A patient presented to the emergency department at UC San Diego Health after a syncopal episode. He had significant hypotension and abnormal electrolytes, including low sodium and high potassium. The patient had recently been treated with the anti-PD-1 cancer immunotherapy drug pembrolizumab (Keytruda), which quickly raised suspicion for Christopher Coyne, MD, an assistant professor of emergency medicine there, that she was experiencing the onset of an adrenal crisis.
“She had been to see her oncologist a few days prior, just complaining of mild fatigue,” said Dr. Coyne. “They had sent off a cortisol test and that came back low, but no one had addressed it, so she came to the ED after experiencing a fainting episode.”
No response to fluids further suggested adrenal insufficiency, and Dr. Coyne said he quickly initiated treatment with high-dose hydrocortisone. “Her blood pressure responded quickly to the steroids, and endocrine evaluation confirmed adrenal insufficiency. She was maintained on steroids during hospitalization, and the workup confirmed adrenal insufficiency related to her therapy. She ended up doing fine.” Had Dr. Coyne not been alert to the signs, however, delayed treatment for the adrenal crisis could have been fatal.
Emergency physicians can expect to encounter more and more patients experiencing complications related to these medications because nearly half of all U.S. cancer patients are eligible for treatment with immune checkpoint inhibitors, and not only at tertiary care institutions with affiliated cancer centers like UCSD. (JAMA Netw Open. 2019;2:e192535; http://bit.ly/2Zb6sIB.)
“You see commercials for Keytruda on TV regularly now, and these therapies are becoming much more commonly used in community oncology practice,” said Dr. Coyne, an author of a recent review on managing immune checkpoint inhibitor toxicities in the emergency department. (J Emerg Med. 2018;55:489.) “Many of the patients we end up treating at our cancer center were already started on immunotherapies at community practices before coming to UCSD, so the potential for these patients coming into community EDs is definitely high.”
All too often, there can be confusion about the types of adverse events these patients experience, as well as their timeline. “A significant challenge is that these patients will come into the emergency department and tell the doctor that they're on chemo for cancer, and they'll use the word chemotherapy interchangeably with immunotherapy,” said Maura Sammon, MD, an assistant professor of clinical emergency medicine at the Lewis Katz School of Medicine at Temple University in Philadelphia. “They don't realize the distinction between the two. A person who is on chemotherapy is immunosuppressed, while a person being treated with immunotherapy has just the opposite: an upregulated immune system. Perhaps a clearer way to frame it in your mind is as something like graft vs. host disease.”
Eddy Lang, MD, the academic and clinical department head and an associate professor of emergency medicine at the University of Calgary's Cumming School of Medicine, called it the newest oncologic emergency. “The key message around the clinical presentation is that these agents can trigger an autoimmune and inflammatory response—basically, an -itis,” he said, “colitis, pneumonitis, dermatitis, any kind of inflammatory organ-specific or multi-organ phenomenon.
“Traditional approaches are out the window. The [emergency] physician who receives one of these patients must be aware that immune-suppression therapy may need to be started sooner rather than later, and that consultation with the oncology team is important. If you misinterpret these patients' symptoms as infectious, you may be giving ineffective or even harmful treatment.”
Worst is First
Operating under the traditional ED maxim of considering the worst first, Dr. Sammon advises physicians to be alert for two particularly dangerous immunotherapy toxicities: endocrinopathies, like the adrenal insufficiency case Dr. Coyne described, and pneumonitis.
Endocrinopathies have a widely varying reported incidence in patients undergoing immunotherapy, and are particularly difficult to diagnose because at low-grade levels they can mimic a viral syndrome. “Patients might present with just fatigue and headache,” Dr. Sammon said. “If the pituitary is involved, the patient might have double vision since that gland is right near the cavernous sinus. Immunotherapies can produce either direct adrenal insufficiency from primary involvement of the adrenal glands or secondary involvement through the pituitary. These toxicities can manifest as an adrenal crisis, with dehydration, hypotension, and electrolyte imbalances, which can be fatal.”
Immunotherapy's other most dangerous complication is the noninfectious lung inflammation pneumonitis. This is a rare event, with an all-grade incidence of three to five percent, but it is subtle and insidious at onset and can be rapidly progressive and fatal. The most common presenting symptoms are dyspnea and cough.
“If a patient is short of breath and you're stuck in a traditional cancer chemotherapy mindset, you might just do a chest x-ray or D-dimer, and if the patient is not very symptomatic, stop there,” Dr. Sammon said. “But early findings for pneumonitis may not be seen on a chest x-ray. You need to keep a high index of suspicion for this if your patient is on immunotherapy, and err on the side of proceeding to a CT. Don't under-image in these patients.”
Most Common Symptoms
Usually less dangerous but more prevalent and with their own risks are the two most common immunotherapy toxicities, diarrhea and rash.
Diarrhea grade is measured by how many stools above baseline the patient is having per day. “Mild diarrhea, less than four additional stools per day, might not necessarily be treated at all, just tested for other potential causes such as via a C. diff stool culture,” Dr. Sammon said. Even patients in the moderate category of four to six additional stools per day might not require hospital admission or immediate treatment; at this stage, the emergency physician may simply elect to hydrate, send stool studies, and discuss with the treating oncologist whether the patient should be admitted and started on steroids.
“If the patient is experiencing severe diarrhea of greater than seven additional stools daily, that could be a dangerous immune-related colitis,” Dr. Coyne said. “Having that index of suspicion is very important. If someone comes in with diarrhea, you could chalk it up to a simple viral or intestinal infection and just send them home, and they could progress to perforation.”
Rash in immunotherapy patients is graded similarly to burn patients based on the total body surface area involved in the reaction. A mild rash of less than 30 percent of body surface area can be treated with topical steroids and diphenhydramine, while a moderate rash of 30-50 percent may begin with a similar approach and move on to systemic steroids if no improvement is shown within a week. “In severe toxicity, involving more than 50 percent of the body surface area, the clinician should be looking for signs like dermal ulcerations, bullous lesions, and necrosis,” Dr. Sammon said. “These patients may clinically resemble Stevens-Johnson syndrome or toxic epidermal necrolysis [TEN], and should be considered for transfer to a burn center.”
Additional toxicities that may present in cancer immunotherapy patients include hepatic findings such as hepatitis, ocular findings such as uveitis and episcleritis, rheumatologic complications such as arthralgia, renal insufficiency, neurologic complications including neuropathy and autoimmune encephalitis, and Guillain-Barré syndrome. “These agents have a wide range of potential toxicities,” Dr. Sammon said. “The [emergency] clinician should focus on the most life-threatening first and then the most common.”
The schedule during which these complications manifest can vary widely, and does not mirror the typical adverse event schedule of cancer chemotherapy that clinicians may be used to. The median onset for many of the immune-related side effects is one to three months, but they can occur within days of starting treatment or after many months of treatment. “Just because the most common time for a certain toxicity to occur is X, that doesn't mean it can't occur at any time during immunotherapy treatment,” Dr. Sammon said, “so it's really important not to hang your hat on a specific time frame, thinking, ‘Oh, this can't be pneumonitis because this person just got [a] second dose.’”
Steroids, Steroids, Steroids
Emergency treatment for all of these complications—major and minor—falls under the same general class: “Steroids, steroids, steroids,” said Dr. Sammon. “The way to stop the upregulation of the immune system is to give steroids. The type of toxicity and its grade decides your dose and when to start. For example, a grade 2 pneumonitis calls for 1 mg/kg per day of a prednisone equivalent.”
Emergency physicians don't need to learn every possible treatment dosage for every toxicity and grade, but should be aware of the common immunotherapy toxicity manifestations and where to find references for these treatments easily. The UpToDate article “Special Considerations and Toxicities Associated with Checkpoint Inhibitor Immunotherapy” includes treatment recommendations and dosages for known toxicities. (Sept. 30, 2019; http://bit.ly/34FzdhW.) Some oncologists will also give their immunotherapy patients a reference card to carry with them.
Regular and open communication with the patient's treating oncologist is essential. “We need to be acting as a team with these patients,” Dr. Sammon said. “Most oncologists will want to be called early and be very involved in these patients' emergency care.”
But the emergency physician will be on the front lines of these complications more often than not. “If an oncology group has great communications and looks after their patients very well, they can often avoid an ED visit if they develop complications, but when a patient does have problems and calls the oncology nurse, they're often told to go to the ED, especially if they're having significant symptoms,” said Dr. Coyne. “Most oncology clinics do not have mechanisms for direct admission of unwell patients at 3 a.m., and these complications can come about fairly suddenly. The patient hasn't seen the oncologist in three months, and, bang, they develop severe diarrhea or shortness of breath. As [emergency] physicians, we will be on the receiving end of more and more of these complications.”
Looking Downstream: More Complications
A patient with agitated delirium was recently taken by ambulance to the University of San Diego emergency department in restraints because he had been combative with paramedics. About an hour after his ED admission, the man's wife was finally located, and she told physicians that he had been treated with CAR-T cell therapy for cancer. “We were able to treat him with the IL-6 inhibitor tocilizumab, and he recovered well,” said Christopher Coyne, MD, an assistant professor of emergency medicine.
Neurotoxicity is one of the two primary toxicities associated with CAR-T therapy, the other being cytokine release syndrome. Now called immune effector cell-associated neurotoxicity syndrome (ICANS), this is characterized by global encephalopathy, aphasia, seizures or seizure-like activity, obtundation, tremors or myoclonus, and hallucinations. Studies have found that as many as 77 percent of CAR-T patients experience at least one neurologic side effect, although these are almost always reversible with treatment. (Brain. 2019;142:1334; http://bit.ly/2rdkxbZ.)
Currently, most of the toxicities associated with CAR-T therapy will be seen by the treating oncology team because patients are typically hospitalized for approximately three weeks. “But these complications can happen several weeks after infusion, and in fact, some of the more severe manifestations can develop pretty late,” said Dr. Coyne. “They're not going to keep these patients hospitalized for three months, so as CAR-T therapies become more prevalent, emergency physicians at community hospitals may begin to see more of the associated toxicities. It's important to be aware of these therapies and have an index of suspicion.”
Watch our webinar, “Immunotherapy-Related Toxicities in the ED: A Case Study Approach,” at http://bit.ly/ImmunotherapyWebinar, to learn more about how these affect your patients. The webinar features Monica Wattana, MD, and Demis Lipe, MD, both assistant professors of emergency medicine, and Ishwaria M. Subbiah, MD, an assistant professor of palliative care medicine, all at the University of Texas MD Anderson Cancer Center.
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Ms. Shawis a freelance writer with more than 20 years of experience writing about health and medicine. She is also the author of Having Children After Cancer, the only guide for cancer survivors hoping to build their families after a cancer diagnosis. You can find her work atwww.writergina.com.