A 63-year-old man, Andrew, presents to the emergency department with a several-day history of worsening diarrhea. He has abdominal pain rated 6/10, has been having over 8 loose stools per day for 4 days, and tells you he has seen some blood and mucus in his stools. He denies any nausea, vomiting, fevers or chills, sick contacts or recent travel. However, he tells you that he is under-going active treatment for Stage IV melanoma.
He is afebrile, normotensive but tachycardic (HR 110), and appears dehydrated. Review of systems is otherwise normal. On exam, his abdomen is quite tender to palpation but not peritonitic.
As you review his medications you see his cancer drug “ipilimumab.” A quick search on UpToDate describes it as an “immunotherapy medication” – you’re not familiar with this class of medication and wonder if it might affect your work-up and management strategy.
Oncology patients often present to the ED acutely ill with complications of their cancer treatment. Approaches to common complications of chemotherapy like febrile neutropenia are well-established among ED clinicians. However, newer classes of anti-cancer drugs, such as immunotherapy, cause a unique set of complications requiring a distinct approach to diagnosis and management in the ED. For oncology on these medications, the standard algorithms for chemotherapy patients no longer apply!1
Overview of Cancer Immunotherapy
Immunotherapy medications are a class of cancer therapeutics that enhance the immune response to cancer cells to improve anti-tumor immune activity.2 The initial approach to cancer immunotherapy used cytokines and other pro-inflammatory immunomodulatory agents.2 In recent years, immunotherapy medications known as immune checkpoint inhibitors (ICIs) have been shown to be highly effective in treating multiple malignancies, such as melanoma, renal cell carcinoma, bladder cancer and lung cancer.2 ICIs are monoclonal antibodies that block the signalling pathways (immune checkpoints) that down-regulate the T-cell response to tumor cells.2,3 These immune checkpoints normally prevent excessive and damaging immune response to foreign antigens.3,4 However, in cancer, these pathways provide a mechanism for tumor cells to escape the immune system.3,4
There are three main classes of immune checkpoint inhibitors, with examples of each class listed below1:
- CTLA-4 inhibitors – ipilimumab
- PD1 inhibitors – nivolumab, pembrolizumab
- PDL1 inhibitors – atezolizumab, durvalumab
All three classes work by increasing T cell activation, proliferation and infiltration, and memory cell formation.1 While blocking immune checkpoint pathways promotes anti-tumour immunity, it also removes some of the normal checks and balances on immune activity, and can lead to uncontrolled and aberrant immune activity. Therefore, complications of ICIs are due to auto-immune toxicity caused by over-activation of the immune system, and are referred to as immune-related adverse events (irAEs).1,4
It is crucial to differentiate immune-related adverse events from adverse events seen with chemotherapy. Chemotherapy works by killing rapidly dividing cells, such as immune cells (leading to complications like febrile neutropenia) and cells lining the GI tract (leading to complications like chemotherapy-related diarrhea). However, complications of immunotherapy drugs are due to the immune system attacking the body’s own cells, and can be equally life-threatening or fatal.1
Immunotherapy-Related Adverse Events
This review will focus on the management of immunotherapy-related diarrhea and colitis, with additional discussion of the management of pneumonitis and dermatologic complications. Information on the diagnosis and management of hepatic, endocrine, hematological, cardiac and rheumatoid complications, which are less common, can be found through Cancer Care Ontario.5 Other resources include the American Society of Clinical Oncology2 and European Society of Medical Oncology Clinical Practice Guidelines.3 Treatment of irAEs outside of acute management in the ED is beyond the scope of this article.
Emergency physicians should have a high level of suspicion for irAEs in patients presenting to the ED on immune checkpoint inhibitors. Complications can affect any organ system and can mimic common auto-immune presentations.1–4 CTLA4 inhibitors (e.g. ipilimumab) have higher rates of complications than PD1/PDL1 inhibitors, but irAEs can occur with any ICI.3 Patients on combination therapy with more than one ICI are at a higher risk of complications.3 Mild dermatologic, respiratory and gastrointestinal side effects are fairly prevalent (up to 40-50% of patients), but rates of serious irAEs are lower (<10%).1–3
Approach to Management
Key Points on History
When cancer patients undergoing active treatment present to the ED, the first step is to clarify the type and stage of malignancy and type of cancer therapy (chemotherapy, targeted therapy, or immunotherapy). An initial approach should include keeping a broad differential in mind and screening for other causes, including infection, malignancy-related complications, or other systemic diseases. If the presenting symptoms are suspected to be related to immunotherapy, the Common Terminology Criteria for Adverse Events (CTCAE) grading system can be used to help guide an assessment of symptom severity.
Basic Investigations
Initial investigations should include basic bloodwork, with the addition of liver enzymes and liver function tests for GI symptoms.1–4 A chest X-ray should be ordered for patients presenting with respiratory symptoms, and abdominal imaging (X-ray, ultrasound, or CT) for patients presenting with GI symptoms.1–4 Stool testing (including for C. difficile) is also indicated for patients with diarrhea.1–4
Principles of Management in the ED
The key considerations for acute management of immune-related adverse events are to contact the on-call oncology team for guidance, decide whether corticosteroid therapy is imminently indicated, and assess the need for admission or consultation of other specialties.1 Immunotherapy is administered intravenously typically every 3-4 weeks, therefore the decision of whether to continue with the next dose of immunotherapy will be made by the treating oncologist.1
The first step is assessing the severity of symptoms and initiate a work-up to investigate other causes of symptoms.1 If there is a high index of suspicion for an irAE and the patient is unstable or presenting with severe symptoms suggesting a need for urgent intervention, corticosteroid therapy can be initiated.1 Contacting the oncology team should be a priority, along with a low threshold for consulting the medicine team or other subspecialists.1 If available, the on-call oncology team should be consulted about management and disposition for patients presenting with suspected immunotherapy-related adverse events.1 The patient’s treating oncologist should also be consulted whenever possible, especially for patients with more severe symptoms.1 All patients discharged directly from the emergency department should be instructed to follow-up immediately with their treating oncologist.1
Symptom Staging and Management for Common Immunotherapy-Related Adverse Events
| Grade | Diarrhea | Colitis | Pneumonitis | Rash |
| Grade 1 | <4 stools/day above baseline | Asymptomatic, clinical or diagnostic observation only | Asymptomatic radiographic changes (e.g. ground-glass appearance or patchy lower lobe opacities) | Asymptomatic or pruritus well-controlled on antihistamines or topical agents, and rash covering <10% of BSA with no erythema or pain |
| Grade 2 | 4-6 stools above baseline | Abdo pain Mucus or blood in stool | Mild to moderate symptoms (dyspnea, cough, chest discomfort) | Symptomatic despite topical agents, with blistering or morbilliform rash covering 10-30% of BSA or with systemic symptoms |
| Grade 3 | ≥ 7 stools above baseline or episodes of incontinence | Severe abdo pain, changes in bowel habits, peritoneal signs | Severe symptoms (dyspnea, cough, chest pain) Requirement of supplemental oxygen | Symptomatic rash refractory to oral steroid therapy, painful blistering >30% of BSA or skin sloughing <10% |
| Grade 4 | Life-threatening severe diarrhea | Life-threatening severe colitis | Severe symptoms, respiratory distress | Intolerable or refractory rash, signs of SJS/TENS/DRESS or blistering >30% of body surface area |
Diarrhea and Colitis
Hydration and supportive therapy is the mainstay of treatment for patients who are systemically well with mild diarrhea (Grade 1 symptoms).1,2 Loperamide can be offered for symptomatic relief if there is no suspicion of infection.1,2,5 Admission is not indicated, and patients should be encouraged to follow-up closely as an out-patient with their oncologist.1,5 For patients with more severe (Grade 2+) diarrhea or with signs of colitis (abdominal pain, blood, or mucus in stool), an infectious work-up should be initiated.1,2,4 Grade 2 diarrhea can often be managed as an out-patient with close follow-up with the treating oncology team, but admission with a gastroenterology consult for consideration of colonoscopy should be considered if patients are systemically unwell or have persistent diarrhea.1,4 Oral steroid therapy (prednisone 0.5-1 mg/kg/day) can be started in the ED if colitis symptoms are present or if diarrhea is persistent.1,4 Patients with persistent or refractory diarrhea may require admission and referral to gastroenterology.5
Patients with Grade 3 or 4 diarrhea or colitis (severe or life-threatening symptoms) should undergo imaging to look for perforation (abdominal X-ray or a CT abdomen).1,2,4 If there is suspicion of an immunotherapy-related adverse event, initiation of intravenous corticosteroid therapy (equivalent of 1-2 mg/kg/day of prednisone) should occur in the ED.1 These patients will require admission, gastroenterology consultation and referral to general surgery if suspicion of perforation.5
Pneumonitis
Oncology should be consulted for patients with suspected immunotherapy-related pneumonitis. Grade 1 pneumonitis is asymptomatic, and is a radiologic diagnosis.5 Patients on immunotherapy with radiographic changes suspicious for pneumonitis (e.g. ground glass appearance or patchy nodular infiltrates) should be instructed to urgently follow-up with their oncologist for consideration of steroid therapy and to return to the ED if they develop dyspnea, cough, or chest pain.1,5 For patients on immunotherapy with mild to moderate cough or dyspnea (Grade 2 symptoms), a work-up should be initiated for infectious causes and pulmonary embolism.1,2 Chest X-rays are a good initial imaging modality, however, up to 25% of pneumonitis cases may be missed on chest X-ray.6 A high-resolution CT chest should therefore be considered for patients with a negative chest X-ray and clinical suspicion of pneumonitis.6 Antibiotics can be started if there is suspicion of a respiratory infection.1,2,5 If no evidence of infection or symptoms have not improved on antibiotics, the equivalent of 1-2 mg/kg of prednisone (oral or IV) should be started in the ED.1,2,5 The oncology team should be consulted about disposition for these patients and admission may be indicated for monitoring.5 If patients are discharged, they should have close oncology follow-up and instructions to return if symptoms persist or worsen.1,5
Patients on immunotherapy with more severe respiratory symptoms, requiring supplemental oxygen or in respiratory distress (Grade 3-4 symptoms) should undergo initial assessment and management of ABCs, with oxygen and ventilatory support as needed. A work-up for infectious or embolic causes should be initiated and empiric antibiotic therapy should be started.1,5 High-dose intravenous corticosteroids (equivalent of prednisone 1-2 mg/kg for Grade 3, and up to 2-4 mg/kg for respiratory distress) should be initiated in the ED, as immunotherapy-related pneumonitis can be life-threatening.1,5 Patients with Grade 3 or greater symptoms of pneumonitis require admission and an oncology consult.1
Rash
Patients with Grade 1 to 2 dermatologic symptoms on immunotherapy do not require admission, but need oncology follow-up. Antihistamines and topical corticosteroids are the first line of treatment, and oral steroids (equivalent of 0.5-1 mg/kg/day of prednisone) can be started for Grade 2 rashes or rash persisting despite topical corticosteroid use.1 Patients with more severe rashes or blistering (Grade 3 or higher) or who are symptomatic despite oral steroid therapy should be started on corticosteroids (0.5-1 mg/kg oral or intravenous).1,5 Mucosal involvement, systemic symptoms or suspicion of infection are all indications for admission to hospital. Grade 4 dermatologic complications are rare, and require immediate initiation of intravenous corticosteroids (equivalent of prednisone 1-2 mg/kg/day), and admission to hospital.5 Patients with signs of Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TENS) or DRESS syndrome will require fluid resuscitation and admission to the burn unit or ICU.1,5
Summary of Approach to Patients on Immune Checkpoint Inhibitors
CTCAE Grading System7
Return to the Case
Initial investigations showed a normal CBC (no neutropenia) and electrolytes. There was no free air under the diaphragm on x-ray.
Andrew’s history and presentation suggest that his diarrhea is likely an immunotherapy-related adverse event. He has more than 7 stools a day (Grade 3 diarrhea) with colitis symptoms, and you recognize that this is best described as a severe (Grade 3) gastrointestinal immunotherapy-related adverse event. While infectious causes should still be ruled out with a more thorough work-up, you recognize that this should not delay the initiation of high-dose steroid therapy and consultation given the severity of his symptoms and lack of obvious infectious etiology.2
You start him on intravenous fluids for rehydration and begin high-dose IV glucocorticoid therapy (equivalent of prednisone 1-2 mg/kg/day).1,2,7 He is referred to medicine for admission, his oncology team is contacted, and gastroenterology is consulted for consideration of further investigations. The decision about whether to continue with the planned next dose of immunotherapy will be made by the treating oncology team.
Summary
In summary, immunotherapy drugs are increasingly used in the treatment of multiple malignancies.1–3 A broad spectrum of immunotherapy-related adverse events exists, with skin, GI tract and lungs most commonly affected.1–3 Immunotherapy is distinct from chemotherapy, and complications require a distinct approach to management. High-dose corticosteroids are the basis of emergency management for severe cases, along with supportive therapy and early consultation to medicine, oncology and other appropriate specialists.1–3 Careful medication reviews (look for drugs ending in “mab”) for oncology patients and a high index of suspicion for immunotherapy-related adverse events are key in the early detection of complications and appropriate management of these patients.
A tool-kit and guidelines by Cancer Care Ontario for management of immunotherapy toxicities can be found at: https://www.cancercareontario.ca/en/guidelines-advice/modality/immunotherapy/immune-therapy-toolkit.5
This article was uploaded by Amy Chung.
References
Reviewing with the staff
Treatment options for oncology patients are rapidly expanding. This is particularly apparent in the field of immuno-oncology where new indications for immmunotherapy are being approved nearly every month. In general, immune checkpoint inhibitors tend to have fewer side effects and lead to a better quality of life when compared to traditional chemotherapy. However, when serious side effects do occur, they must be recognized and treated immediately to prevent the subsequent deterioration of patients. This requires an entirely new skillset and knowledge-base for front-line practitioners in the Emergency department.
This article neatly sums up the differences in mechanism of action, side effects and management algorithms between traditional chemotherapy and immunotherapy. Key resources in this article include:
- The helpful CTCAE grading system used to guide assessment of severity of these immune-related adverse events
- Easily accessible chart indicating the emergency management of common immune-related adverse events
- Practical guidance on the role of steroids in the immediate management of unwell patients
- A link to our provincial toolkit: https://www.cancercareontario.ca/en/guidelines-advice/modality/immunotherapy/immune-therapy-toolkit
Ultimately, the importance of involving the oncology team as early as possible in the work-up and treatment of suspected or proven immune-related adverse events cannot be overstated. This is particularly important for patients enrolled in clinical trials involving immune checkpoint inhibitors.
Arden Azim