# Guideline Resource Unit

# Background
Immune checkpoint inhibitors (CPIs) are monoclonal antibodies (mAb) which increase antitumour activity by blocking intrinsic downregulators of immunity. The primary targets of CPIs include the programmed cell death-1 (PD-1) and its ligand PD-L1, as well as cytotoxic T lymphocyte-associated antigen 4 (CTLA-4). CPIs are effective in a broad range of cancers and it is anticipated that their indication will continue to expand to a number of additional malignancies. 1 Currently, their use is approved in the setting of melanoma, non-small cell lung carcinoma, renal cell carcinoma, and bladder cancer. 1 Additionally, CPI therapy has shown utility in other malignancies, including head and neck squamous cell, gastric, hepatocellular and ovarian cancers, certain types of breast or colorectal cancer, and Hodgkin lymphoma. 1,2 Drugs in this class include ipilimumab, a selective humanized IgG-4 kappa monoclonal antibody that inhibits CTLA-4 to ultimately activate T cells against malignant tumour cells. 3 Ipilimumab was approved for use in Canada in 2012. The PD-1 targeting monoclonal antibodies nivolumab and pembrolizumab were approved in 2015. 3 Immunotherapies are associated with better tolerance overall compared to traditional chemotherapy agents 2 . By modulating the activity of immune system, immune checkpoint blockade can cause inflammatory side effects, termed immune-related adverse events. Immune-related adverse events (irAEs) are toxicities caused by non-specific activation of the immune system and can affect almost any organ system. Most commonly these irAEs can be organized into the following categories: dermatologic, pulmonary, gastrointestinal, hepatic, and endocrine. 1 Other rarer and potentially lifethreatening toxicities can also occur, involving the central nervous system, cardiovascular, musculoskeletal, and hematologic systems and treatment-related deaths have been reported in up to 2 percent of patients in clinical trials. 1,4,5 irAEs resulting from CPI therapy can have delayed onset and prolonged duration compared to chemotherapy, primarily due to pharmacodynamics differences. 5 For this reason, the clinician needs to remain vigilant. The management approach to irAEs is primarily based on clinical experience, as no prospective trials are available to inform irAE treatment strategies. There is a wide spectrum of potential immune-mediated toxicities which requires collaborative, multidisciplinary management. 4 The underlying pathophysiology of irAEs is thought to be secondary to the role that immune checkpoints play in maintaining immunologic homeostasis. 4 The precise mechanisms that result in irAEs are still being elucidated but potential mechanisms include increasing T cell activity against antigens that are present in tumours and healthy tissue, increasing levels of pre-existing autoantibodies, increase in levels of inflammatory cytokines, and enhanced complement mediated inflammation. 4 PD-1 is thought to inhibit T cells at later stages of the immune response in peripheral tissues, whereas CTLA-4 is believed to act at a more proximal step in immune response, acting in several ways including attenuating T cell response. The irAEs are also different between these two classes of mAb, with more severe toxicities often seen in patients treated with CTLA-4 inhibitors. 6 Guideline Resource Unit PD-L1 mAb Renal cell carcinoma Special access: mesothelioma, non-small cell lung cancer nivolumab (Opdivo) PD-1 mAb Melanoma, renal cell carcinoma, non-small cell lung cancer, head and neck squamous cell carcinoma, Hodgkin lymphoma Special access: gastric adenocarcinoma, esophageal or GE junction cancer pembrolizumab (Keytruda) PD-1 mAb Melanoma, non-small cell lung cancer, head and neck squamous cell carcinoma, urothelial carcinoma, gastric adenocarcinoma, Hodgkin lymphoma, renal cell carcinoma Special access: MMR deficient tumours, bladder cancer, esophageal cancer, triple negative breast cancer, MSI-H endometrial cancer avelumab (Bavencio) PD-L1 mAb Merkel cell carcinoma, urothelial carcinoma durvalumab (Imfinzi) PD-L1 mAb Special access: non-small cell lung cancer, bladder cancer cemiplimab (Libtayo) PD-1 mAb Cutaneous squamous cell carcinoma Special access: basal cell carcinoma, non-small cell lung cancer Guideline Questions
- What are the appropriate protocols for follow-up to monitor for irAEs in adult patients treated with checkpoint inhibitors for cancer? 2. What are the recommended management strategies for irAEs associated with checkpoint inhibitors in adult cancer patients? 3. Is it safe to restart treatment after an irAE?

# Search Strategy
PubMed was searched for articles published before March 2018 with the search terms 'immune checkpoint inhibitor', and 'adverse events', and 'cancer'. Additionally, guidelines from other organizations were included in the literature search. For a detailed description of the literature search and results, please see Appendix A.

# Target Population
The recommendations contained in this guideline are intended for use in adult patients over the age of 18 years who are being considered for or are receiving checkpoint inhibitors as part of their treatment for cancer. Different principles may apply to pediatric and adolescent patients.

# Guideline Resource Unit

# Recommendations
General Approaches to Toxicity Management 1. It is widely acknowledged that cancer patients with pre-existing autoimmune disorders are at an increased risk of developing immune-related adverse events (irAEs). The treating oncologist should weigh the potential benefits of therapy against the risks of adverse events before deciding to proceed with treatment. 2. The current approach to managing irAES incorporates prevention, anticipation, detection, treatment and monitoring. 1 Patients on checkpoint inhibitors (CPI) should be monitored by a health care professional with experience identifying and managing irAEs. 3 Collaborative, multidisciplinary management should be employed by providers across a clinical spectrum.
Patients may play an active role in detecting irAEs, therefore, education in early detection and reporting is paramount in the effective management of irAEs.
No prospective trials have defined the best strategies to manage irAEs. Recommendations for management are based upon expert opinion.
- Immunosuppression is the mainstay of management of immune-mediate toxicity to reduce the state of inflammation. Glucocorticoids are the first-line agent used. If these are not sufficient to manage symptoms, additional immune modulatory drugs may be necessary (e.g. tumour necrosis factor antagonists, mycophenolate mofetil, anti-thymocyte globulin (ATG), calcineurin inhibitors, methotrexate, or intravenous immunoglobulin and plasmapharesis). These agents should be prescribed judiciously to reduce the risk of short-term and long-term toxicities. 5 Retrospective studies suggest that steroid use doesn't change effectiveness of CPI inhibitor therapy but other immunosuppressive medications have not been sufficiently studied. 7,8 Dermatology: Prevention Recommendations 1. At this time, it is not possible to accurately predict which patients are going to be more susceptible to immune-related dermatologic adverse events (irDAEs).
There is no role for pre-treatment with anti-inflammatory dose glucocorticoids to prevent irDAEs with CPI therapies. However, a low threshold for the initiation of irDAE empiric treatment must be maintained. Patients with pre-existing immune-related skin conditions such as psoriasis, bullous pemphigoid, or lupus should be closely monitored both by the treating medical oncologist and dermatologist.
- Avoid skin irritants and excessive sun exposure to limit other aggravating factors to the skin.

# Guideline Resource Unit
Dermatology: Anticipation Recommendations 1. Be aware of the potential immune-related dermatologic toxicities that may occur in patients on CPI therapy, and especially in those who have pre-existing immune-related skin conditions such as psoriasis, bullous pemphigoid, or lupus.
- Patients should be counseled on the potential toxicities that may occur on therapy with these agents as well as the significance of potential symptoms that indicate these irAEs. Skin toxicities are among the most frequent AEs observed in patients treated with CPIs inhibiting either CTLA-4 (~45% with ipilimumab) or PD-1/PD-L1 (~35% with nivolumab and pembrolizumab) for all grade, but equal for grade 3 or higher (1-3%). 9,10 These are typically low grade in severity, and commonly present as maculopapular rash and pruritus. Vitiligo is commonly seen and reported exclusively in the melanoma population and is associated with response to therapy. 11,12 Less commonly, patients can develop lichenoid, eczematous, and bullous dermatitis, and psoriasis. Rare, life-threatening exfoliative conditions have been reported in the literature including Stevens-Johnson Syndrome/toxic epidermal necrolysis (SJS/TEN) and drug rash with eosinophilia and systemic symptoms (DRESS). Both patients and clinicians should be aware of the signs and symptoms of these life-threatening immune-mediated dermatologic toxicities.
- Remain vigilant in monitoring for cutaneous toxicities. Skin toxicity typically occurs early on after initiation of therapy but there can be substantial variability in clinical presentation and timing of symptom onset. This mandates careful vigilance for signs of cutaneous toxicity at all points on therapy. Aside from causing potential morbidity and mortality, these are also well recognized factors in treatment patient non-compliance and discontinuation.

# Dermatology: Detection Recommendations
- Complete a thorough physical examination of the skin including the mucosal membranes and an assessment including vital signs and lymph node assessment.  7. Where prolonged corticosteroid treatments are used, consider PJP prophylactic antibiotics, proton pump inhibitors, calcium, and Vitamin D.

# Pulmonary: Prevention Recommendations
- Careful patient selection is recommended. At this time, it is not possible to accurately predict which patients are going to be more susceptible to immune-related pulmonary adverse events (irPAEs). There is no role for baseline serology, imaging, or other testing. Take caution in patients with underlying lung disease thought to be from an immune-mediated cause.

# Guideline Resource Unit
Pulmonary: Anticipation Recommendations 1. Be aware of the potential immune-related pulmonary toxicities that may occur in patients on CPI therapy. Pulmonary irAEs can be challenging to diagnose as they typically have non-specific presentations (e.g. cough, dyspnea).
- Patients should be counseled on the potential toxicities that may occur on therapy with these agents as well as the significance of potential symptoms that indicate these irAEs. Pneumonitis is the most common lung toxicity observed and accounts for one of the highest rates of CPI-related mortality. 5 The incidence of pneumonitis is higher in patients treated with PD-1/PD-L1 therapy than with CTLA-4 therapy. The combination of PD-1/PD-L1 therapy and anti-CTLA-4 mAbs significantly increases the risk of pneumonitis. 5 Rates of any grade pneumonitis have been documented in 2-5% of patients of patients treated with PD-1 therapy, with 1-2% grade 3 events.
In patients treated with combination PD-1/CTLA-4 therapy this increases to 5-10% for any grade toxicity, and up to 4% grade 3 events 14,15 .
- Have a low threshold for further investigation in patients being treated with CPIs. Pneumonitis secondary to CPIs can have a wide range of variability both in timing of onset and presentation from a clinical and radiographical perspective 16 .

# Pulmonary: Detection Recommendations
- Pulmonary irAEs can be very challenging to identify due to their non-specific presentation and their occurrence in patients with either primary or metastatic malignancy in the lungs. Any new respiratory symptom should prompt a dedicated evaluation to rule out CPI-induced lung toxicity.
- Complete a comprehensive history and physical exam considering infections processes, other potential drug reactions, radiotherapy, granulomatous diseases, and possible associations with interstitial lung disease.
- Investigate including chest x-ray (repeat weekly if grade 2 or higher) and baseline bloodwork.
Consider screening for viral, opportunistic, or bacterial infections, and consider pulmonary function tests as clinically indicated. A CT scan should be obtained if pneumonitis is suspected. Radiographic features of pneumonitis are not pathognomonic and can have variable appearance including ground glass opacifications, reticular pattern, and focal areas of consolidation. These may reflect patterns consistent with organizing pneumonia or hypersensitivity pneumonitis. 17 4. Typically a lung biopsy is not required for diagnosis. However, if there is clinical or radiographical doubt about the etiology of the presentation then bronchoscopy with bronchoalveolar lavage and biopsy may be helpful. This may rule out acute infection, lepidic or lymphatic spread of disease or other pulmonary inflammatory changes.
Guideline Resource Unit medications should be started immediately in the setting of grade 2 or higher. If there is a suspicion of underlying infection, or in the case of a high-grade pneumonitis, patients may require bronchoscopy to rule out infection before starting immunosuppression. If the infectious status cannot be definitively determined, patients may require oral or IV antibiotics, particularly in the case of high-grade pneumonitis.
- Grade 1 pneumonitis can be followed clinically and repeat radiographic imaging completed in 3-4 weeks. If there is evidence of radiographic improvement or resolution, can consider resuming CPI with close monitoring. If there is no improvement, should be treated as grade 2.
- Grade 2 pneumonitis should be treated with oral corticosteroids at a dose of 1-2 mg/kg/day prednisone (or equivalent). Patients should receive close follow-up to ensure clinical improvement, with repeat chest x-ray in one week. Steroids should be slowly tapered over 4-6 weeks. If there is no clinical improvement after 48-72 hours, treat as grade 3. If there is resolution of symptoms and radiographic improvement to grade 1 or less, can consider re-challenging with CPI.
- If pneumonitis is grade 3 or 4 the patient should be admitted to hospital. Treatment should consist of high-dose IV steroids, methylprednisolone 1-2 mg/mg/d. If there is clinical improvement, start slow taper over 6-8 weeks. If symptoms do not improve after 48-72 hours, additional immunosuppressive strategies should be employed. There is no standard agent in this setting, tumour necrosis alpha (TNF) inhibitors (e.g. infliximab 5 mg/kg IV), mycophenolate mofetil (MMF) (e.g. 1 g PO/IV bid), tocilizumab, and cyclophosphamide can all be considered. CPI therapy should be permanently discontinued.
Where prolonged corticosteroid treatments are used, consider PJP prophylactic antibiotics, proton pump inhibitors, calcium, and Vitamin D.

# Gastrointestinal: Prevention Recommendations
- Recommend careful patient selection. Exhibit caution when considering therapy in a patient with underlying diagnosis of inflammatory bowel disease including Crohn's disease or ulcerative colitis, Guideline Resource Unit especially in those with severe underlying disease. These patients may be at higher risk for transient exacerbation of their underlying condition. 4 2. There are currently no known agents to effectively prevent immune-mediate colitis. Studies with budesonide were found to be negative. 18,19 Gastrointestinal: Anticipation Recommendations 1. Be aware of the potential immune-related gastrointestinal (GI) toxicities that may occur in patients on CPI therapy. Have a high degree of clinical suspicion, as some of these toxicities can be nonspecific.
- Patients should be counseled on the potential toxicities that may occur on therapy with these agents as well as the significance of early detection and assessment. The most common presenting symptom is watery diarrhea. Other presenting symptoms include abdominal pain, weight loss, fever, and vomiting. Patients can also present with aphthous ulcers, fissures, and extra-intestinal manifestations of inflammatory bowel disease including skin changes and arthralgias. Upper GI symptoms including dysphagia and epigastric pain have also been reported. 5 3. Have a low threshold for further investigation of GI toxicities in patients being treated with CPIs. Although these can occur with all agents, they are most commonly seen in patients treated with CTLA-4 inhibitors. GI toxicity is one of the most frequent and severe if the irAEs seen with anti-CTLA-4 therapy, with approximately one-third of treated patients developing irAEs related to the GI tract. These include aphthous ulcers, esophagitis, gastritis, diarrhea, and colitis. Diarrhea is the most common of these toxicities, occurring in 27-31% of patients with acute and chronic colitis seen in 8-22%. The rates of diarrhea and colitis are even higher in patients treated with a combination of anti-PD-1/PD-L1 and anti-CTLA4 agents.
- The onset of immune-mediated GI toxicity typically occurs days to weeks after the start of therapy but can occur at any time even after discontinuation of the drug. Studies have shown the time course for colitis to be anywhere from 1-10 doses of ipilimumab with variable pattern.  It is seen less commonly with PD-L1 therapy with a median onset of 3 months.
- At this time, it is not possible to predict which patients are going to be more susceptible to colitis from CPI therapy. Ongoing studies are evaluating the role of microbiome composition of a patient's gastrointestinal flora in the development of immune-mediated colitis as well as genetic factors. 23 Gastrointestinal: Detection Recommendations 1. Gastrointestinal irAEs are common and can be potentially severe, therefore both patients and clinicians should recognize the importance of early detection and investigation.
- Complete a comprehensive history and physical exam in patients with diarrhea while on CPI therapy considering infections processes, exposures, and other drugs (including antibiotics).
- Bloodwork should be completed to evaluate for complications including CBC, electrolytes, serum albumin, urea, creatinine. Inflammatory markers such as erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) can be helpful.
- Rule out infectious causes of diarrhea including viral (CMV in particular) and bacterial pathogens.
Complete stool tests for enteric pathogens including Clostridium difficile toxin. Be aware that immune mediated colitis and infectious colitis can co-occur.
- Investigate using abdominal x-ray and CT as clinically indicated. These investigations are useful to rule out obstruction, perforation and toxic megacolon.
- Patients who develop persistent or high-grade (grade 2) symptoms should be assessed with endoscopy. Immune-mediated colitis typically affects the rectum and sigmoid colon, so sigmoidoscopy is typically sufficient for diagnosis. It may appear as areas of erythema, erosions, exudates, and ulceration. Be aware that normal appearance of endoscopy does not rule out colitis, and biopsies must be obtained. 24 There is evidence that the presence of ulceration may be predictive of a steroid-refractory course, and these patients may require early infliximab. 25,26 7. Screening laboratory investigations such as HIV, hepatitis as well as TB testing should be done in patients who may require infliximab.  24 In the setting of grade 3 diarrhea restarting PD-L1/PD-1 once recovered to grade 1 can still be considered with significant caution, permanently discontinue CTLA-4 agent. In grade 4 toxicity, permanently discontinue CPI.
Note: contraindications to infliximab include severe infection, TB, hypersensitivity to drug, and moderate to severe congestive heart failure. 27 5. Where prolonged corticosteroid treatments are used, consider PJP prophylactic antibiotics, proton pump inhibitors, calcium, and Vitamin D.

# Hepatic: Prevention Recommendations
- Recommend careful patient selection. An underlying diagnosis of chronic hepatitis is not an absolute contraindication to therapy with PD-1/PD-L1 inhibition. 28
Hepatic: Anticipation Recommendations 1. Complete bloodwork including serum transaminases and bilirubin measurement prior to every cycle of therapy.
- Immune-mediated hepatitis is typically asymptomatic and discovered on routine bloodwork. Hepatic toxicity is seen in ~5-10% of patients treated with anti-PD-1/PD-L1 and anti-CTLA-4 monotherapy and 1-2% of this is  grade 3 in severity. When these drugs are used in combination, the incidence of hepatitis increases to ~25-30%, ~15% of this is  grade 3 in severity. 29,30 Guideline Resource Unit 3. Although most patients are asymptomatic from immune-mediated hepatitis, note any potential symptoms of hepatitis including fever, right upper quadrant pain, and nausea. Counsel patients to inform their health care provider if they develop symptoms of jaundice, drowsiness, dark urine, increase in bruising/bleeding.

# Hepatic: Detection Recommendations
- If serum transaminase elevation is noted, complete a careful assessment of potential causes including drugs (prescription, OTC including Tylenol, herbals), alcohol use, viral causes, and disease progression.
- Liver biopsy is not typically required but may be considered in the case of severe hepatitis of unclear etiology. 1. At this time, there is insufficient evidence to recommend screening with antibodies to predict which patients are going to be more susceptible to CPI-related endocrine complications. There is no role for pre-treatment with anti-inflammatory dose glucocorticoids to prevent the autoimmune endocrinopathies associated with CPI therapy.
Endocrine: Anticipation Recommendations 1,19, 1. Be aware of the potential immune-related endocrine adverse events (irEAE) that can occur with the use of CPIs. It is essential to identify these potential complications early, given the significant morbidity and mortality risk. Endocrine toxicities typically have non-specific symptomatology and endocrinopathies are often long lasting.
- Although the relative frequency of adverse events may vary between agents, in broad groups, hypophysitis (inflammation of the pituitary leading to dysfunction of pituitary hormone secretion and end-organ insufficiency), thyroid disorders (both hypo-& hyperthyroidism), autoimmune diabetes, and adrenalitis (primary adrenal insufficiency) are largely the endocrine complications seen with these drugs.
- Table 6 lists the details on endocrinopathy prevalence with various CPI agents. In addition to the difference in prevalence of endocrinopathy with each CPI agent, it seems that the risk of endocrine side effects vary between tumour groups. The risk of CPI-induced endocrinopathy seems to be increased in the presence of pre-existing organ-specific autoimmune disease and a family history thereof. However, this does not constitute a contraindication to the use of CPIs. It seems that CTLA4 agents and combination CPI therapy (simultaneous or sequential) have the highest rates of associated endocrinopathy. The presented data are approximate based on both clinical trials and clinical experience, they will vary further based upon tumour group, agent and patient comorbidities. 4. Identification of these clinical presentations can be challenging, given that they are often very nonspecific. Consequently, a treating clinician should have a high level of suspicion for irEAEs when evaluating patients on CPIs. Patients need to be counselled on the significance of symptoms that indicate the above endocrine complications. The difficulty lies in that many of the symptoms are non-specific and overlap with symptoms from the underlying tumour, CPI therapy and other nonendocrine side-effects. Due to this, a treating clinician should be aware to have a low threshold to investigate with laboratory investigations and imaging.
- Patients should be advised to monitor for the following symptoms: new onset or persistent headaches, visual changes, palpitations, excess sweating, extreme fatigue or weakness, dizziness or episodes of fainting, change in weight (gain or loss), muscle aches, salt craving, notable behaviour changes, polyuria, polydipsia, nausea, vomiting, or abdominal pain. Details of the more specific symptoms and signs are included in Table 7. 1. Given the prevalence of the side effects, it is reasonable to screen patients on therapy at every clinic visit. It is recommended that baseline levels of thyroid hormone (TSH), blood glucose, electrolytes be done before each treatment cycle. Subsequent thyroid function tests should be Guideline Resource Unit measured during treatment, (e.g. every 4 weeks during the first 6 months then every 3 months for 6-12 months, then every 6 months subsequently). Blood glucose should be monitored with each treatment cycle during induction for 12 weeks, then every 4-6 weeks thereafter. The remainder of imaging and extended laboratory investigation can be completed on a symptom-driven/clinical exam basis. Consider monitoring with baseline early-morning ACTH and cortisol levels at baseline. It is important to assure that the end-organ hormones be ordered in the case of hypophysitis.

# Specific endocrine organ testing as clinically indicated:
- Hypothyroidism (primary): TSH, fT4  1. With the need for ongoing CPI therapy, treatment of endocrine complications should happen with the involvement of an endocrinologist experienced in the management of these complications.

# Endocrine adverse event specific recommendations:
- Hypothyroidism: for thyroid replacement in patients without risk factors full replacement with thyroxine can be estimated at 1.6mcg/kg/d (synthroid or eltroxin are the most common preparations). If the patient is elderly or has significant comorbid cardiac disease, consider 30% replacement dose and a slower titration to normal TSH target.
- If adrenal dysfunction is present, this must always be replaced before thyroid hormone therapy is initiated.
- Hyperthyroidism: For severe hyperthyroidism/concern for thyroid storm: beta blockade, propylthiouracil, steroids (prednisone 1-2mg/kg/d or equivalent), followed by KI solution in an ICU/high observation unit monitored setting is suggested. For less severe forms of hyperthyroidism, methimazole (doses between 5-20 mg daily depending on the biochemistry) may be all that is needed.
- Diabetes: Insulin can be used in any case of hyperglycemia in connection with a diabetes education service for support and titration of doses to glycemic target. A basal bolus insulin regimen should be initiated in the setting of autoimmune diabetes.
- Adrenal Insufficiency: For adrenal replacement, glucocorticoid replacement maintenance with prednisone 5-10 mg daily or hydrocortisone 10 mg twice daily for grade 1. Patients may require mineralocorticoid replacement using fludrocortisone in the setting of primary adrenal insufficiency which is delivered as 0.1mg/day. Titrate based on symptoms. For outpatient management of acute symptoms of grade 2 adrenal insufficiency initiate at two to three times maintenance (if prednisone, 20 mg daily; if hydrocortisone, 20-30 mg twice daily to manage acute symptoms. Taper stress-dose corticosteroids down to maintenance doses over 5-10 days. For grade 3 or 4 adrenal insufficiency urgent hospitalization is required for fluid resuscitation, and IV stress-dose steroids (hydrocortisone 100 mg or dexamethasone 4 mg ). Taper down to maintenance doses over 7-14 days after discharge. o Patient education is crucial. All patients must have education as well as obtaining a medical alert bracelet to trigger stress dosing in the setting on illness, surgery, etc.
- Hypophysitis: Hypophysitis can affect the anterior pituitary, the posterior pituitary or both. Involvement of the posterior pituitary induces diabetes insipidus. Involvement of the anterior pituitary can cause secondary adrenal insufficiency, secondary hypothyroidism, secondary hypogonadism and growth hormone deficiency. These pituitary hormone deficiencies can occur synchronously or metachronously. From an acute management perspective, ADH and cortisol deficiencies are the most critical to diagnose and treat. Corticosteroids should be initiated first when planning hormone replacement therapy for multiple deficiencies. Thyroid replacement follows next in terms of clinical urgency. Initiate corticosteroids several days before thyroid supplementation to prevent adrenal crisis. Detection and replacement of sex steroids and growth hormone are long term considerations. Thus, these do not need to be measured in the acute setting. Given the effect of illness on both gonadal steroid and growth hormones, routine replacement is beyond the scope of these guidelines.
Endocrine: Monitoring Recommendations 1,8,31
- Once identified, the hormone replacement can be achieved and managed throughout the duration of the CPI therapy. It has also been recommended to continue to screen for the symptoms of endocrinopathy after treatment has been completed. This can be accomplished by the routine lab panel being performed q3 months for the first year, q6 months for the second year and symptomguided thereafter. Follow FT4 for thyroid hormone replacement titration (TSH is not accurate).
- Unlike the resolution of many CPI immune-related adverse effects, the endocrine insufficiencies are more likely to be permanent, especially hypothyroidism.
- For many of the non-endocrine immune-mediated toxicities (grade 2-4), anti-inflammatory doses of steroids are recommended to be given. As long as the steroid dose is greater than 10 mg/day of prednisone (or equivalent), the potential for co-existing adrenal insufficiency is moot as adrenal replacement is already being adequately achieved. However, once the dose is below this threshold, there is a potential concern for iatrogenic hypothalamic-pituitary-adrenal (HPA) axis suppression and illness management should be considered until the integrity of the HPA axis has been assessed.
Neurology: Prevention Recommendations 29,30, 1. At this time, it is not possible to accurately predict which patients are going to be more susceptible to immune-related neurologic adverse events (irNAEs). There is no role for baseline serology, imaging, or other neurology testing.
- Patients with pre-existing neurologic conditions, such as myasthenia gravis (MG), multiple sclerosis, or Guillain-Barre syndrome (GBS), should be closely monitored both by the treating medical oncologist and neurologist. There is no role for pre-treatment with anti-inflammatory dose glucocorticoids to prevent irNAEs with CPI therapies. However, a low threshold for the initiation of an irNAE workup and empiric treatment must be maintained.
Neurology: Anticipation Recommendations 1,32
- Be aware of the potential immune-related neurological adverse events (irNAE) that can occur with the use of CPIs. Although irNAEs are rare in patients treated with CPIs, it is essential to identify these potential complications early, given the significant morbidity and mortality risk.
- The relative frequency of adverse events may vary between agents, but irNAE can affect both the central and peripheral nervous systems. Potential neurological adverse events include: immunemediated polyneuropathies (e.g. acute inflammatory demyelinating polyneuropathy (AIDP), GBS, chronic immune demyelinating polyneuropathy (CIDP), other sensory and motor neuropathies), enteric neuropathy, MG, aseptic meningitis, autoimmune encephalitis, transverse myelitis, and ocular inflammatory toxicity. Although these adverse events may occur at any time during treatment, the most common time to onset appears to typically occur between 6 to 13 weeks. 17 3. Identification of these clinical presentations can be challenging, given that they are often very nonspecific. Consequently, a treating clinician should have a high level of suspicion for irNAEs when evaluating patients on CPIs. Although the data on irNAE incidence rates from individual agents is limited (see Table 9), a high level of suspicion for irNAEs must be maintained when evaluating patients on CPIs. Patients should be counselled on the significance of symptoms that can indicate irNAEs. Details of the more specific symptoms and signs are included in Table 10.
- Patients should be advised to monitor for the following symptoms: numbness/tingling in hands/feet, severe muscle weakness/fatigability, headache, fever, confusion, changes in mood/behavior, extreme sensitivity to light, neck stiffness, hallucinations, seizure, blurry/double vision, eye pain/redness.  1. Given the potential for serious irNAE complications, as well as their non-specific clinical presentations, clinicians should monitor patients for signs and symptoms suggestive of acute and subacute polyneuropathies (including AIDP), MG, enteric neuropathy, meningitis, encephalitis, and ocular inflammatory toxicity. No routine screening investigations are indicated, unless there is clinical suspicion. Imaging and extended laboratory investigation should be completed on a clinical basis. Rule out progression of underlying malignancy, seizures, infectious processes, and metabolic derangement as causes of neurological impairment.
- Early involvement of a neurologist is recommended to guide specific testing.
- AIDP can present with symmetrical, progressive weakness and paresthesias. In low grade 1-2, it can manifest with mildly affected mobility/gait limitations. In severe grade > 3 GBS, weakness may affect respiratory muscles and facial oculomotor and oropharyngeal muscles, dysautonomia, and diminished reflexes may be identified. The following should be performed if there is clinical suspicion of GBS:
- Urgent neurological consultation is necessary.
- Prompt exclusion of other potential causes of weakness. This may require MRI to rule out a compressive lesion and evaluate for nerve root enhancement/thickening. - Lumbar puncture may be performed. CSF can show high protein and normal to elevated white blood cell counts in patients with classic GBS. Cytology should be sent on any CSF sample in patients with cancer. - Electromyography (EMG) and nerve conduction studies (NCS).
- Pulmonary function testing with negative inspiratory force and vital capacity.

# Guideline Resource Unit
Note: all grades require work-up and intervention given the potential for progression and risk of respiratory compromise.
- MG may present with fluctuating and fatigable muscle weakness. Weakness often affects the bulbar, ocular, limb, and respiratory muscles. Classically, ptosis, diplopia, dysarthria, and dysphagia may be encountered. If there is clinical suspicion of MG of any grade, the following should be performed:
- Urgent neurological consultation is necessary - Bedside tests have high false-positivity, but the tensilon and ice-pack test, may be performed - EMG and NCS - Autoantibody serum testing for acetylcholine receptor (AChR-Ab). If AChR-Ab are negative, muscle specific tyrosine kinase (MuSK-Ab) may be sent - Creatinine phosphokinase (CPK), ESR, CRP, for concomitant myositis - Pulmonary function assessment with negative inspiratory force and vital capacity Note: all grades require work-up and intervention given the potential for progression and risk of respiratory compromise. 50 5. Autoimmune meningitis (aseptic meningitis) is characterized by fever, nuchal rigidity, and altered mental status. The following should be performed if there is clinical suspicion of meningitis: 1. Treatment of irAEs should occur with the involvement of a neurologist experienced in the management of these complications.
- Grade 2 MG, meningitis, encephalitis, or AIDP should result in permanent discontinuation of CPI treatment. The oncologist may consider reinstituting CPI in the setting of grade 1 maximum toxicity after assessing risk/benefits with the patient. The differential must remain broad, necessitating the previously mentioned investigations and initial treatment for severe causes until they are ruled out. In particular, infection must be ruled out. Urgent neurology consultation should be strongly considered to guide management; depending upon the etiology, methylprednisolone (e.g. encephalitis) or IVIG (e.g. AIDP) may be indicated. Other non-corticosteroid immunosuppressive agents may be considered.
- Following the acute use of corticosteroids, a slow taper of corticosteroids must occur over a minimum of 1 month. Where prolonged corticosteroid treatments are used, consider PJP prophylactic antibiotics, proton pump inhibitors, calcium, and Vitamin D.
In grade 1-2 irNAEs (not including MG, meningitis, encephalitis, or AIDP), re-initiation of CPI therapy may be considered once grade 0-1 is achieved, the steroid dose is <10 mg/day of a prednisone equivalent, and there is no need for a non-corticosteroid immunosuppressant. Close monitoring is necessary for recurrence or worsening of irNAEs.
- Grade > 3 irNAEs must result in the discontinuation of CPI therapy. MG, meningitis, encephalitis, or AIDP of any grade must also result in discontinuation of CPI therapy. A high clinical suspicion must be maintained for recurrence of these irNAEs.
Rheumatology: Prevention Recommendations 31,53,57 1. At this time, it is not possible to accurately predict which patients are going to be more susceptible to immune-related rheumatologic or autoimmune disorder adverse events (irRAEs). There is no role for baseline serology, imaging, or other testing.
- There is no role for pre-treatment with anti-inflammatory dose glucocorticoids to prevent irRAEs with CPI therapies. However, a low threshold for the initiation of an irRAE workup and empiric treatment must be maintained. Patients with pre-existing autoimmune disorders should be closely monitored both by the treating medical oncologist and rheumatologist.

# Guideline Resource Unit
Rheumatology: Anticipation Recommendations 1,32,57
- The first step in anticipation is to be aware of the potential immune-related rheumatologic or autoimmune disorder adverse events (irRAE). It is possible to exacerbate or unmask a rheumatologic condition with CPI therapies. It is important to note that patients with autoimmune disorders were excluded from the clinical trials investigating these CPI agents.
- Patients should to be counselled on the significance of symptoms that indicate the above irRAEs.
Patients with pre-existing autoimmune disorders should be advised that it may be exacerbated by CPI therapy. Unfortunately, the identification of many of these clinical presentations is challenging, given the non-specific and general symptoms. Consequently, a treating clinician should be aware to have a low threshold to investigate with laboratory investigations and imaging. Details of the more specific symptoms and signs are included in Table 12. Patients should be advised to monitor for the following symptoms: painful or swollen joints, rash, weakness, muscle ache or pain, shortness of breath, cough, dry eyes and mouth.
- The relative frequency of adverse events may vary between agents, but potential irRAEs may include: polymyalgia rheumatic (PMR), vasculitis, leukocytoclastic vasculitis, psoriasis, rheumatoid arthritis (RA), tenosynovitis, gout, polymyositis, myositis, ocular myositis, sarcoidosis, systemic lupus erythematosus (SLE), Behcets disease, scleroderma, Sjogren's, and erythema multiforme.
- Data on irRAEs in CPI-treated patients is limited. Mild to moderate arthralgias are seen most commonly at an incidence of up to 40%. 42,54,55 Grade 3 irAEs are less commonly seen but can have a significant impact on quality of life. The most common musculoskeletal and rheumatic irAEs are arthritis, polymyalgia-like syndromes, and myositis 50 . Other irRAEs have also been described, including vasculitis, polymyositis, and temporal arteritis, but at a lower incidence. 56 Although these can occur with both anti-CTLA-4 and PD-1/PD-L1 agents, they occur more frequently with PD-1/PD-L1 inhibitors and with combination therapy.
- Remain vigilant with patients on CPI therapy as irRAEs may occur at any time on treatment and even after treatment discontinuation. 1. Given the potential for serious irRAE complications, as well as their non-specific clinical presentations, clinicians should monitor patients for signs and symptoms suggestive of irRAE conditions including; inflammatory arthritis, polymyositis, myositis, PMR, and be aware for the potential of developing vasculitis, psoriasis, sarcoidosis, SLE, Behcets disease, scleroderma, Sjogren's, and erythema multiforme.
- Inflammatory markers are usually very elevated in patients with irRAE and are useful to differentiate these events from other causes of their symptoms.

# Inflammatory arthritis:
- Clinical presentation can vary, affecting large and/or small joints, can have extra-articular symptoms including rash, tenosynovitis, axial involvement, conjunctivitis and urethritis. - Complete a thorough history and physical exam with examination of all peripheral joints for swelling, pain, and range of motion. - Exclude other causes including septic arthritis, viral polyarthritis, gout.
- Consider imaging of affected joints with plain film x-ray to evaluate for joint damage and rule out bony metastatic disease. - Consider serological testing including ANA, rheumatoid factor (RF), anti-citrullinated protein antibody (anti-CCP), and inflammatory markers erythrocyte sedimentation rate (ESR) and CRP. If symptoms are suggestive of reactive arthritis or affect the spine, consider HLA B27 testing. - Early recognition is critical to avoid erosive joint damage. Referral to a rheumatologist if there is evidence of joint swelling (synovitis) or if symptoms of arthralgia persist >4 weeks.

# Myositis:
- Myositis is a rare but potentially fatal toxicity of CPIs. Patients most commonly present with weakness, primarily in the proximal extremities. In severe cases, can also have myalgia. It can have a fulminant necrotizing course with rhabdomyolysis and involve other skeletal muscle, such as myocardium which can be potentially fatal if treatment is delayed.
- Complete a thorough rheumatologic, neurologic, and dermatologic exam paying specific attention to symptoms of muscle weakness or rash. - Complete blood testing for creatinine kinase (CK), transaminases (AST, ALT) and LDH, inflammatory markers (ESR, CRP). There is no evidence that autoantibodies (anti-Jo, anti-Mi2) have a role in CPI-induced myositis. - Evaluate for other potential causes including drugs, alcohol, infectious, metabolic or electrolyte disorders. - Consider troponin level to evaluate myocardial involvement as well as other cardiac investigations (e.g. echocardiogram) as required. - Consider electromyography (EMG), imaging (MRI), and/or biopsy on an individual basis when diagnosis is uncertain. - Consider paraneoplastic autoantibody testing for myositis and neurologic conditions, such as MG.
- Early referral to a rheumatologist if myositis is grade 2 or higher.

# Polymyalgia rheumatica:
- PMR presents as proximal myalgias and systemic symptoms including fatigue and low grade fever. - Complete a thorough rheumatologic and neurologic examination.
- Assess for symptoms of temporal arteritis including headache, jaw claudication, vision loss, and urgent temporal artery biopsy if this is suspected. - Complete blood testing for inflammatory markers (ESR, CRP) which are elevated in PMR, and investigations required for differential diagnosis; CK, ANA, RF, and anti-CCP (negative in PMR). - Early referral to a rheumatologist if PMR is grade 2 or higher.

# Sjogren's syndrome:
- Can present with sicca symptoms including dry eyes and mouth, enlarged parotid gland, and non-glandular involvement including arthritis and vasculitis. - Complete a thorough rheumatologic and dermatologic examination with assessment of the oropharynx for cracked tongue, lack of saliva pooling. - Complete blood testing including serological markers such as ANA, ENA (anti-Ro/SSA and/or anti-La/SSB antibodies), RF, anti-CCP antibody as sicca symptoms can occur with SLE and RA. - Early referral to a rheumatologist for considering of Schirmer test, minor salivary gland (lower lip) biopsy, sialometry.

# Sarcoid
- Most commonly seen with anti-CTLA4 or anti PD1 use in melanoma
- Presents as cutaneous sarcoidosis, or systemic with lymphadenopathy, lung or neurological and ocular involvement - No specific serum findings - May present with mediastinal or hilar lymphadenopathy on CT, but also parenchymal lung CT changes, such as ground glass opacities 8. Ultimately, early involvement of rheumatology can help to guide testing. 1. With the need for ongoing CPI therapy, treatment of rheumatologic complications should happen with the involvement of a rheumatologist experienced in the management of these complications.
- Corticosteroids can be used as part of initial therapy in inflammatory arthritis as in other irAEs but due to likely prolonged treatment requirements, physicians should consider starting corticosteroid-sparing agents earlier than typically required with other irAEs.
- Following the acute use of corticosteroids, a slow taper of corticosteroids must occur over a minimum of 1 month. Where prolonged corticosteroid treatments are used, consider PJP prophylactic antibiotics, proton pump inhibitors, calcium, and Vitamin D.
- A number of other rheumatic disorders have been documented as case reports of patients receiving CPIs including vasculitis and lupus-like syndromes. Management and treatment principles are similar to those reported for other CPI-induced rheumatic syndromes.
It is recommended that all patients with inflammatory arthritis be monitored with serial rheumatologic examinations, including inflammatory markers, every 4 to 6 weeks after treatment is instituted.

# Appendix A: Literature Search Details
The literature search performed included a PubMed search that was conducted on 2016 October 8. The following terms for immune checkpoint inhibitors, adverse events and cancer were used in the search.
((immune checkpoint inhibitor*) OR ipilimumab OR pembrolizumab OR lambrolizumab OR nivolumab OR "Anti CTLA-4" OR "Anti CTLA 4" OR "Cytotoxic T-Lymphocyte Associated Protein 4" OR "PD-1" OR "PD-L1" OR "programmed cell death protein 1" OR IDO OR "indoleamine 2,3-dioxygenase" OR tremelimumab OR atezolizumab OR ticilimumab OR indoximod OR 1-methyl-d-tryptophan OR D-1MT OR MDX-010 OR MDX-101 OR BMS-734016 OR MK-3475 OR "SCH 900475") AND ("Drug-Related Side Effects and Adverse Reactions" OR "adverse events" OR toxicity) AND ("Neoplasms" OR oncolog- OR cancer OR malignan*) This search was limited to humans and the English language. No restrictions were applied in regards to study type or publication year. Articles met inclusion criteria if they were peer-reviewed guidelines, reviews or studies that reported on the presentation and prevalence of irAEs, their monitoring, management or follow up. Case reports on the management of toxicities were excluded with the exception of those which were included in overarching reviews. This search yielded 480 articles, of which 9 review articles (6 meta-analyses and 3 pooled analyses) with a focus on investigating checkpoint inhibitor therapy related toxicities in cancer patients were included for data extraction. Eleven studies (7 retrospective reviews, 3 retrospective observational studies, 1 randomized controlled trial and 1 secondary analysis of a phase III trial) were included, as well as 3 guidelines. These articles provided recommendations for the follow-up and management of immune-mediated adverse events.
Another aspect of the search included looking for existing guidelines on this topic that had already been published by prominent cancer associations, including the Canadian Partnership Against Cancer, the National Comprehensive Cancer Network and the American Cancer Society. The mineralocorticoid effect of commonly administered glucocorticoids may be estimated as follows:
- When given at replacement doses, triamcinolone, dexamethasone, and betamethasone have no clinically important mineralocorticoid activity. - 20 mg hydrocortisone and 25 mg of cortisone acetate each provide a mineralocorticoid effect that is approximately equivalent to 0.1 mg fludrocortisone. - Prednisone or prednisolone given at antiinflammatory doses 50 mg per day provide a mineralocorticoid effect that is approximately equivalent to 0.1 mg of fludrocortisone.

# Development and Revision History
This guideline was reviewed and endorsed by members of the Alberta Provincial Tumour Teams, including medical oncologists, gynecologic oncologists, hematologists, nurse practitioners, and pharmacists. Evidence was selected and reviewed by a working group comprised of members from the Alberta Provincial Tumour Teams, external participants identified by the Working Group Lead, and a methodologist from the Guideline Resource Unit. A detailed description of the methodology followed during the guideline development process can be found in the Guideline Resource Unit Handbook.
This guideline was originally developed in 2020.

# Maintenance
A formal review of the guideline will be conducted in 2021. If critical new evidence is brought forward before that time, however, the guideline working group members will revise and update the document accordingly. 

# Abbreviations