13 Jun Potential Side Effects of Immunotherapy in Head and Neck Cancer
Dan Zandberg, MD
Currently, two immunotherapy medications, Nivolumab (Opdivo) and Pembrolizumab (Keytruda) are approved in the USA for recurrent and or metastatic squamous cell carcinoma of head and neck (HNSCC) after a patient received and failed “platinum” based chemotherapy. Both Nivolumab and Pembrolizumab belong to a class of immunotherapy medications called checkpoint inhibitors, specifically they are anti-PD-1 monoclonal antibodies. With the success and subsequent wide spread use of these drugs the identification and proper management of side effects has become even more important. This article will discuss potential side effects with anti-PD-1 monoclonal antibodies Nivolumab and Pembrolizumab. This discussion will not encompass all side effects ever reported with these medications but rather will focus on those that are more common and those that your treating physician will be evaluating you for.
As mentioned in the introduction, Nivolumab and Pembrolizumab are anti-PD-1 monoclonal antibodies, which means that they block Programmed Death 1 (PD-1), which is a molecule expressed on immune cells. Thinking about the immune system like a car, there are two ways to make a car go faster. One is to push on the gas pedal and the other is to take your foot off the break. The immune system has many breaks and many gas pedals that help it determine precisely when to attack and when to stop attacking. PD-1 is akin to a “break” of the immune system, and cancers, including head and neck cancer, can step on this break. Cancers do this primarily via expressing another molecule called PD-L1, which sends a signal through PD-1 on an immune cell to tell that immune cell to stop attacking the cancer. Nivolumab and Pembrolizumab and other drugs with the same target block this break so it cannot be “stepped on” by the cancer to slow down the immune system.
Every drug has potential side effect. These anti-PD-1 monoclonal antibodies have general side effects as well as other side effects that are specific to how these drugs work on the immune system. These later side effects are called immune related adverse events. Because these drugs take the foot off the break of the immune system to allow it to go faster and try and attack the cancer, the immune system can also potentially attack and cause inflammation of normal tissue and organs in the body. When this happens the side effects are described as immune related adverse events.
General Side Effects
General side effects that may commonly be experienced include fatigue, nausea, and decreased appetite. Every patient is an individual, and so there can be variability in these side effects. Some patients experience little if any change in appetite or energy, while others may experience significant fatigue and low appetite. However, most patients experience some element of fatigue and mild decreased appetite. Nausea can occur, however it is typically significantly less than with traditional chemotherapy medications, like Cisplatin, that are commonly used in head and neck cancer. Additionally, like other cancer medications, a patient may have an allergic reaction to the drug when it is infused.
Immune Related Adverse Events
Immune related adverse events can affect any part of the body. The more common areas that may be affected include the glands, the lungs, the liver, the skin, and the colon. They can occur at any time during your treatment. If a patient develops an immune related adverse event, the severity will determine the treatment. General treatment for mild immune related adverse events includes stopping treatment until the side effects resolves. For moderate or severe adverse events, treatment is stopped and immunosuppressive medications are started to suppress the immune system and stop it from attacking the normal tissue/organs in your body. Steroids are the first type of immunosuppressive medication that is started, and if the steroids start working, it is recommended that they continue for at least a month. In most cases, immune related adverse events can be managed effectively with immunosuppressive medications, and after the immune related adverse event resolves and the steroids are finished, the immunotherapy may be restarted depending on the initial severity of the side effect that occurred.
However, these adverse events can become very serious and life threatening if treatment for them does not occur early. Therefore, it is important for your physician to always consider whether your symptoms are immune related and for you to always report how you are feeling, so that your physician can make an assessment. As will be described below, some of the symptoms of immune related adverse events are non-specific and like side effects that you may have experienced in the past with other treatments. Some of them, like diarrhea for example, you may have managed prior by yourself at home without a call to the physician. Therefore, a patient undergoing this treatment must stay vigilant in letting their physician know if you have developed any new symptoms. There is not one sole diagnostic test that can determine if you have an immune related adverse event. The diagnosis is often based on ruling out other non-immune related causes to the symptoms. Just as you stay vigilant in terms of reporting your symptoms, your treating physician will remain on alert to consider whether a symptom that has developed is an immune related adverse event.
Organs That May be Affected by Immune Related Adverse Events
The Endocrine System (Glands)
The glands in the body, including the thyroid gland, the adrenal glands, and the pituitary gland, make substances called hormones that help regulate how the body works. While if the glands are inflamed and not working properly you may feel symptoms, your treating physician will need to draw blood work to confirm if the endocrine system is being affected.
The thyroid gland makes thyroid hormone which has a number of functions including metabolism. Treatment with these immunotherapy medications may make the thyroid work too much (hyperthyroid) or not enough (hypothyroid). If the thyroid is working too much there will be higher than normal levels of thyroid hormone in the body which may cause you to feel hyper, feel hot, have heart palpitations, have frequent bowel movements, or lose weight, among other symptoms. If the thyroid is not working enough, then there will be too little thyroid hormone and you may feel fatigued, constipated, feel cold, or gain weight. The thyroid gland is the most common gland to be potentially affected, with hypothyroid being more common than hyperthyroid. If the thyroid gland is not working enough, your physician will give you thyroid hormone in the form of a pill.
The pituitary gland, which is located at the base of the brain, is called the “master gland” because it sends out hormones that control other glands. If the pituitary gland becomes inflamed as a side effect, this is called hypophysitis. If this develops, you may feel headache and fatigue and other glands in the body will not work as well because there is no signal coming from the pituitary gland. If hypophysitis occurs, in addition to starting immunosuppressive medication, your physician will also refer you to an endocrinologist for management and replacement of hormones that are needed.
Finally, the adrenal glands make numerous different substances for the body including steroids. While it is rare for the adrenal glands to become affected by these drugs, if they do, the glands typically are underactive, which can lead to fatigue, electrolyte imbalances, dizziness, and nausea. During treatment, your physician should check thyroid hormone levels in the blood regularly and will check for other glands as needed if there is suspicion based on symptoms.
The lungs are another organ system that can be affected by the immune system. This can lead to inflammation of the lungs called pneumonitis. Symptoms of pneumonitis include trouble breathing, cough, pain with deep breaths, and fever. While pneumonitis is rare, occurring in around only 2% of patients, it can become severe, and so it is important to let your physician know right away if you are having any new respiratory symptoms. The physician will then based on your symptoms initiate a work up which in most cases includes doing imaging to visualize what is going on in the lungs and depending on the findings may include have you see a lung specialist (pulmonologist).
The Gastrointestinal System
The intestine includes the small intestine as well as the large intestine. Both the small and large intestine can become inflamed by the immune system. If this inflammation occurs a patient may experience diarrhea and abdominal pain. Diarrhea is something that you may have experienced from other chemotherapy medications you received prior and while in the past you may have just taken anti-diarrheal medications at home, it is very important to report these symptoms to your physician right away. Your treating physician will rule out any other infectious cause and may have you undergo imaging to evaluate what the small intestine and large intestine look like. Potentially an endoscopy (camera study) may be done to work up the symptoms.
The liver can become inflamed which is called hepatitis. If the liver becomes very inflamed you may turn yellow which is called jaundice and additionally feel weak, nauseous, have pain underneath your rib cage on the right side and have itchy skin and light-colored stools. Most of the time hepatitis is picked up on labs called liver function tests which are drawn routinely by your physician. Similar, to diarrhea the treating physician will want to rule out other causes, including medication or viruses, that can also cause abnormalities in your liver function tests.
The skin is the most common organ to be affected by an immune related adverse event. This is most commonly in the form of a rash. The rash is typically red and involves the trunk and the arms/legs. Your physician will usually start with creams to apply directly to the skin if it appears. You may also experience some itching. Vitiligo, where the skin loses pigmentation and may become whiter, can also occur.
Other Organ Systems
Very rarely the heart, kidney, muscles, or nerves can become inflamed as a side effect of anti-PD-1 monoclonal antibodies.
Rarely when being treated with anti-PD-1 monoclonal antibodies the tumor can enlarge before then responding to the drug and shrinking. This phenomenon termed pseudoprogression is felt to be from inflammation of the tumor itself from the immune system attacking it, which leads to enlargement before subsequent shrinkage. In the head and neck because tumors are close to the airway and areas that may cause pain with enlargement, a patient may experience some worsening of breathing or pain. These symptoms must be reported to your physician right way and that physician will decide as to whether the symptoms are felt to be from the cancer growing and not responding to the anti-PD-1 monoclonal antibody, or if he/she feels this may be pseudoprogression. Often times an imaging study is needed to evaluate the tumor to help make this determination. However, currently there are no specific tests or imaging studies that can be done to say for certain whether enlargement is failure of the cancer to respond to the drug or pseudoprogression. Therefore, your physician will weigh many factors, including how you are feeling overall, in determining whether to stop the drug because it is not working or to continue for a short time period longer to re-evaluate whether this is pseudoprogression or not.
Checkpoint inhibitors targeting PD-1, like Nivolumab and Pembrolizumab, are now approved across many tumor types in addition to HNSCC, and have changed how we treat patients. The success of these drugs as single agents has led to a lot of exciting research and clinical trials attempting to continue to make outcomes better by combining these drugs with other immunotherapy medications, chemotherapy, and/or radiation. While this article has discussed a lot of potential side effects, importantly these drugs, including in head and neck cancer, have been generally well tolerated, with only a minority experiencing significant side effects. Importantly, in the large study where Nivolumab was compared to chemotherapy in HNSCC, that led to the approval of Nivolumab by the FDA, patients treated with Nivolumab had less side effect overall and less severe side effects compared to those treated with chemotherapy. Additionally, treatment with Nivolumab improved patients’ quality of life more than chemotherapy in this clinical trial. The different spectrum of side effects and generally good tolerance of these drugs compared to traditional chemotherapy, also allows physicians to offer these to patients that may have lasting side effects from prior treatment for their HNSCC. That being said, as this article highlights, immune related adverse events can become severe if not recognized and treated early. Therefore, vigilance and good communication by both patient and physician is imperative for safe and successful treatment of head and neck cancer with anti-PD-1 monoclonal antibodies.
Editors Note: Dr. Dan Zandberg obtained his MD from Jefferson Medical College and his internal medicine residency at the George Washington Univ. Medical Center. He is currently at the University of Pittsburgh Medical Center Hillman Cancer Center, as Associate Professor of Medicine, Director of the head and neck and thyroid cancer disease sections for the division of hematology/oncology, and co-director of the UPMC Hillman head and neck cancer research program.