Adverse Effects From Cancer Immunotherapy Checkpoint Inhibitors

Which side effects will your doctor look for?

Potential Obstacles to Watch out for When Taking Immunotherapy
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Like any therapy, there is an upside and a downside. The upside is that immunotherapy is being used to improve the prognosis of certain types of cancer like advanced non-small cell lung cancer, melanoma, renal cell cancer, colon cancer, and Hodgkin's lymphoma. In other words, people are being given a second chance at living longer and more comfortable lives—a phenomenon that is literally changing the face of cancer therapy.

Of course, the delve into immunotherapy is just beginning, and this is an evolving and extremely exciting area in cancer research and care right now.

With that, as more and more people are being treated with immunotherapy, specifically the checkpoint inhibitors (ipilimumab, nivolumab, and pembrolizumab), doctors are noting the unique problems that may arise as a result of taking these new drugs.

Overview of Checkpoint Inhibitors

In order to understand the adverse effects or toxicities of checkpoint inhibitors, it's important to grasp how this type of immunotherapy works.

In brief, immune checkpoints normally lie on the surface of immune system cells (called T cells). These checkpoint molecules work through a complex signaling pathway to stop a person's T cells from attacking healthy cells—only bad, foreign cells (for example, cells infected with a virus).

Unfortunately, cancer cells are deceptive in that they make and express their own checkpoint molecules, and this is why your body does not attack a malignant tumor, as you would think it would.

Scientists, though, have fought back by creating therapies that block these checkpoints located on cancer cells in the hopes that now the body's immune system would recognize cancer as foreign, launch an attack, and clear it.

Toxicities of Checkpoint Inhibitors

Of course, problems may arise if a person's immune system gets a bit confused and begins attacking normal, healthy cells in addition to the bad cancer cells.

In other words, severe inflammation, organ damage, and autoimmune diseases can occur with use of these checkpoint inhibitors.

In fact, research shows that these toxicities, called immune-related adverse events, occur in up to 85 percent of people after treatment with the checkpoint inhibitor ipilimumab. They occur in up to 70 percent of people after treatment with the checkpoint inhibitors nivolumab or pembrolizumab.

As an aside, ipilimumab inhibits the immune checkpoint CTLA-4 (cytotoxic T- lymphocyte-associated protein 4) and has been used to treat melanoma.

Nivolumab and pembrolizumab target PD-1 (programmed death receptor-1) and have been used to treat cancers like melanoma, renal cell cancer, non-small cell lung cancer, and Hodgkin's lymphoma.

Getting back to the toxicities, though, the primary target systems that these checkpoint inhibitors "wrongly" attack in the body are the skin, gastrointestinal tract, liver, and endocrine systems.

Skin Toxicities

Skin problems are the most common immune-related adverse event linked to taking a checkpoint inhibitor, and they also tend to occur the earliest on in treatment.

Examples of skin problems include rash, itching, alopecia (hair loss), and vitiligo.

Mouth problems like dry mouth and oral mucositis (when ulcers form in the mouth) may also occur.

Treatment of a rash usually entails using a topical corticosteroid cream. Although if the rash is severe, an oral corticosteroid is sometimes needed. Taking an oral antihistamine like Benadryl (diphenhydramine) can be helpful for the itching.

Rarely, if the rash is severe, meaning it covers over 30 percent of the body, a person will likely need steroids given through the vein (intravenously) followed by a taper of oral steroids.

It's also important to note that very severe rashes like Stevens-Johnson syndrome have been rarely reported in people taking a checkpoint inhibitor.

This is why you or your loved one's cancer doctor will be monitoring you very carefully while taking an immunotherapy and promptly have you see a dermatologist if your rash looks worrisome (like if it is forming blisters) or if you are not getting relief with simple measures like a corticosteroid cream.

Gastrointestinal Tract Toxicities

Diarrhea and colitis, which causes abdominal pain and sometimes blood in the stool, are two intestinal problems that may occur as a result of taking a checkpoint inhibitor. If these effects occur, they show up generally six weeks or later after starting immunotherapy.

That said, these adverse effects appear to be more common in those receiving CTLA-4 blocking antibodies (for example, ipilimumab for advanced melanoma), as compared to those receiving PD-1 inhibitors (for example, nivolumab for advanced squamous cell non-small cell lung cancer).

Treatment of mild and early diarrhea includes ample fluid intake, an anti-diarrheal diet, and possibly an anti-diarrheal medication like Imodium (loperamide). But if diarrhea persists for more than two or three days, despite these simple remedies, or if the diarrhea is more severe (four or more bowel movements per day over usual), a thorough evaluation will be performed to further evaluate the diarrhea—like if an infection is a culprit, not the drug.

If an infection is ruled out, and the cause is deemed to be treatment-related, corticosteroids are needed and sometimes even stronger medications that suppress the immune system like Remicade (infliximab) are required.

One of the major life-threatening, albeit uncommon, complications of colitis that doctors watch out for is intestinal perforation (where a hole forms in the intestine wall from the severe inflammation).

Liver Toxicities

Checkpoint inhibitors can lead to elevations in liver enzymes, which signal liver inflammation. These elevations are generally seen about two to three months after starting therapy.

Usually, a doctor will monitor your liver blood tests, especially before each dose of immunotherapy, and if the enzymes are increased, a work up will be performed to determine whether the cause is related to the immunotherapy or something else (for example, another medication or a viral infection).

Like other immune-related adverse effects, if the cause is determined to be related to the immunotherapy, corticosteroids will be prescribed. If the liver toxicity is severe, treatment with the immunotherapy may need to be stopped altogether.

Endocrine System Toxicities

Immune-related adverse events may occur within the endocrine system of the body, which includes the pituitary gland, thyroid gland, and adrenal glands. On average, symptoms appear around nine weeks after starting treatment and may include:

  • Fatigue
  • Weakness
  • Nausea
  • Confusion
  • Headache
  • Loss of appetite
  • Vision problems
  • Fever

One of the most common endocrine adverse effects is hypothyroidism, which is when a person develops an underactive thyroid.

An overactive thyroid gland, called hyperthyroidism, has also been reported. Both conditions can be managed by an endocrinologist and diagnosed through blood tests, most notably the thyroid stimulating hormone (TSH) blood test. Hypothyroidism requires treatment with thyroid hormone, called Synthroid (levothyroxine).

In addition to hypothyroidism, another common endocrine problem that may develop as a result of taking a checkpoint inhibiting immunotherapy is hypophysitis, which is inflammation of the pituitary gland—referred to as the master gland because it releases numerous hormones into the body.

Hypophysitis may cause fatigue and headache and blood tests reveal several low hormone levels. Imaging tests may also reveal swelling of the pituitary gland. If detected soon enough, high-dose corticosteroids may calm the inflammation down enough to prevent the need for long-term hormone replacement drugs.

If the adrenal glands are affected, a person may develop low blood pressure, dehydration, and electrolyte problems like high potassium levels and low sodium levels in the bloodstream. This is a medical emergency and requires that a person be hospitalized and receive corticosteroids.

Finally, new-onset type I diabetes has rarely been linked to taking a PD-1 inhibitor. This is why doctors will often check glucose (sugar in your bloodstream) levels when starting therapy.

Rarer Toxicities

An immunotherapy can also trigger inflammation in the lung, and this is called pneumonitis, although it's rare, as compared to the above-mentioned toxicities. This adverse effect is especially worrisome in people with advanced lung cancer undergoing immunotherapy, as their lung function is already impaired from cancer. It may cause symptoms like cough or breathing difficulties.

While typically an uncommon adverse effect, pneumonitis can be life-threatening. If suspected, your doctor will rule out other causes of lung inflammation like a lung infection (called pneumonia) or cancer progression. A doctor will usually order a CT scan of the chest to assist in the diagnosis.

Treatment often includes stopping the immunotherapy for a designated period of time while the person undergoes close monitoring of their lungs. Corticosteroids are also often given, and in severe cases, an immunosuppressant like Remicade (infliximab) may be needed if a person does not get better with steroids.

Finally, other rare immune-related adverse effects have been reported like nerve or eye problems. In this instance, your doctor will refer you to a specialist, a neurologist or an ophthalmologist, for a proper diagnosis and treatment plan.

A Word From Verywell

If you or a loved one are taking a checkpoint inhibitor, it's good to be knowledgeable about the different toxicities associated with it, as they are unique from those associated with traditional chemotherapies.

In other words, the subtle signs and symptoms of these adverse effects are somewhat novel to cancer doctors too. Even so, do not be scared off by them. Instead, be educated and on the alert, as many will resolve if recognized promptly.

Sources:

Kroschinsky F et al. New drugs, new toxicities: severe side effects of modern targeted and immunotherapy of cancer and their management. Crit Care. 2017;21:89.

Linardou H, Gogas H. Toxicity management of immunotherapy for patients with metastatic melanoma. Ann Transl Med. 2016 Jul;4(14):272.

Michot JM et al. Immune-related adverse events with immune checkpoint blockade: a comprehensive review. Eur J Cancer. 2016 Feb;54:139-48.

Postow M, Wolchok J. Toxicities associated with checkpoint inhibitor immunotherapy. In: UpToDate, Atkins MB (Ed), UpToDate, Waltham, MA.

Villadolid J, Amin A. Immune checkpoint inhibitors in clinical practice: update on management of immune-related toxicities. Transl Lung Cancer Res. 2015 Oct;4(5):560-75.

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