Immune Checkpoint Inhibitor Toxicity — Viva Defence

Candidate's opening statement (SASPOP)

"Thank you. I have reviewed Mr K, a 64-year-old retired engineer who presents to the emergency department with a three-week history of progressive bloody diarrhoea, a diffuse itchy rash, fatigue and dizziness on standing, three weeks into cycle 4 of combination ipilimumab and nivolumab for metastatic melanoma. His cardinal findings are postural hypotension, abdominal tenderness, a maculopapular rash over 25 per cent of his body surface area, and laboratory evidence of panhypopituitarism with secondary adrenal insufficiency, transaminitis, and acute kidney injury. My integrated diagnosis is multisystem grade 3 immune-related adverse event from his checkpoint inhibitors, with the adrenal crisis as the immediate life threat." [1]

Prioritised problem list

1. Secondary adrenal insufficiency from hypophysitis with adrenal crisis — the immediate life threat (postural drop, sodium 126, low cortisol and ACTH).
2. Grade 3 immunotherapy colitis — the index emergency; perforation risk.
3. Grade 2 immunotherapy hepatitis — exclude viral and obstructive causes.
4. Central hypothyroidism — to be replaced AFTER cortisol.
5. Grade 2 maculopapular rash — manageable alongside.
6. Metastatic melanoma — the underlying disease.
7. Acute kidney injury — likely pre-renal and interstitial; will improve with resuscitation. [1]

Integrated management plan

Immediate (first hour):

• Intravenous hydrocortisone 100 mg stat then 50 mg every 6 hours — adrenal crisis first.
• Intravenous fluids (1 L normal saline over the first hour, then resuscitate to haemodynamics); correct sodium slowly.
• Stool studies sent before steroids — culture, C. difficile toxin, ova cysts and parasites (already done).
• Once stool is in the lab, intravenous methylprednisolone 1 to 2 mg/kg per day for the colitis (covers the hepatitis and rash too).
• Hold both checkpoint inhibitors; thromboprophylaxis. [1]

First 24 to 72 hours:

• Pituitary MRI once stable to confirm hypophysitis.
• Gastroenterology and surgical review; abdominal CT if peritonism develops.
• Viral and autoimmune hepatitis screen; abdominal ultrasound with Doppler.
• Plan infliximab 5 mg/kg at 48 to 72 hours if colitis is steroid-refractory (QuantiFERON and hepatitis B surface antigen first).
• Add mycophenolate if hepatitis is steroid-refractory (avoid infliximab in liver toxicity).
• Topical steroid and antihistamine for the rash. [1]

Medium term:

• Lifelong endocrine replacement (hydrocortisone, levothyroxine, testosterone).
• Slow corticosteroid taper over 4 to 6 weeks once irAEs resolve.
• Multidisciplinary decision on permanent discontinuation of combination therapy; consider anti-PD-1 monotherapy if melanoma is responding, after shared decision-making.
• Patient education, GP communication, patient-held irAE card. [1]

Probing questions and model answers

Examiner: Why did you treat the adrenal crisis before the colitis? [1]

Candidate: "Adrenal crisis is the immediate life threat — the postural drop, hyponatraemia and hyperkalaemia can progress to cardiovascular collapse within hours, and the treatment (a single dose of hydrocortisone) is safe, rapid and reversible. The colitis is serious but its definitive management (immunosuppression) takes days to work, and the first dose of methylprednisolone does not depend on the stool result being back as long as the sample is in the lab. So the order is: hydrocortisone and fluids first, stool sent, then methylprednisolone. I would NOT give levothyroxine before hydrocortisone because thyroid replacement increases cortisol clearance and can precipitate collapse." [1]

Examiner: When would you add infliximab, and what do you check first? [1]

Candidate: "I would add infliximab 5 mg/kg at 48 to 72 hours if the colitis has not improved on adequate-dose intravenous methylprednisolone — that is the definition of steroid-refractory disease in the ASCO and ESMO guidelines. Before giving infliximab I would screen for tuberculosis with an interferon-gamma release assay, check hepatitis B surface antigen and core antibody, and exclude active infection, because infliximab is an anti-TNF monoclonal antibody and can reactivate latent TB and hepatitis B. Vedolizumab, a gut-selective anti-integrin, is the alternative if infliximab is contraindicated or ineffective." [1]

Examiner: Why is mycophenolate the second-line agent for hepatitis and not infliximab? [1]

Candidate: "Infliximab is itself hepatotoxic and has been associated with drug-induced liver injury, so it is specifically avoided in checkpoint-inhibitor hepatitis. Mycophenolate mofetil inhibits inosine monophosphate dehydrogenase in lymphocytes and is the preferred second-line agent for steroid-refractory hepatitis, and also for nephritis, at a dose of 500 to 1000 mg twice daily." [1]

Examiner: What is the evidence that stopping the checkpoint inhibitors for toxicity does not harm the cancer? [1]

Candidate: "Schadendorf and colleagues pooled the randomised phase II and III trials of nivolumab plus ipilimumab and showed that patients who discontinued therapy because of adverse events had antitumour responses and overall survival that were at least as good as patients who continued therapy. The immune response, once primed, can persist. This means I should treat the toxicity decisively and not under-dose the steroids out of oncological anxiety." [1]

Examiner: Will you re-challenge this patient with immunotherapy? [1]

Candidate: "After a grade 3 event in two vital organs — colitis and hepatitis — the combination regimen is permanently discontinued. If the melanoma is responding and further immunotherapy is warranted, I would discuss switching to anti-PD-1 monotherapy, which carries a lower irAE rate than the combination, in a multidisciplinary meeting with the patient's oncologist and the patient. Endocrine irAEs managed with replacement are the exception where the checkpoint inhibitor can be continued, but that is not the situation here." [1]

Examiner: What single bedside finding would make you check a troponin urgently in a patient on a checkpoint inhibitor? [1]

Candidate: "Any cardiac symptom — chest pain, dyspnoea or palpitations — or any unexplained tachycardia, warrants troponin and an ECG. Checkpoint-inhibitor myocarditis is rare, around 1 per cent in the Mahmood registry, but has a case fatality of 25 to 50 per cent and frequently coexists with myositis and myasthenia gravis. The threshold to check troponin should be very low." [1]

Examiner: How would your management differ if this were a patient on anti-PD-1 monotherapy rather than combination therapy? [1]

Candidate: "The grading framework and the steroid doses are identical, but the irAE burden is lower with monotherapy — grade 3 to 4 events occur in roughly 10 to 15 per cent of patients on anti-PD-1 versus 55 per cent or more on combination. Pneumonitis and thyroiditis are more characteristic of anti-PD-1, while hypophysitis and severe colitis are more characteristic of anti-CTLA-4. The threshold for permanent discontinuation is also slightly lower with combination therapy; with a single grade 3 event on monotherapy that responds well to steroid, the oncologist may consider resuming a different or the same agent after multidisciplinary discussion." [1]

Short-case discussion — the general examination routine

Examiner: Describe your examination routine for a patient with suspected immunotherapy toxicity. [1]

Candidate: "I begin with general inspection — looking for rash, Cushingoid features from steroids, alopecia, vitiligo, hydration, and dyspnoea. I record the vital signs including oxygen saturation and a postural blood pressure, because a postural drop signals adrenal insufficiency or significant dehydration. I then examine the skin systematically — the morphology (maculopapular, bullous, pruritic), the body-surface-area involvement, and crucially the mucous membranes, because mucosal involvement escalates the diagnosis to Stevens-Johnson syndrome or toxic epidermal necrolysis. I examine the abdomen for tenderness, distension, peritonism and bowel sounds (for colitis and its complications), the chest for fine crackles (pneumonitis, excluding heart failure), the cardiovascular system for a new murmur, rub, raised jugular venous pressure or signs of heart failure (myocarditis), a focused neurological examination for ptosis and fatigability (myasthenia), reflexes (Guillain-Barre, myelitis) and sensorium (encephalitis), and an endocrine screen — thyroid, adrenal stigmata, and confrontation visual field testing for bitemporal hemianopia from hypophysitis." [1]

Examiner: How would you present a grade 2 maculopapular rash in a patient on pembrolizumab? [1]

Candidate: "I would describe the morphology — an erythematous maculopapular rash, confluent over the trunk, sparing the mucous membranes, involving approximately 25 per cent of the body surface area. I would grade it by CTCAE — grade 2, because it covers more than 10 per cent of body surface area. I would exclude Stevens-Johnson syndrome and DRESS by confirming no mucosal involvement and checking the eosinophil count. My plan: hold the pembrolizumab, topical corticosteroid and an oral antihistamine, with a plan to resume when the rash returns to grade 1 or less. If it progresses to grade 3 or if there is any mucosal involvement, I would escalate to systemic corticosteroid and involve dermatology urgently." [1]

Examiner: What signs would prompt you to check a troponin in this patient? [1]

Candidate: "As I said, any cardiac symptom or unexplained tachycardia. The cardinal exam findings that trigger troponin are chest pain, dyspnoea without a clear respiratory cause, palpitations, syncope, a new murmur, or signs of heart failure. In a patient on any checkpoint inhibitor with any of these, the troponin and ECG are mandatory." [1]

Insight into the patient perspective

"Mr K is frightened — he understands his immunotherapy is working against his melanoma, and he is worried that stopping it means his cancer will progress. I would explain that the very fact he has developed toxicity is a signal that his immune system is active against the tumour, and that the data show patients who stop immunotherapy for toxicity often do as well as those who continue. I would reassure him that the immediate priority is his safety, that the adrenal crisis and colitis are treatable, and that we will involve him in the decision about future cancer therapy once he is stable. I would give him a written irAE action plan, a steroid taper calendar, and a patient-held card naming the drug and the toxicity, so that any future clinician can recognise the context immediately." [1]