotherapy.

Table 2: The patient’s laboratory findings on the day of the fifth course (Case 2).

Figure 4: Clinical Course (Case2).

Discussion

We are reporting two cases of ACTH deficiency during atezolizumab plus bevacizumab therapy for HCC. The first case was identified as IAD with normal levels of other pituitary hormones and no abnormalities found in the pituitary gland. The second case was diagnosed as ACTH deficiency, as no testing of other hormones or pituitary imaging was conducted.

ICI-related IAD is rare [5]. Among 1615 patients with ICI treatment, fourteen (0.87%) patients developed IAD [8]. Among some types of ICIs, such as anti-CTLA4 and anti-PD-1/PD-L1, atezolizumab-related IAD has been infrequently reported. IMbrave 150 trial reported only one case of hypopituitarism [2]. Out of 1,548 patients with non-small cell lung cancer who were treated with atezolizumab monotherapy, 85 patients developed endocrinopathy irAEs, and 4.7% of them had adrenal gland-related AEs [9]. In a systematic review of 60 IAD cases induced by ICI, no case was reported due to atezolizumab [10]. Out of 206 patients with ICI-induced adrenal deficiency, 191 had secondary AD. The distribution of the causes of secondary adrenal deficiency was as follows: ipilimumab (anti-CTLA-4) 53(27.7%), nivolumab (anti-PD-1) 69(36.1%), pembrolizumab (anti-PD-1) 22(11.5%), and atezolizumab (anti-PD-L1) 2(1.0%) [11].

Atezolizumab-related IAD has only been described as case reports [12,13] (Table 3). All cases required the continuation of corticosteroids as hormonal replacement therapy (HRT), which aligns with findings from previous studies [14]. In our report, case 1 continued HRT, while case 2 showed a rapid improvement in the levels of ACTH and cortisol without HRT. Case 2 had mild symptoms, and no additional examination was performed, such as imaging or testing of other hormones, so it was not classified as IAD, but it might be hypophysitis. Although careful observation and continuing ICI are recommended for patients with Grade 1 (mild) hypophysitis [15], hypophysitis sometimes evolves into IAD [16]. If case 2 were IAD, this would be the first report suggesting that follow-up without HRT is a viable option for IAD with Grade 1 (mild) symptoms.

Table 3: The Clinical Characteristics of Atezolizumab-induced Isolated ACTH Deficiency.

It is now well established from a variety of studies that irAEs are linked to either enhanced effectiveness of immunotherapy (such as increased response rates and prolonged survival) [9,17] or similar effectiveness as compared to those who do not experience irAEs [18]. Therefore, it is crucial to continue treatment with appropriate management of side effects. Prior studies and our case have demonstrated that atezolizumab-induced IAD can be managed with corticosteroids [12,13], and therapy can be continued. However, since cancer patients, particularly those receiving ICIs, often report non-specific symptoms of cortisol deficiency, such as weakness and loss of appetite, early detection of cortisol and ACTH abnormalities is important. Ideally, regular endocrinologic testing should be conducted. However, this can be challenging in practice due to limitations in insurance coverage or facility capabilities. It has been found that relatively basic tests, such as sodium and eosinophil levels, can predict these endocrinologic abnormalities. Cho et al. reported that hyponatremia (sodium <135 mEq/l) occurs early in IAD caused by ICIs and that comparison of sodium levels before and after treatment is useful as a monitoring indicator [19]. Ariyasu et al. showed eosinophilia in 4 of 5 patients with IAD caused by anti-PD-1 and antiCTLA-4 antibodies, 3 of whom had eosinophilia more than 1 month before the onset of clinical symptoms [20]. These findings reflect those of Iglesias P et al. (2021), who also found that hyponatremia (68%) and eosinophilia (31.8%) were the laboratory abnormalities most frequently associated with IAD [10]. Our case also presented with eosinophilia in addition to the non-specific symptoms of cortisol deficiency.