By A/Prof Tony Caccetta and Dr Helena Collgros, Dermatologists
Immunotherapy has transformed cancer treatment by shifting the focus from directly killing cancer cells to activating the immune system to fight cancer – improving survival in many advanced cancers without chemotherapy related side effects.
However, immunotherapy related adverse events (irAEs) are common and may be serious or life-threatening.
Immune checkpoint inhibitors (ICIs), for example ipilimumab, nivolumab, pembrolizumab, atezolizumab, may cause cutaneous toxicity in 30-50% of patients. Often occurring in the first few weeks – months of treatment, the onset can be unpredictable, occuring at any time.
Most cases are mild and manageable, not requiring systemic corticosteroids or immunotherapy interruption/cessation – interventions which may shift the tipping point for durable cancer response. We present some of the more common and serious presentations of ICI-related cutaneous toxicity below.
Psoriasis
Immunotherapy has the potential to trigger or exacerbate existing psoriasis, which may affect skin nails or joints.
It is essential to ask about a personal or family history of psoriasis before commencing immunotherapy. Immunotherapy related psoriasis may be widespread, however can often be managed effectively with skin directed treatments such as topical steroids, phototherapy and/or oral acitretin (retinoid).
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A lack of response or the development of arthritis may require treatment escalation with immunosuppressive agents such as methotrexate or biologic therapy.
Oral prednisolone or intravenous methylprednisolone can potentially destabilise psoriasis upon withdrawal, with rebound/unstable flares, which may be sometimes pustular or erythrodermic.
Vitiligo
Vitiligo, an autoimmune disease, can be triggered or exacerbated by immunotherapy treatment targeting melanocytes. It may be a good prognostic sign and marker of treatment response in melanoma patients.
Treating vitiligo can be challenging and the response unpredictable. However, topical steroids, topical calcineurin inhibitors and phototherapy may trigger repigmentation in these patients.
Spontaneous re-pigmentation can also occur without specific treatment. While vitiligo can be a very significant adverse event for patients, immunosuppressive treatments, for example emerging oral JAK inhibitors, should currently be avoided in this setting.
Lichenoid eruption
Lichenoid immunotherapy eruptions often present as violaceous flat-topped papules or plaques which may coalesce, often affecting the limbs and trunk. They often occur 6-12 weeks after ICI commencement.
Skin biopsy and lupus serology can be helpful to distinguish a lichenoid reaction from immunotherapy induced subacute cutaneous lupus (SCLE). Skin directed treatment includes topical steroids, phototherapy and acitretin.
Lichenoid eruptions can often be managed without systemic corticosteroids or immunotherapy interruption/cessation.
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Phototherapy should be avoided in SCLE and topical steroids +/- oral hydroxychloroquine are often considered. SCLE management would be escalated if associated with systemic lupus erythematosus.
Pruritus
Pruritus in this setting is often multifactorial. It can be related to immunotherapy, but often there is an underlying contributing factor, commonly dry skin.
Not all skin related presentations are due to immunotherapy side effects. A co-existing morbilliform or other rash, related or unrelated to immunotherapy, may also contribute to pruritus. General skin care measures, for example soap-free wash and moisturising immediately following showering, are simple and often helpful.
Anti-pruritic creams containing menthol can be very soothing and used regularly. If there is an underlying dermatosis, specific treatment will improve pruritus. Pruritus and morbilliform rash can often be managed without systemic corticosteroids or immunotherapy interruption/cessation.
Bullous pemphigoid
Bullous pemphigoid is an immunobullous disorder that commonly affects older people and presents with a prodromal urticarial eruption (pre-bullous pemphigoid) before evolving into tense blisters on an erythematous base.
Immunotherapy may trigger bullous pemphigoid at any time during treatment. However, delayed presentations are common.
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It requires a diagnostic biopsy sent for histopathology and direct immunofluorescence. Treatments include topical steroids, doxycycline + nicotinamide or off-label dupilumab (IL-4 and IL-13 inhibitor).
If not controlled by the above, oral prednisolone, methotrexate, IVIG and rituximab may be considered. Immunotherapy interruption/cessation may be required.
Steven-Johnson Syndrome (SJS) & Toxic Epidermal Necrolysis (TEN)
This is a rare but serious life-threatening adverse reaction to immunotherapy. Immediate cessation of immunotherapy is required upon suspicion of SJS/TEN.
All medications require review as potential culprits. Skin pain, flaccid blistering with a positive Nikolsky’s sign and mucosal involvement are important diagnostic features.
A skin biopsy can be useful. Admission to a tertiary hospital with experience in supportive care and SJS/TEN management is required.
Managing the risks
When managing ICI related cutaneous toxicity, the risks of continuing or resuming immunotherapy treatment are carefully considered and may include:
- Worsening of cutaneous toxicity, which may potentially become treatment refractory and permanent
- The development of other systemic toxicities, like colitis, hepatitis, pneumonitis, endocrinopathies, which may also potentially become treatment refractory and permanent.
Most cancer patients developing dermatological issues are not referred to a dermatologist. Improving timely access to dermatology services for oncology patients with cutaneous toxicity is required.
The interval between immunotherapy doses, often 2-4 weeks, is when skin directed therapies may be trialled, with close dermatology monitoring for skin progression and oncology monitoring for other systemic toxicities.
Even if a grade 2/3 cutaneous toxicity improves significantly with skin directed treatments, continuing or resuming immunotherapy comes with careful consideration and caution.
Rapid access dermatology services for assessment of ICI cutaneous toxicity, allows for timely and accurate diagnosis and offers oncology patients effective skin directed treatment options.
This can improve quality of life (QOL) and potentially avoid systemic corticosteroids and immunotherapy interruptions/cessation for advanced cancer patients.
Key messages
- Rapid access pathways to dermatologist care can improve quality of life for cancer patients
- Skin directed treatments are often safe and effective and may provide options prior to considering systemic corticosteroids and immunotherapy interruption/cessation
- Not all cutaneous eruptions are related to immunotherapy.
Author competing interests -nil
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