Overview
Definition:
Immune checkpoint inhibitors (ICIs) are a class of drugs that block inhibitory pathways in the immune system, releasing the brakes on T cells and allowing them to attack cancer cells
Toxicities, also known as immune-related adverse events (irAEs), occur when this enhanced immune response is directed against healthy host tissues
In adolescent oncology, ICIs are increasingly used for various malignancies, leading to a growing recognition of their unique toxicity profiles in this age group.
Epidemiology:
The incidence of irAEs in pediatric patients treated with ICIs is variable and can range from 50-90%, depending on the drug, regimen, and patient population
Adolescents may experience a different spectrum or severity of irAEs compared to adults due to differences in immune system maturation and baseline health status
Commonici used include nivolumab, pembrolizumab, and ipilimumab.
Clinical Significance:
Understanding and promptly managing ICI toxicities is critical for optimizing treatment outcomes in adolescent oncology
Unrecognized or poorly managed irAEs can lead to significant morbidity, treatment discontinuation, and impact the long-term quality of life for young patients
Early recognition and intervention are key to preventing severe sequelae and ensuring successful cancer treatment.
Clinical Presentation
Symptoms:
Symptoms are diverse and can affect virtually any organ system
Common presentations include fatigue, fever, rash, arthralgias, myalgias, diarrhea, nausea, vomiting, and cough
Endocrine dysfunction (e.g., thyroiditis, hypophysitis) may present with subtle symptoms like fatigue, weight changes, or mood disturbances
Neurological symptoms can include headache, seizures, or peripheral neuropathy
Ocular manifestations can involve dry eyes or uveitis
Cardiac involvement is rare but serious, presenting as myocarditis with chest pain or dyspnea.
Signs:
Physical examination findings may include skin changes such as maculopapular rash, pruritus, or vitiligo
Gastrointestinal signs can include abdominal tenderness and diminished bowel sounds
Endocrine examination may reveal thyroid enlargement or signs of adrenal insufficiency
Neurological examination might show focal deficits or altered mental status
Cardiovascular examination may reveal murmurs or pericardial rub in cases of myocarditis
Lymphadenopathy can be present in some cases.
Diagnostic Criteria:
Diagnosis of irAEs is primarily clinical, based on temporal association with ICI therapy and exclusion of other causes
Grading of irAEs is typically done using the Common Terminology Criteria for Adverse Events (CTCAE) v5.0
Specific diagnostic workups are guided by the affected organ system and may include laboratory tests (e.g., thyroid function tests, cortisol levels, inflammatory markers), imaging (e.g., echocardiography, MRI), and biopsies when indicated.
Diagnostic Approach
History Taking:
A detailed history is crucial, focusing on the onset, duration, and character of symptoms, as well as their temporal relationship to ICI initiation, dose, and interruptions
Inquire about prior autoimmune conditions, family history of autoimmune diseases, and concurrent medications
Specific questions should address common irAE sites: skin, gastrointestinal tract, endocrine glands, lungs, heart, and nervous system
Ask about recent travel or infections that could mimic irAEs.
Physical Examination:
A comprehensive physical examination is essential, with a systematic evaluation of all organ systems
Pay close attention to skin for rashes, dryness, or vitiligo
Auscultate lungs for Adventitious sounds
Palpate the abdomen for tenderness or organomegaly
Assess for thyroid enlargement
Perform a thorough neurological examination
Evaluate for signs of cardiac dysfunction
Monitor vital signs closely.
Investigations:
Laboratory investigations are guided by clinical suspicion: Complete Blood Count (CBC) to assess for anemia or eosinophilia
Comprehensive Metabolic Panel (CMP) for electrolyte imbalances and renal/hepatic function
Thyroid Stimulating Hormone (TSH), free T4, free T3 for thyroiditis
cortisol levels for adrenal insufficiency
Antinuclear Antibodies (ANA) and other autoantibodies if autoimmune conditions are suspected
Imaging may include chest X-ray or CT for pneumonitis, echocardiography for myocarditis, and MRI for neurological involvement
Biopsies may be necessary for definitive diagnosis (e.g., skin biopsy for rash, colonoscopy with biopsy for colitis).
Differential Diagnosis:
Differential diagnoses for irAEs include infections (bacterial, viral, fungal), drug-related toxicities (chemotherapy, antibiotics), underlying malignancy progression, new primary diseases (e.g., autoimmune disorders not related to ICIs), and treatment-related complications
Differentiating irAEs from these conditions requires a high index of suspicion, careful clinical correlation, and appropriate investigations.
Management
Initial Management:
The cornerstone of management is prompt recognition and grading of irAEs
For mild (Grade 1) irAEs, close monitoring and symptomatic management may suffice
For moderate (Grade 2) or severe (Grade 3-4) irAEs, ICI interruption is usually indicated
In cases of severe, life-threatening irAEs, permanent ICI discontinuation may be necessary
Consultation with relevant specialists (e.g., endocrinologist, gastroenterologist, pulmonologist) is paramount.
Medical Management:
Corticosteroids are the first-line immunosuppressive therapy for most significant irAEs, starting with high-dose pulses (e.g., 1-2 mg/kg/day of prednisone) for severe cases, with gradual tapering
For steroid-refractory irAEs, second-line immunosuppressants such as infliximab, mycophenolate mofetil, or tacrolimus may be considered depending on the affected organ system
Specific treatments are also instituted for organ dysfunction (e.g., thyroid hormone replacement for hypothyroidism).
Surgical Management:
Surgical intervention is rarely the primary management for irAEs
However, surgical consultation may be required for complications such as bowel perforation in severe colitis or management of abscesses
Close collaboration between oncologists and surgical teams is vital.
Supportive Care:
Supportive care includes vigilant monitoring of vital signs and laboratory parameters, adequate hydration and nutrition, pain management, and psychological support
Patient education regarding symptoms to report and the importance of adherence to treatment is crucial
Prophylaxis for opportunistic infections may be necessary in patients on prolonged immunosuppression.
Complications
Early Complications:
Early complications can include severe gastrointestinal manifestations (hemorrhagic colitis, perforation), endocrine crises (thyroid storm, adrenal crisis), neurological deficits, severe myocarditis leading to heart failure or arrhythmias, and pneumonitis
Sepsis can also arise secondary to immune dysregulation or treatment-induced immunosuppression.
Late Complications:
Late complications can include persistent endocrine deficiencies (hypothyroidism, hypopituitarism, adrenal insufficiency), chronic inflammatory conditions, neurological sequelae, and infertility
Autoimmune syndromes may develop long after ICI treatment has been completed.
Prevention Strategies:
Prophylactic strategies are limited, but patient education on early symptom recognition and prompt reporting is key
Careful patient selection and risk stratification may help identify individuals at higher risk
Close monitoring during ICI therapy, including regular clinical assessments and targeted laboratory tests based on potential irAE sites, can facilitate early detection and intervention, thereby preventing severe complications.
Prognosis
Factors Affecting Prognosis:
Prognosis depends on the organ system involved, the severity of the irAE, the timeliness and efficacy of treatment, and the patient's underlying health status
Early recognition and aggressive management of irAEs are associated with better outcomes
The presence of co-existing autoimmune diseases can also influence prognosis.
Outcomes:
With appropriate management, the majority of irAEs are reversible and do not necessitate permanent ICI discontinuation
However, some irAEs can lead to long-term sequelae or, in rare cases, be life-threatening
Successful management of irAEs allows for continuation or re-initiation of ICI therapy in many cases, preserving anti-tumor efficacy.
Follow Up:
Patients treated with ICIs require long-term follow-up to monitor for the development of new irAEs or chronic sequelae, particularly endocrine dysfunction
Regular clinical examinations and periodic laboratory assessments (e.g., thyroid function tests, assessment for adrenal insufficiency) are recommended
Patients should be educated on potential long-term risks and advised to report any new or worsening symptoms.
Key Points
Exam Focus:
High-yield facts for DNB/NEET SS include understanding the mechanism of ICIs, common irAEs and their affected organs, grading systems (CTCAE), first-line (corticosteroids) and second-line management options, and the importance of early recognition and multidisciplinary care
Differentiate irAEs from infection and malignancy progression.
Clinical Pearls:
Always consider irAEs in any adolescent patient on ICIs presenting with new-onset symptoms, even if seemingly unrelated to cancer
A high index of suspicion is critical
Remember that symptoms can be subtle and evolve over time
Consult specialists early for complex or severe irAEs
Educate patients and families about potential toxicities and when to seek medical attention.
Common Mistakes:
Common mistakes include attributing all new symptoms to cancer progression without considering irAEs, delaying diagnosis and management of irAEs, inadequately grading irAE severity, inappropriate use of immunosuppression (e.g., not using corticosteroids for significant irAEs), and failing to consider long-term sequelae of irAEs
Over-reliance on autoantibody testing without clinical correlation can also lead to diagnostic confusion.