Immune Checkpoint Inhibitor Therapy- Toxicity Management

Corticosteroids and considerations required

• Summary
• Background
• Diagnosis
• Investigation
• Treatment/Management

Summary of Guideline

Patients undergoing treatment with immune checkpoint inhibitors (ICPIs) are at risk of developing a range of immune-mediated toxicities, most commonly cutaneous toxicity, colitis, hepatitis and endocrinopathies. Corticosteroid treatment is usually the “go to” treatment for these toxicities when drug cessation and symptomatic management have failed to control the toxicity (excepting the case of endocrine toxicities where often hormone replacement is required). High doses of steroids are often utilized in the early stages of management and then require a gradual wean of dose to prevent recurrence of toxicity or adrenal crisis. Patients also require consideration of prophylactic treatment for the potential toxicities of steroids (gastric protection, bone health, immune suppression and steroid-induced hyperglycaemia/diabetes) if staying on steroid treatment for over 4 weeks.

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Background

One of the hallmarks of cancer is the ability of tumour cells to evade immune detection. Immune checkpoint inhibitors (ICPIs) are a class of drugs designed to combat this hallmark to allow immune recognition and destruction. Patients receiving ICPIs are at risk of developing adverse effects of ICPIs which can present as multi-system immune related adverse events. The risk of this occurring can be as high as 60% in patients treated with a combination of ICPIs. For grade one and some grade two toxicities observation and symptomatic management are advised in local, national and international guidelines. Once toxicity is graded beyond this or has not improved with withholding treatment and symptomatic management, steroids are indicated to try and reduce the inflammatory response. Steroids can be very effective at achieving this, however, high doses are often utilized. These then require a wean of the dose down prior to cessation of steroid treatment, this is both to reduce the risk of adrenal suppression following cessation of therapy and to reduce the risk of flare of symptoms/inflammation following steroid withdrawal.

A patient information leaflet to educate patients on steroids can be found at: https://www.leedsth.nhs.uk/patients-visitors/patient-and-visitor-information/patient-information-leaflets/cancer (Steroids and cancer).

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Diagnosis

Please see individual toxicity guidelines for the diagnosis of immune-related toxicities.

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Investigation

Please see individual toxicity guidelines for the investigation of immune-related toxicities.

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Treatment/Management

Weaning steroids 

It is common practice within and beyond oncology is to taper and wean systemic steroids but the evidence base for best practice approach to weaning steroids is not robust in the setting of immune-related toxicities.

Duration of systemic steroids is affected by:

1. starting dose (i.e. higher doses generally lead to longer duration of steroids)
2. duration of initial plateau
3. pace of wean

During steroid wean patient & clinical team need to be vigilant for:

1. re-emergence of index immunotherapy toxicity
2. newly emergent immunotherapy toxicity
3. adrenal suppression. Consider a switch to hydrocortisone at physiologic dose prednisolone (5-7.5mg/day).

Pace of wean:
ESMO guidance broadly recommends faster wean (2-4 weeks) after resolution of Grade 2 toxicity and slower wean (4-8 weeks) after resolution of Grade 3-4 toxicity. Recommendations after pneumonitis are cautious. First flare of symptoms or bloods after steroid dose reduction in a well patient can usually be managed by re-escalation (e.g. increase by 10mg/day prednisolone) but may require urgent reassessment and/or change in treatment. See individual guidance.

When immunotherapy re-challenge is a feasible option for the patient consider the funding timing window.

We hope to be able to audit use & outcomes of suggested patterns.

Suggested patterns: 

Fast wean: reduce by 10mg every 5 days. If flare requires dose escalation consider the duration of plateau dose before attempting further slow wean. 

Slow wean: reduce by 10mg every 7 days 

Slow wean allows dose change, safety bloods & symptom review calls to be set up on a weekly pattern.

In practice, patients may require a slower wean of steroids as they reach the lower doses and consideration should be given to suppling 1mg tablets to support a slower reduction in dose in discussion with the Oncology site-specialist team.

Mitigating steroid side effects

Consider 

1. Adrenal suppression
   Decreased or inadequate endogenous cortisol as a result of steroid therapy.
   Symptoms often initially vague. Dose and duration are not reliable predictors of adrenal suppression. Empirically wean is used but symptoms can still emerge and patients are at risk of acute adrenal crisis. Risk is higher with longer acting formulations (i.e. dexamethasone>prednisolone>hydrocortisone) (Liu. Allergy, Asthma & Clinical Immunology 2013, 9:30).
   Patients who will be on equivalent doses of>5mg prednisolone per day for > 4weeks should be educated on the risk of adrenal insufficiency secondary to steroids and be given a steroid alert card. Please see the guidance on the Society for Endocrinology webpage for further details. Adrenal crisis | Society for Endocrinology
2. Bone health.
   Check vitamin D & replace/maintenance dose (specialist guidelines in melanoma), as part of the bone health screen the patient should also have U&E and LFTs checked as baseline (if not already checked).
   Consider calcium supplementation with AdCal-D3 (current trust formulary guidance can be found at: http://www.leedsformulary.nhs.uk).
   Meta-analysis >80 studies finds reduced bone mineral density and increased risk of fracture and osteonecrosis within 3-6 months with 5mg/prednisolone/day (van Staa Osteoporos Int 2002, 13:777-787).
   Consider oral bisphosphonate if other osteoporosis risk factors & duration of steroids (5mg/prednisolone/day) is likely to be 3 months or longer. FRAX score can be found here: https://www.sheffield.ac.uk/FRAX/tool.aspx?country=9
3. Diabetes risk increases with glucocorticoid dose.
   Initial fasting glucose & HBA1c measurement. Trust guidelines regarding steroid induced diabetes and hyperglycaemia can be found at: http://nww.lhp.leedsth.nhs.uk/common/guidelines/detail.aspx?ID=5974
   Educate & screen for classic symptoms: polyuria, polydipsia, weight loss.
   Monitor glucose parameters 3-6 monthly.
4. Infection risk.
   Consider PCP prophylaxis where steroid duration is likely to exceed 4 weeks.
   Avoid live vaccines until 3 months after high dose glucocorticoids.
   Meta-analysis RR 1.6 over 10mg/prednisolone/day & where cumulative dose >700mg prednisolone (Stuck, Rev Infect Dis 1989, 11:954-963). Retrospective observational study in patients with rheumatology conditions explored trimethoprim/sulfamethoxazole prophylaxis for PCP infection estimates number needed to treat to prevent one case 52 (range 33-124) but varies with steroid dose (>60mg/prednisolone/day). Potentially serious side effects include: rash (10%), hyperkalaemia (10%), fungal infection (10%) and rare Stevens-Johnson syndrome (SJS), thrombocytopaenia and pancytopaenia. Estimate number needed to harm 131 (55-∞) (Park, Ann Rheum Dis 2018;77:644-649). Anecdotally some concern that after immunotherapy patients may be at higher risk of adverse drug reactions.
5. Cardiovascular risk
6. Optical issues
   Cataract risk (classically posterior capsule) is a late side effect. Onset is usually after 12 months of at least 10mg/prednisolone/day.
   Glaucoma risk is more serious and acute. Painless increase in intraocular pressure can lead to visual field loss, optic disc cupping & permanent damage to the optic nerve. Risk is higher in those with diabetes, high myopia, connective tissue diseases and/or a personal/family history of glaucoma. Consider initial/early ophthalmic assessment.

For ALL patients discharged on high dose steroids, please ensure the following are supplied* :

*Suitable alternatives of the drugs listed above can be used based on clinical judgement  

**If PO weaning course initiated whilst inpatient, round to nearest full box

*** Ensure interactions with regular medication checked prior to supply