An article by John Haanen released in occasion of ESMO Immuno-Oncology Congress 2017, 7-10 December, Geneva, Switzerland.
Toxicity Associated with Cancer Immunotherapy
Antibody-based immunotherapies are now being used to treat a broad range of cancers. Immune checkpoint inhibitors (ICPis) that target cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and the programmed death-1 (PD-1) receptor (PD-1) and its ligand, PD-L1, have become standard of care for some malignancies (1). A spectrum of distinct, immune-related adverse events (irAEs) results from blockade of these immune checkpoints (2,3). Common manifestations include toxicities involving the skin, colon, endocrine organs, liver and lungs. As treated patient numbers and duration increases, less frequent and unusual side effects are being documented that include neurological disorders and myocarditis (2). This review summarises the irAEs associated with ICPis and recent ESMO Clinical Practice Guidelines for their diagnosis, treatment and follow-up (2).
Immune checkpoints blockade toxicity
Before initiating ICPis, patients should be assessed for increased risk and clinicians should be aware of toxicity profiles in order to identify and manage symptoms promptly (2). In general, irAEs occur quite early in treatment (within 1 week to 3 months after initiation) but the first onset of irAEs has been documented as long as 1 year after treatment discontinuation. Action should be taken to prevent further aggravation of adverse events (AEs) and especially in the most severe cases, immunotherapy should be discontinued immediately, and immunosuppressive or immune modulating drugs initiated promptly. Importantly, so far there is no evidence that the clinical outcome of patients on ICPis is affected by immunosuppression for the management of immune-related toxicities.
Systemic adverse events
Fatigue is a common side effect, and occurs in up to 40% of anti-CTLA-4 treated patients and in 16–37% of anti-PD-1, and 16–24% of anti-PD-L1 treated patients (4,5). Although the pathogenesis is poorly understood, it is important to exclude thyroid, pituitary, and other endocrine disorders (2).
The most frequent skin AEs are rash, pruritus and vitiligo, usually occur early during treatment and are among the most frequent AEs associated with ICPis (Table 1) (2,3). Differential diagnosis involves exclusion of dermatological disorders of any other aetiology such as infection. The severity of the dermatological irAE must be carefully evaluated through physical examination of the skin and mucosa, an assessment of patient’s health status (fever, enlarged lymph nodes etc.), and if required blood cell count, liver and kidney tests should also be performed (2). Management strategies are summarised in Table 2 and do not usually require ICPi dose reductions or treatment discontinuation (2).
Gastrointestinal immune-related adverse events
Diarrhoea and colitis as the most common gastrointestinal irAEs are more frequently associated with anti-CTLA-4 than anti-PD-1 or anti-PD-L1 treatment (Table 1) (2,3). Diagnosis of a gastrointestinal event is primarily based on symptoms which can occur at any time during treatment and can persist long after drug clearance (2). Stool analyses for bacterial enteropathogens and Clostridium difficile toxin should be performed in every ICPi patient with significant diarrhoea, and, enterocolitis should be confirmed by flexible sigmoidoscopy or colonoscopy with biopsies. As described in Table 2, mild gastrointestinal events should be managed symptomatically whilst continuing ICPi (2). For grade 2 diarrhoea, ICPi should be interrupted; patients with severe gastrointestinal events should permanently discontinue ICPi (2).
ICPis can cause autoimmune breakthrough in the form of immune-related endocrinopathies affecting the pituitary (hypophysitis), the thyroid (hyperthyroidism and hypothyroidism) and the pancreas (diabetes mellitus) and in contrast to other irAEs, are often irreversible (2,6). They are typically grade 1 or 2 in severity and often present with non-specific symptoms making them difficult to diagnose (6).
Thyroid gland disorders are one of the most common immune-related endocrinopathies and hypothyroid disorders occur more frequently than hyperthyroidism (Table 1) (2,3). In most cases, thyroid dysfunction is diagnosed by routine blood test (thyroid stimulating hormone (TSH) and FT4) which should be carried out before every infusion or at least once a month (2). Management strategies for hyper and hypothyroidism may include disruption of ICPi and are summarised in Table 2 (2).
Hypophysitis has been reported in anti-CTLA-4 patients but is extremely rare in patients treated with anti-PD-1 or anti-PD-L1 (Table 1) (2,3). Patients present with a variety of symptoms with headaches/visual disturbances requiring immediate investigation (2). Diagnosis is based on the presence of TSH, adrenocorticotropic hormone (ACTH), luteinizing hormone (LH), and follicular stimulating hormone (FSH) (2). In any grade 2 or higher hypophysitis, ICPis should be interrupted as outlined in Table 2 (2).
Although diabetes induced by treatment with ICPis occurs at low frequency (<1%) it appears to be more commonly associated with anti-PD-1 and anti-PD-L1 than anti-CTLA-4 (1). It is recommended that blood glucose levels are regularly monitored in order to identify the emergence of type 1 or type 2 diabetes in ICPi patients, and once the patient has been stabilised, restarting ICPi treatment may be considered (Table 2) (2).
Immune-related hepatotoxicity manifesting as elevated alanine transaminase (ALT) or aspartate transaminase (AST) is associated with ICPi treatment (Table 1). Hepatitis is usually asymptomatic and all patients undergoing ICPi treatment should be assessed for ALT, AST and bilirubin before every cycle of treatment (2). Liver biopsy may be considered in assisting in the differential diagnosis of more severe hepatotoxicity and recommendations for management including permanent ICPi discontinuation are outlined in Table 2 (2).
This is more frequently associated with anti-PD-1/anti-PD-L1 than anti-CTLA-4 (Table 1) and is variable in both onset and appearance (2,3). Pneumonitis tends to occur later than other irAEs, commonly some months after initiation of treatment (2). All ICPi patients presenting with pulmonary symptoms should be assessed by computed tomography. Respiratory symptoms must be carefully monitored, since fatal and life-threatening cases of pneumonitis have been reported (2). Management strategies are summarised in Table 2 with ICPi therapy interrupted in grade 1 and 2 and permanently discontinued in grade 3 and 4 pneumonitis (2).
Rare immune-related adverse events
Although renal failure associated with ICPi treatment is rare (Table 1), serum sodium, potassium, creatinine and urea should be assessed before every infusion (2). Renal dysfunction should initially be managed by discontinuing nephrotoxic drugs, excluding infection, urinary tract obstruction and correcting hypovolaemia. In the event of significant renal dysfunction and renal failure, a nephrologist should be consulted. A kidney biopsy should be considered and ICPi therapy should be withheld (Table 2) (2).
Neurological-related AEs are rare (Table 1) (2). They can occur 6–13 weeks after initiation of treatment and include polyneuropathy, facial nerve palsy, demyelination, myasthenia gravis, Guillain-Barre´ syndrome, posterior reversible leukoencephalopathy, transverse myelitis, enteric neuropathy, encephalitis and aseptic meningitis (2). Diagnosis is based on clinical presentation, imaging of the central nervous system, nerve conduction studies and lumbar puncture. Early consultation with a neurologist is recommended and for all but mild (grade 1) neurological symptoms, ICPi should be withheld (Table 2) (2).
Rheumatological-related AEs including mild or moderate myalgias and arthralgias, vasculitis, polymyositis, myositis and temporal arteritis have also been described and severe symptoms should prompt consultation with a rheumatologist and consideration of the use of high-dose corticosteroids (Table 2) (2).
Cardiac-related AEs are extremely rare and include myocarditis, pericarditis, arrhythmias, cardiomyopathy and impaired ventricular function (2). Early consultation with a cardiologist is recommended and high-dose corticosteroids should be rapidly initiated if ICPi induced cardiac AEs are suspected (Table 2) (2).
Ocular-related AEs are also rare and include ocular inflammation, orbital inflammation and retinal and choroidal disease and treatment depends on severity (Table 2) (2).
- Topalian SL. Targeting immune checkpoints in cancer therapy. JAMA 2017; 318(17):1647-1648.
- Haanen J, Carbonnel F, Robert C, et al. Management of toxicities from immunotherapy: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2017; 28(suppl_4):iv119-iv142.
- Kumar V, Chaudhary N, Garg M, et al. Current diagnosis and management of immune related adverse events (irAEs) induced by immune checkpoint inhibitor therapy. Front Pharmacol 2017; 8:49.
- Hodi FS, O'Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 2010; 363(8):711-723.
- Naidoo J, Page DB, Li BT, et al. Toxicities of the anti-PD-1 and anti-PD-L1 immune checkpoint antibodies. Ann Oncol 2015; 26(12):2375-2391.
- Sznol M, Postow MA, Davies MJ, et al. Endocrine-related adverse events associated with immune checkpoint blockade and expert insights on their management. Cancer Treat Rev 2017; 58:70-76.
Table 1 Immune-related adverse events of immune checkpoint inhibitors
Table 2 Recommendations per type of irAE
AE, adverse event; ALT, alanine transaminase; AST, aspartate transaminase; ATG, anti-thymocyte globulin; HRT, hormone replacement therapy; ICPi, immune checkpoint inhibitor; ICU, intensive care unit; Ig, immunoglobulin; i.v., intravenous; MMF, mycophenolate mofetil; MRI, magnetic resonance imaging; NSAIDs, nonsteroidal anti-inflammatory drugs; TNFa, tumour necrosis factor alpha; TSH, thyroid-stimulating hormone.
- Grade 1–2: continue (at least 1 week) with ICPis. Start topical emollients, antihistamines in the case of pruritus and/or topical (mild strength) corticosteroid creams. Reinitiate ICPi when ≤ grade 1
- Grade 3: interrupt ICPi and start immediate treatment with topical emollients, antihistamines and high strength corticosteroid creams
- Grade 4: permanently discontinue ICPi, consider admitting patient and always consult dermatologist immediately. Start i.v. corticosteroids and taper based on response of AE
- Symptomatic hyperthyroidism (usually grade 1 or 2); interrupt ICPi, start beta-blocker therapy (propranolol or atenolol/metoprolol). Restart ICPi when asymptomatic
- Hypothyroidism (rarely >grade 2): start HRT depending on the severity and increase dose until TSH normal. Consider interruption of ICPi treatment when symptomatic
- Hypophysitis (rarely >grade 2): when headache, diplopia or other neurological symptoms are present, start oral prednisone and taper over 2–4 weeks. Start HRT depending on the affected hormonal axis (levothyroxine, hydrocortisol, testosterone)
- Type I diabetes (grade 3 to 4 [ketoacidotic (sub)coma]): admit to hospital immediately and start treatment of newly onset type I diabetes. Role of corticosteroids in preventing complete loss of insulin producing cells is unknown and not recommended.
- Grade 2 hepatitis: withhold ICPi and monitor AST/ALT levels closely (1–2 times/week). When no improvement over 1 week, start (methyl)prednisone and taper over several weeks under close monitoring of AST/ALT and bilirubin
- Grade 3 hepatitis: discontinue ICPi and immediately start with (methyl)prednisone. When no improvement in 2–3 days, add MMF. Taper immunosuppression over 4–6 weeks under close monitoring of AST/ALT and bilirubin
- Grade 4 hepatitis: permanently discontinue ICPi, admit patient to the hospital and initiate (methyl)prednisone. Add MMF if no improvement is observed within 2–3 days. Consult hepatologist if no improvement under double immunosuppression. Other immunosuppressive drugs to consider are ATG and tacrolimus. Consult or refer patient to an experienced centre. Taper over 6 weeks under close monitoring of liver tests
- Grade 1 diarrhoea (non-severe): ICPi continued. Treatment with anti-diarrhoeal medication
- Grade 2 diarrhoea: ICPi interrupted and patient start with corticosteroids depending on the severity and other symptoms. In the case of no improvement within 3–5 days, colonoscopy should be carried out and, in the case of colitis, infliximab should be administered
- Grade 3–4 diarrhoea (severe): permanently discontinue ICPi. Admit patient to the hospital and initiate (methyl)prednisone. Add infliximab if no improvement is observed within 2–3 days
- Grade 1 and 2: interrupt ICPi, try to rule out infection and start with prednisone. Taper over 4–6 weeks
- Grade 3 and 4: permanent discontinue of ICPi, admit patient to hospital, and immediately start high-dose (methyl)prednisone. Add infliximab, MMF or cyclophosphamide in the case of deterioration under steroids. Taper over a period of 4–6 weeks
- Mild: withhold ICPi and perform work-up (MRI scan, lumbar puncture) to define nature of neurotoxicity. In the case of deterioration or severe neurological symptoms, admit the patient and start (methyl)prednisone. In the case of Guillain-Barre´ or myasthenia-like symptoms, consider adding plasmapheresis or i.v. immunoglobulin
- When a myocarditis is suspected, admit the patient and immediately start high-dose (methyl)prednisone. In the case of deterioration, consider adding another immunosuppressive drug (MMF or tacrolimus)
- For mild arthralgia, start NSAIDs, and in the case of no improvement, consider low dose steroids (10–20 mg prednisone). In the case of severe polyarthritis, refer patient to or consult a rheumatologist and start prednisone. Sometimes infliximab or another anti-TNF drug is required
- In case of nephritis, rule out other causes of renal failure first. Interrupt or permanently discontinue ICPi depending on the severity of the renal insufficiency
- Stop other nephrotoxic drugs. Start (methyl)prednisone. Consider renal biopsy to confirm diagnosis