The immunotherapy drug pembrolizumab, even as offering significant advancements in cancer treatment, carries a risk of a rare but potentially life-threatening side effect: adrenal insufficiency (AI). Recognizing this immune-related adverse event (irAE) is crucial for timely diagnosis and management, particularly in patients with non-small cell lung cancer (NSCLC) receiving pembrolizumab as part of their treatment plan. The challenge lies in the often subtle and delayed onset of symptoms, requiring clinicians to maintain a high index of suspicion.
Adrenal insufficiency occurs when the adrenal glands don’t produce enough cortisol, a vital hormone regulating stress response, metabolism and blood pressure. Pembrolizumab-induced AI is considered a secondary form, stemming from a deficiency in adrenocorticotropic hormone (ACTH), which signals the adrenal glands to produce cortisol. This differs from primary adrenal insufficiency, where the adrenal glands themselves are damaged. A recent case report highlighted the complexities of diagnosing this condition even 17 months after pembrolizumab treatment ended, emphasizing the need for vigilance beyond the active treatment phase.
Understanding the Risk in NSCLC Patients
Research indicates that pembrolizumab-induced AI, while uncommon, can have serious consequences if left untreated. A study published in PubMed observed that five out of 49 patients with advanced NSCLC developed AI between April 2017 and February 2021 after receiving pembrolizumab as a first-line treatment. Notably, four of these patients experienced severe (grade >3) AI requiring hospitalization. The median time to onset of AI following the start of treatment was approximately 4.63 months, highlighting the importance of ongoing monitoring during and after immunotherapy.
The diagnostic process can be complicated by the often indolent clinical presentation of AI. Symptoms can be non-specific, including fatigue, anorexia, nausea, and dizziness – all of which can overlap with other cancer-related effects or treatment side effects. This necessitates a structured approach to differentiate between central (ACTH deficiency) and primary causes of adrenal insufficiency, as outlined in a report from Pharmacy Times.
Diagnosis and Treatment Strategies
Accurate diagnosis typically involves hormone level testing, specifically measuring cortisol and ACTH levels. In cases of suspected secondary AI, as seen in a recent case report published in Springer, a detailed endocrine workup is essential to confirm ACTH deficiency. Once diagnosed, treatment involves corticosteroid replacement therapy, which effectively restores cortisol levels and alleviates symptoms. All patients in the PubMed study improved after initiating corticosteroid replacement.
The efficacy of immunotherapy in patients with AI as an irAE is too noteworthy. The study in PubMed showed that among the five patients who developed AI, one achieved a complete response to treatment, while four experienced a partial response. The median progression-free survival was 37.7 months, and overall survival had not been reached during the study period. This suggests that AI does not necessarily preclude continued successful immunotherapy treatment.
Long-Term Monitoring and Considerations
A key takeaway from recent case studies, including one reported in the Journal of Thoracic Oncology, is that adrenal insufficiency can occur significantly after pembrolizumab treatment has ceased. The case detailed in the journal involved a patient who developed secondary AI 15 months after stopping pembrolizumab. This underscores the need for clinicians to consider AI in the differential diagnosis even in patients who have completed immunotherapy, particularly if they present with unexplained fatigue or other suggestive symptoms.
Currently, there is no established consensus regarding the optimal monitoring of adrenal function during subsequent chemotherapy in patients previously treated with ICIs like pembrolizumab. The case report published in Springer highlights this gap in clinical guidance, emphasizing the need for further research to determine the most appropriate monitoring strategies.
As immunotherapy continues to play an increasingly important role in cancer treatment, awareness of potential irAEs like pembrolizumab-induced adrenal insufficiency is paramount. Early recognition, accurate diagnosis, and prompt treatment are essential to ensure the best possible outcomes for patients with NSCLC. Continued research will refine our understanding of the long-term effects of these therapies and optimize patient care.
This information is for general knowledge and informational purposes only, and does not constitute medical advice. This proves essential to consult with a qualified healthcare professional for any health concerns or before making any decisions related to your health or treatment.
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