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Open Access
Acute endocrine presentations in general practice

Endocrine immune-related adverse events

VENESSA H. TSANG, Bernard Champion
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Does this refine your diagnosis?
Answer: It is reassuring that there are no known cerebral metastases, given his headaches, nausea and vomiting. The known abdominal lymph nodes could give the picture of gastrointestinal discomfort. Given that he has not had imaging done for three months there could be progression of his disease during this time. However, it is more likely he is experiencing a novel adverse effect to treatment.

 

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How do ipilimumab and pembrolizumab work?
Answer: Ipilimumab is a cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) inhibitor, available on the PBS for the treatment of metastatic melanoma and renal cell carcinoma.1,2 It is the only drug available for use in this class. Pembrolizumab is a programmed cell death protein 1 (PD-1) antibody, available on the PBS for the treatment of melanoma, nonsmall cell lung cancer, and head and neck squamous cell carcinoma.3 Nivolumab is a PD-1 inhibitor additionally approved for use in clear cell renal cancer, Hodgkin’s lymphoma and urothelial carcinoma.4 There are also PD ligand 1 (PD-L1)inhibitors (e.g. atezolizumab). Together these drugs are a novel class of cancer treatment known as immune checkpoint inhibitors (ICIs) (Table 1).

ICIs aim to manipulate the immune system to offer a novel target for susceptible cancer types. Both CTLA-4 and PD-1 are involved in protection against T-cell mediated self-antigen destruction. CTLA-4 inhibitors block T-cell inhibition, which leads to T-cell potentiation. PD-1 is expressed on T-cells and PD ligand on tumour cells. The interaction between these prevents the tumour cells from being destroyed by inflammatory cells. PD-1 and PD-L1 inhibitors disrupt this negative signal and allow tumour cells to be susceptible to destruction.

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These drugs were first used to treat melanoma, improving overall survival and progression of disease, with greater efficacy in combination therapy than monotherapy of either class. 

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What are the side effects?
Answer: As a result of their unique mode of action (different to traditional cytotoxic chemotherapy) there are new immune-related adverse effects (irAEs) of ICIs.5-7 The spectrum depends on the ICI given, with more irAEs in combination therapy than monotherapy, the dose of the ICI and the tumour type being treated. In melanoma, the most common irAEs are seen in the skin, including vitiligo and rash (occurring in more than 30% of patients), and gastrointestinal (occurring in about 15% of patients). These have a median time of onset of less than eight weeks. Other irAEs include hepatic dysfunction (median time to onset seven weeks), respiratory (nine weeks) and endocrine dysfunction (10 weeks). It should be noted that irAEs can occur many months after initiation of therapy and even after therapy has been suspended.8 

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Dr Tsang is Staff Specialist in the Department of Endocrinology at the Royal North Shore Hospital, Sydney; and Senior Lecturer in the Northern Clinical School, Faculty of Medicine and Health at The University of Sydney, Sydney, NSW. Associate Professor Champion is an Endocrinologist and Associate Professor in Medicine at Macquarie University; and Honorary Associate Professor at Nepean Clinical School, The University of Sydney, Sydney, NSW.