Immune Checkpoint Inhibitor Therapy-Toxicity Management

Immune related pneumonitis

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

Summary of Guideline

Patients receiving treatment with ICPIs are at risk of developing pneumonitis during their treatment. Whilst this toxicity is less common than some of the other documented toxicities (around 5-10% depending on whether mono- or combination therapy is being used), pneumonitis can cause respiratory failure which can be fatal. It is therefore crucial that patients with new respiratory symptoms are assessed and managed appropriately.
Any patient developing new respiratory symptoms during or following treatment with immunotherapy should have a thorough history and examination. However, history and examination alone cannot effectively rule out pneumonitis owing to the symptoms overlapping with other common complications of cancer treatment (e.g. infection, pulmonary disease progression). Therefore, patients usually require cross-sectional imaging to aid with the diagnosis.
Treatment is directed at pausing the immunotherapy treatment and considering early input with oral or IV corticosteroid treatment. If the patient is not improving within 2-3 days of commencing steroid therapy, then escalation of immunosuppression must be considered. Infliximab, mycophenolate and cyclophosphamide are the most used agents in this setting.

Back to top

Background

This guideline has been put together to guide clinicians when reviewing patients presenting with a new deterioration in respiratory symptoms or radiological changes on cross-sectional chest imaging whilst undergoing or after finishing treatment with ICPIs. When a patient presents with a toxicity of ICPIs it is important to also consider screening in the history for any other potential ICPIs which could be co-presenting, for example, endocrine dysfunction, ocular toxicity.

Unlike other immune-related adverse events of ICPIs, the incidence of pneumonitis is potentially higher in those treated with anti-PD-1/anti-PD-L1 therapies (around 4-5%) when compared to anti-CTLA4 agents(<1%) (Robert C et al. Pembro vs ipi in advance melanoma in advanced melanoma, NEJM 2015). The risk is increased when these treatments are used in combination. The reported incidence of pneumonitis in monotherapy verse combination therapy is 3% vs 10% respectively.

Risk factors for development of pneumonitis include smoking (though not a large increase), previous radiotherapy to the lung and a history of lung disease. Those on combination immunotherapy are also at higher risk (Cui et al, 2018). At the time of consenting for treatment, patients receive written information on the risks of toxicity and this is discussed at completion of the consent form. Patients are notified of the importance of flagging new respiratory symptoms whilst on treatment and how to contact the oncology helpline. All patients are given smoking cessation advice at the time of diagnosis.

Pneumonitis can present unpredictably and does not have well defined peaks and troughs of when it present in the time course of treatment unlike some of the other immune related adverse events. It can present at any time following the start of treatment and can potentially present later on during treatment and certainly well beyond the 6 months of treatment mark. The median time of onset is around 3 months. Therefore it is important to continue to have a clinical suspicion of pneumonitis on the list of potential diagnoses throughout ICPI therapy.

For those colleagues working in the primary care setting, this guideline hopefully serves to demonstrate the investigation/management plan a patient maybe on when being reviewed in primary care. The expectation that investigation and management will be overseen by secondary care, however, patients will not be an inpatient for duration of stay therefore may seek primary care input whilst still on steroids etc.

Back to top

Diagnosis

Pneumonitis is difficult to clinically discern from other potential complications of cancer/cancer treatment owing to its overlapping symptoms with other respiratory disorders. The most common symptoms of pneumonitis include a new non-productive cough or persistent dyspnea, however, it is also possible for patients to present with these symptoms alongside a fever, making the distinction from infection difficult. Patients may also develop chest pain or simply be hypoxic and lethargic. It is also possible for patients to present with no respiratory symptoms but radiological changes only.

This, therefore, makes the diagnosis of pneumonitis clinically quite difficult and a low index of suspicion is required alongside close monitoring and follow-up if the decision is made to treat potential infection in isolation and a low threshold for imaging and reconsideration of initiation of steroid treatment should be had.

Back to top

Investigation

Plain radiographic imaging of the chest is not a reliable tool for differentiating the diagnosis of pneumonitis from other causes of respiratory dysfunction in this setting. The recommendation therefore is for patients to have cross-sectional imaging to aid the correct diagnosis and to further subtype the diagnosis as there have been different radiographic patterns of pneumonitis described in this setting. The most commonly reported subtypes of pneumonitis are organizing pneumonia, hypersensitivity pneumonitis, non-specific interstitial pneumonia and acute interstitial pneumonia/ARDS patterns (Thomas R et al, 2020). Other patterns have been described, including patterns similar to Sarcoidosis with pulmonary infiltrates and hilar lymphadenopathy which can be concerning for disease progression and may require bronchoscopy and biopsy to look for evidence of granulomatous change (Simeone, E. 2019. Nishino M 2018).

Trans-bronchial or VATs biopsy is not routinely recommended but can be useful to determine between a sarcoid-type reaction, lymphangitis or immune-related pneumonitis.

Back to top

Treatment/Management

The management of pneumonitis is documented below as a flow chart according to symptoms/grade.

Steroid weaning is advised to be gradual with an expert committee suggesting that in grade 2, steroid wean should occur over 6 weeks and then grade 3-4 this should be extended to at least 8 weeks. It is recommended that all patients be commenced on gastro-protection whilst receiving steroids unless contraindicated. For those requiring longer weaning courses of steroids, consider bone health and PJP prophylaxis.

For those patients whose symptoms are not responding to high dose steroid rescue therapy it is important to consider early escalation of immunosuppressive therapies. In the main, the literature in this area is limited to case reports of patients. Naidoo et al report a series of 43 patients with pneumonitis of which 5 clinically worsened on steroids requiring further immunosuppression with infliximab +/- cyclophosphamide with poor outcome results (Naidoo, J 2019). ESMO guidance recommends the use of infliximab 5mg/kg infusion, however suggests that mycophenolate mofetil may be a good second option, particularly in those with multi-organ involvement.