Immunotherapy & Adrenal Insufficiency Immunotherapy is a treatment approach used by oncologists all over the world. It helps a patient's immune system to recognise and attack disease, most commonly cancer. While it can be highly effective, it can also affect the body, including the adrenal glands, in unexpected ways. This article is to help share information about adrenal insufficiency caused as a result of immunotherapy. Introduction Immunotherapy has transformed how many cancers are treated. It is used in the “adjuvant” setting after surgery for some people and also used to control the disease when it has spread to other sites in the body. ‘Adjuvant’ is as an additional treatment to eliminate any remaining cancer cells to reduce the risk of it returning at a future date. Increasingly it is being used in the neoadjuvant setting – before surgery. Immunotherapy is now used to treat many types of cancers. While it can be highly effective, it can also affect the body, including the adrenal glands, in unexpected ways. This guide explains what immunotherapy is, why it can lead to adrenal insufficiency, and what that means for you. It also answers common questions patients have when they are navigating both cancer treatment and hormone (or “endocrine”) health. What is Immunotherapy (IO)? IO is a type of treatment that helps your immune system recognise and attack disease, most commonly cancer. Instead of directly targeting tumours (like chemotherapy does), it “switches on” your immune system so it can do the job itself. We sometimes describe it as “taking the brakes off” the immune system, which is why the drugs are also known as “checkpoint inhibitors”. This activation of the immune system explains why it can cause a range of ‘inflammation type’ side effects. It is used to treat a wide range of conditions, including: Melanoma Lung cancer Kidney cancer Upper gastrointestinal cancer Some blood cancers Increasingly, other many other tumour types and subgroups of cancer e.g. those affected by Lynch Syndrome What are the Advantages of Immunotherapy? It can produce long-lasting responses It is often better tolerated than chemotherapy In some cases, it can lead to durable remission Some of the drugs are now available as subcutaneous injections that take only a matter of minutes to give every 4 or 6 weeks; a regimen that is much easier to manage than some other treatment options. Why can immunotherapy cause adrenal insufficiency? IO works by boosting the immune system but sometimes this boost goes too far. The immune system may begin to cause inflammation of healthy tissues, including hormone-producing glands. When this affects the adrenal glands that sit above the kidneys (or the pituitary gland in the brain that controls them), it can lead to adrenal insufficiency. This is a condition where your body does not produce enough cortisol and other steroid hormones essential for life. If the IO affects the pituitary gland then it will be levels of adrenocorticotropic hormone (ACTH) that are affected. This is known as hypopituitarism. Adrenal insufficiency caused by the immune system attaching the adrenal glands is called Primary Adrenal Insufficiency. Adrenal insufficiency caused by a lack of ACTH from the pituitary gland is called Secondary Adrenal Insufficiency. What are the Symptoms of Adrenal Insufficiency? How do I know if my symptoms are from adrenal insufficiency? Adrenal insufficiency symptoms can overlap with cancer treatment side effects or even other life changes (like menopause). As the common symptoms (shown on the left) are non-specific, blood tests are usually needed to confirm the cause. However, we are trying to raise awareness with immunotherapy patients that if they develop any of these vague symptoms and are fatigued, it is very important to get it checked and to continue to monitor the situation if things are not improving. Adrenal insufficiency from IO can even occur after the immunotherapy treatment has finished so raising awareness is key. Scientists who have reviewed cases of IO adrenal insufficiency describe fatigue, anorexia/loss of appetite, headache, nausea/vomiting, weakness, and drowsiness/lethargy were the most prevalent symptoms, while less common symptoms included abdominal pain, syncope (fainting) and insomnia. How is Adrenal Insufficiency Treated? Adrenal insufficiency can be effectively treated with daily replacement steroid medication (a glucocorticoid), taken at set times each day. It is a time-critical medication, which means it is one that you need to take promptly in order to avoid symptoms of low cortisol. Usually this medication will be hydrocortisone (chemically identical to cortisol in the body) taken twice or three times a day or prednisolone (similar chemically, to cortisol in the body), usually taken once a day. Inherent with adrenal insufficiency is a risk of adrenal crisis: a life-threatening but treatable condition, when the body experiences very low cortisol. Emergency treatment is with a hydrocortisone injection into the muscle or intravenously, followed by fluids and monitoring. To explore adrenal insufficiency medication, adrenal crisis and emergency hydrocortisone injections in more detail, please see links below: Times when your body needs more cortisol At certain times, the body needs more cortisol than at others. This is particularly during times of physical stress (eg illness or injury) or extreme psychological stress (e.g. bereavement). At these times, the usual replacement glucocorticoid (steroid) medication you take is not enough so you need to increase your dose (known as 'updosing', 'stress dosing' or 'sick day dosing'). The Sick Day Rules are a set of guidelines from endocrine clinicians, to help you to manage your adrenal insufficiency during these times of physcial and extreme physiological stress and to help prevent an adrenal crisis. Following the Sick Day Rules is very important to prevent adrenal crisis. The Sick Day Rules typically include: Taking an increased daily dose of your steroid medication during illness, fever, infection, or severe emotional stress Using an emergency hydrocortisone injection if you cannot keep tablets down, or are unable to take your medication (e.g. during an operation) Your care teams (endocrine and or oncology) will give you instructions and training. Read more about Sick Day Rules Frequently Asked Questions (FAQs) How common is IO caused adrenal insufficiency? Adrenal insufficiency caused by IO itself is relatively uncommon; It occurs in roughly 1- 2% of patients on immunotherapy, though it may be seen in up to 5% of some patient groups. However, related conditions (like pituitary inflammation, which is called hypophysitis) can increase the overall risk of adrenal insufficiency. The exact risk depends on the type of immunotherapy used. Combination treatments (using more than one drug) carry a higher risk than single treatments. Is adrenal insufficiency caused by immunotherapy temporary or permanent? Permanent: In most cases, especially when the adrenal or pituitary glands are significantly affected, the condition is long-term and life-long Most doctors are reluctant to stop replacement therapy once commenced so we do not know if some patients would recover partial or full function, this is still being researched. Because any recovery is unpredictable, patients are usually treated as if the condition is permanent unless proven otherwise. Do I need to see an endocrinologist? In most cases, yes, people are referred to endocrinology for further assessment. Cancer doctors and emergency doctors frequently diagnose and will start treatment urgently as many patients are still presenting acutely unwell. However, as awareness of adrenal insufficiency increases in healthcare professionals working in this sector, we are identifying it from blood test results earlier. Patient education is key, as is proactively warning patients who start IO and who may develop any suggestive symptoms. It is important to ensure they are safety netted and there is ongoing education about what to look out for. Your cancer doctor (oncologist) will refer you to an endocrinologist (a hormone specialist) The endocrinologist may confirm the diagnosis, manage long-term care and ensure there is not a mixed pattern of hormone deficiencies. The endocrine team will also advise about sick day rules (changing your dose of daily replacement medication in line with your body’s changing needs for cortisol), although increasingly the cancer teams and Clinical Nurse Specialists are supporting patients with this also. Who manages my care – my oncologist or my endocrinologist? Both, they need to work together to ensure you receive the correct treatment. Your Oncologist: manages your cancer treatment which sometimes includes additional steroids for other IO side effects which can also occur e.g. colitis (inflammation of the colon) Your Endocrinologist: manages your hormone replacement and adrenal health Communication between teams is important, especially for: Medication adjustments Managing side effects Planning treatment changes or if having surgery or other medical therapies Taking your own copies of letters, medication doses and also asking for copies of letters. Ensuring anaesthetists are aware and have documented it and sharing access to Guidelines for the management of glucocorticoids during the peri‐operative period for patients with adrenal insufficiency - Woodcock - 2020 - Anaesthesia - Wiley Online Library Access other resources Surgical Guidelines | Addison's Disease Self-Help Group Will I need an emergency injection kit? Yes, when you are diagnosed with adrenal insufficiency, you are given: An emergency hydrocortisone injection kit Training on when and how to use it A complete kit should contain:100mg hydrocortisone sodium succinate powder for infusion or injection, 2ml/5ml of sterile water (diluent to mix with the powder), a blue needle, a 2ml or 5ml luer syringe and instructions on how to administer the injection. This is essential to have to prevent or treat adrenal crisis, a medical emergency. Your endocrinology team will usually provide this initially and your GP will organise repeat prescriptions as needed. For more information on emergency injection kits, how to store them, how to give an injection, training and what to do if you are refused one, click on the link below Emergency Injection Kits What medication will I be prescribed? Most patients are treated with steroid replacement therapy, such as: Hydrocortisone (most common).This comes in tablets of 10mg, 5mg and 2.5mg. Hydrocortisone is usually taken twice or three times daily, with the first, largest dose being taken on waking up. For more information click on the Medication link below Prednisolone (sometimes used instead of hydrocortisone). This is usually taken once a day, on waking. Typical dosing Doses will be tailored to your body, symptoms and lifestyle The goal is to mimic your body’s natural cortisol rhythm so that you have the cortisol you need throughout the day. At times when the body needs an increased amount of cortisol due to physiological stress (e.g. illness or trauma) or severe psychological stress, dosing is increased (called stress dosing or ‘updosing’– see the section above on Sick Day Rules.) Will I need to take fludrocortisone? Possibly. Fludrocortisone is a medication that you will need to take if your body also lacks another type of hormone called aldosterone, which is also produced by the adrenal glands. This is a mineralocorticoid – a hormone that helps control your fluid and salt balance in the body. Its use varies and it is not standard for everyone. If you are experiencing symptoms of dehydration and salt cravings, you should mention this to your doctor. Medication Final thoughts Adrenal insufficiency can feel overwhelming, and even more so when you are already dealing with cancer treatment. The positive news is that it is manageable with the right treatment and support. Once people start on their replacement steroids they usually feel much better quickly and more like themselves again. Effective support for adrenal insufficiency means a proper diagnosis, medication, and education: Once diagnosed, and once taking steroid replacement medication, most people feel much better very quickly Many people with adrenal insufficiency can lead full, active lives Symptoms can be well controlled with a medication regimen that has been optimised for you Risks can be minimised with education and preparation If you’re unsure about symptoms or treatment, don’t hesitate to raise concerns with your care team, they’re there to help you navigate both conditions safely. The Addison’s Disease Self-Help Group are here to support anyone with adrenal insufficiency to be aware, be prepared and be understood. Having a life-long rare condition like adrenal insufficiency can feel overwhelming. For information on managing psychological stress, see our links below. 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