When Cancer Treatments Affect Endocrine Function

By Pratima Nayak, MD

The incidence of cancer is increasing, particularly some cancers such as melanoma. In response to the evolving need for more effective treatments for these cancers, research into chemotherapy used to treat cancer has accelerated over the past few decades. The result is that now there are many new cancer treatment drug classes. One of these new drug classes, used in the treatment of cancers such as melanoma and certain lung cancers, is known as immune checkpoint inhibitors.

These drugs have shown some spectacular benefits and successes in their use against several cancers, stopping the disease in its tracks and even decreasing the amount of cancer in the body. But like the traditional chemotherapy that has been used in the past, the newer immune checkpoint inhibitors come with the risk of potential side effects.

While more common side effects such as nausea can be present, other potential side effects of this drug class are quite a bit different from what typically has been seen in patients: they include consequences that are specific to the hormonal (endocrine) functions of the body which can be very serious, even life-threatening or permanent.

What are immune checkpoint inhibitors and how do they work?

Checkpoint receptors are the body’s way of preventing the immune system from attacking its own cells. When immune cells detect checkpoint receptors on the cell surface, the immune cells are able to identify that cell as “self” and avoid destroying those cells. Cancer cells and tumors have developed the ability to hide from the body’s immune system by placing these checkpoint receptors on their own surface. As a result, the immune system identifies these cancer cells as “self” and avoids destroying them as well.

The development of medications that mimic immune checkpoint inhibitors prevents these cancer cells from tricking the immune system. Immune checkpoint inhibitors (i.e., nivolumab, ipilimumab, pembroluzimab) work by alerting immune cells to attach to the cancer “self” receptors to destroy the cell. Unfortunately, this effect is not limited to the receptors on cancer cells only. Therefore, both normal cells and cancer cells may be destroyed by the immune system.

What are some of the potential side effects of these medications?

Many commonly seen side effects of these agents are likely due to the destruction of normal cells and can include skin rashes (dermatitis), irritation of the liver (hepatitis), inflammation of the large and small intestinal tracts (colitis) and inflammation of lung tissue (pneumonitis).

But changes in the body’s endocrine systems, referred to as “endocrine-related complications,” have been found to be fairly common. These changes include the development of new diabetes mellitus, which often responds only to insulin administration; thyroid gland function abnormalities; and pituitary gland function abnormalities.

Unfortunately, it is not clear who is at risk of developing these complications. Studies are being done to find out who might be at higher risk based on blood tests or medical history and, hopefully, identify those requiring closer monitoring for the development of these complications. But as yet, there are scarce clues.

Figure 1. Immune cells attach to self receptors on self cells and prevent destroying them. Cancer cells that have learned to display these receptors also avoid dexstruction. Those that do not have these receptors are destroyed by immune cells.

Figure 2. Immune checkpoint inhibitors attach to self receptors on both cancer cells and immune cells. This prevents the cancer cells that display self receptors from tricking the immune cells into thinking they are self cells. By not detecting these "self" receptors, the immune cells destroy the cancer cells.

How can these endocrine complications be avoided?

Since the benefit of cancer control or remission often outweighs the risk of side effects (especially treatable endocrine complications), these cancer therapies — while unique in their possible side-effects — can be lifesaving. Regular blood testing and physical exams can prevent the life-threatening situations that can develop as a result of untreated, unidentified conditions such as diabetes. Informing individuals, their family members and healthcare support team about the possible symptoms can help catch these conditions before they become dangerous. All patients on these cancer drug treatments should get lab tests done regularly to insure the thyroid and pituitary are not showing any signs of dysfunction and that blood sugars are not elevated. Monitoring can be spaced out to longer intervals after 6 to 12 months on treatment.

What happens if endocrine system side effects occur?

When diabetes develops, insulin is the most appropriate treatment and can prevent a life-threatening condition called diabetic ketoacidosis (DKA) that occurs when your body produces high levels of blood acids called ketones.

Although many patients are apprehensive when faced with the prospect of starting insulin, the often-rapid improvements they experience are an undeniable benefit. Similarly, if thyroid tests show changes in normal hormone levels, treatment with thyroid medication can prevent thyroid-related medical emergencies. If signs of pituitary dysfunction are revealed in lab testing, it is important to start adrenal hormone replacement, then other hormone replacements as needed. Unfortunately, most of the endocrine side-effects will be permanent and require lifelong treatment and monitoring.

While immune checkpoint inhibitors have given many patients with cancer new hope for a longer survival, the side effects are many, and regular monitoring is needed to prevent dangerous conditions. If endocrine-related side effects develop, they are easily treatable with standard medications. Being aware of the symptoms related to these side effects and following up regularly with your healthcare team can help prevent a medical crisis and ensure optimal health.