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Introduction

Recently, immune checkpoint inhibitors (ICIs) have been used in the treatment of many cancers, including lung cancer, and the management of immune-related adverse events (irAEs) caused by ICIs is important. Although the time of irAE onset depends on the type of ICI and whether they are used in combination, the median onset time for most irAEs is 2 to 4 months (1,2). However, it is generally difficult to predict the time of onset of irAEs, since they can occur even in patients long after the start of ICI treatment (2).

The optimal duration of ICI use in advanced non-small cell lung cancer (NSCLC) has not been fully evaluated. In clinical practice, many patients with advanced NSCLC continue therapy beyond 2 years; however, in the pivotal trials that established the use of ICIs in patients with NSCLC, patients were treated with ICI therapy for up to 2 years (3).

The case of a lung cancer patient who responded to anti-programmed death-1 (PD-1) antibody treatment, namely nivolumab monotherapy, and continued for more than 4 years, and then developed diabetes mellitus (DM) 3 years and 3 months and polymyalgia rheumatica (PMR) 4 years and 5 months after starting nivolumab treatment is reported.

Case report

In June 2014, a 54-year-old man was referred to Kainan hospital complaining of pain in the right hip joint region for the past two months. He was an ex-smoker (60 pack-years), was on no regular medications, and had no medical history except for colitis. Computed tomography (CT) showed an ~25-mm nodule in the right upper lobe of the lung (Fig. 1A) and a 50-mm mass in the right pelvic region. On 18F-fluorodeoxyglucose positron emission tomography-CT, intense accumulation was seen in the right S2 nodule of the lung [standardized uptake value (SUV) max: 15.2], right adrenal gland, and a pelvic mass from the right sciatic/pubic bone to the right internal obturator muscle (SUV max: 10.81) (Fig. 1B). On histopathological examination of the transbronchial biopsy (TBB) specimen from the nodule in the right lung, carcinoma with neuroendocrine features was identified; hematoxylin and eosin staining showed small tumor cells with a relatively high nucleus-to-cytoplasm ratio and hyperchromatic nuclei (Fig. 1C), and immunohistochemical analysis was positive for synaptophysin (Fig. 1D), napsin A, Ki-67 (30% positive), and thyroid transcription factor-1, and negative for p63 and chromogranin A. According to the 7th edition of TNM staging, the patient was classified as having stage IV lung cancer (T1bN0M1b). Mutation status was negative for epidermal growth factor receptor and anaplastic lymphoma kinase gene, and the programmed death-ligand 1 (PD-L1) tumor proportion score using the 22C3 antibody was less than 1%. In light of the pathologically atypical presentation for small cell carcinoma and his good performance status (PS), the decision was made to treat him according to standard treatment guidelines for stage IV NSCLC.

Figure 1 (A) Chest CT shows a primary lung tumor in the right upper lobe (arrowhead). (B) 18F-fluorodeoxyglucose positron emission tomography-CT shows a pelvic mass from the right sciatic/pubic bone to the right internal obturator muscle (standard uptake value max, 10.81) (arrow). Histopathological and immunohistochemical findings of the specimen obtained by transbronchial biopsy (magnification, x400): (C) Hematoxylin and eosin staining shows small tumor cells with a relatively high nucleus-to-cytoplasm ratio and hyperchromatic nuclei, and (D) immunohistochemical analysis shows positivity for synaptophysin (granular staining of cytoplasm). CT, computed tomography.

From July 2014, he was treated with radiation therapy for the pelvic lesion (45 Gy/15 Fr), as well as chemotherapy (carboplatin + paclitaxel + bevacizumab for four courses), which was followed by bevacizumab maintenance therapy. After 15 cycles of maintenance therapy, the right adrenal metastasis was larger, and a new left adrenal metastasis was observed. Pemetrexed monotherapy was started as second-line therapy (total of two courses), followed by docetaxel monotherapy as third-line therapy (total of six courses). Although he had a period of remission, in January 2018, re-enlargement of the right adrenal metastasis was detected, and he was treated with radiation therapy for the right adrenal lesion (50 Gy/25 Fr), as well as chemotherapy (two courses of docetaxel monotherapy).

However, in February 2019, enlargement of the left adrenal metastasis was detected, and he was administered nivolumab monotherapy as fifth-line therapy. Prior to the initiation of nivolumab treatment, the patient exhibited PS 0, with preserved organ function and no suggestion of DM or autoimmune disease. Nivolumab treatment was very effective, and a partial response was achieved two months after the start of treatment. He continued nivolumab treatment and achieved an almost complete response. Therefore, discontinuation of nivolumab was considered after two years of treatment, but nivolumab was continued as the patient wanted to continue treatment due to concerns about relapse. At a regular medical visit in May 2022, he complained of thirst and polydipsia that had started a few days earlier, and his blood glucose level, which had previously been within reference limits, was increased to 468 mg/dl. Urinary ketones were negative, pancreatic amylase was not elevated, and autoantibodies, including anti-glutamic acid decarboxylase (GAD) antibodies, were negative. He was diagnosed with DM and started on insulin therapy, after which a decrease in the serum C-peptide level was observed.

Nivolumab treatment was resumed with continued glycemic control, but one year after resumption of treatment, muscle pain in the femoral area and neck appeared, which did not improve with nonsteroidal anti-inflammatory drugs. Although nivolumab treatment was discontinued, he developed worsening arthralgia, muscle pain in both shoulders and knees, muscle weakness, and weight loss. CT and magnetic resonance imaging showed no obvious cancer progression, and rheumatoid factor, anti-citrullinated protein antibody, antinuclear antibody, anti-neutrophil cytoplasmic antibody, and anti-aminoacyl transfer ribonucleic acid synthetase antibodies were negative, and C-reactive protein was high (11.81 mg/dl), whereas the serum creatine phosphokinase level was not elevated. Four years and 5 months after the start of nivolumab treatment, he was diagnosed with PMR and treated with prednisolone (PSL) (10 mg daily). Subsequent symptom control of his PMR was good, and PSL was tapered and discontinued in ~7 months. Almost 20 months have passed since the discontinuation of nivolumab treatment, but recurrence of the lung cancer has not been observed.

Discussion

This was a rare case of a lung cancer patient receiving nivolumab monotherapy for more than 4 years who developed DM and PMR as irAEs. Although the median onset time for most irAEs is 2 to 4 months (1,2), it is considered that patients should always be carefully monitored for the development of irAEs during ICI administration. Specifically, imaging studies, including chest X-rays, and blood tests, including endocrine function tests and cardiac markers, should be performed regularly, and non-specific symptoms such as fatigue and appetite loss, which are common in cancer patients, should also be considered as possibly related to irAEs. Aberrant T cell activity is thought to be a prime factor in the development of irAEs (4); however, the type and timing of their development remain challenging to predict due to the complexity of the underlying mechanisms, which have not yet been fully elucidated.

In a Japanese study, 0.14-0.33% of patients developed type 1 DM after anti-PD-1 antibody monotherapy, and the median time from the date of the first anti-PD-1 antibody injection to the onset of type 1 DM was 155 days (range: 13-504 days) (5). Compared to Western patients, Japanese patients are less likely to be positive for autoantibodies such as anti-GAD antibodies, and ketosis and ketoacidosis are often observed (5). In the present case, DM developed more than 1,000 days after the start of nivolumab treatment, which was a relatively long time to the onset of DM. In addition, in the present case, anti-GAD antibodies and other autoantibodies were negative, and there was no evidence of ketosis.

With respect to PMR, 0.2-2.1% of patients developed PMR after anti-PD-1 or anti-PD-L1 antibody administration, and the time from the date of the first ICI injection to the onset of PMR ranged from <1 to 53 months (6-8). ICI-mediated PMR may have a milder course with less intense inflammation than primary PMR, and ICI-mediated PMR can be managed with a relatively low glucocorticoid dose (9). In addition, in a prospective observational study including all cancer patients treated with ICIs, the disease control rates in patients with rheumatic irAEs, non-rheumatic irAEs, and those without irAEs were 85.7, 75.1, and 35.3%, respectively (7,8). In the present case, PMR developed 53 months after the start of nivolumab treatment, which was a relatively long time to the onset of PMR. The patient was treated with PSL 10 mg/day, the subsequent symptom control of PMR was good, and the lung cancer was also well controlled.

Patients with advanced NSCLC were treated with ICI therapy for up to 2 years in the pivotal trials that informed the use of ICIs; in clinical practice, however, many patients continue therapy beyond 2 years (3). In addition, the CheckMate 153 trial suggested that continuing nivolumab beyond 1-year improved outcomes (10). Although the optimal duration of ICI use had not been adequately evaluated, a recent retrospective cohort study showed that for patients with advanced NSCLC whose disease is still responding to ICI therapy at 2 years, stopping therapy and monitoring rather than continuing immunotherapy indefinitely is a reasonable strategy with sustained clinical benefit (3). In other research, when comparing NSCLC patients treated with anti-PD-1 antibodies for 2 years with those who discontinued treatment and those who continued treatment, in the continued treatment group, 19.5% of patients had grade 1, 9.7% had grade 2, and 3.2% had grade 3-4 irAEs, whereas only 6.6% of patients had grade 1 irAEs in the discontinued treatment group (11). Furthermore, there have been reports of delayed irAEs such as adrenal insufficiency, hypothyroidism, pneumonia, and alopecia after the end of treatment (3 to 28 months), even after short-term administration (12). In that report on delayed irAEs (12), endocrine disorders were the most common, followed by neurologic, cutaneous, and pulmonary disorders, and corticosteroids were often used as an interim treatment. In the present case, discontinuing nivolumab was considered 2 years after the start of nivolumab treatment, but nivolumab treatment was continued at the patient's request. At the time this patient was treated, there was insufficient evidence to support stopping immunotherapy in patients with NSCLC who were responding well to treatment at 2 years, however, it might have been necessary to make a decision not to continue nivolumab treatment because of the risk of irAEs. It may also have been necessary to more fully explain the risks of irAEs to the patient.

In conclusion, a case of a lung cancer patient successfully treated with nivolumab monotherapy who developed DM 3 years and 3 months after starting nivolumab and PMR 4 years and 5 months later was described. The underlying cause of delayed irAEs and how long to follow up on irAEs remains to be elucidated and warrants further investigation. This report provides oncologists and pulmonologists with further insight into the importance of long-term management of irAEs and the appropriate treatment duration of immunotherapy. In addition, since irAEs have been reported even after the completion of ICI administration, it should be noted that long-term management of irAEs is necessary for patients receiving and who have received ICIs.

Acknowledgements

The authors would like to thank Dr. Hidefumi Sato (Department of Health Management, Kainan Hospital), Dr. Yoshiharu Ozawa (Diabetes and Endocrinology, Kainan Hospital), Dr. Takuji Tsuyuki (Department of Pathology, Kainan Hospital) and Dr. Kaneshige Sasaki (Department of Rheumatology, Kainan Hospital) for their assistance and stimulating discussions.

Funding

Funding: No funding was received.

Availability of data and materials

The data generated in the present study may be requested from the corresponding author.

Authors' contributions

MakN analyzed and interpreted the patient data and made a major contribution to writing the manuscript. HM contributed to data collection and assisted in the preparation of the manuscript. AH, MasN, SH, MK and NT advised on patient treatment and assisted in patient data interpretation. In addition, AH, MasN, SH, MK and NT confirmed the authenticity of all raw data, and critically revised and edited the manuscript. All authors read and approved the final manuscript.

Ethics approval and consent to participate

Not applicable.

Patient consent for publication

The patient provided written, informed consent for the publication of the data.

Competing interests

The authors declare that they have no competing interests.

References