Shortness of breath

Dyspnoea/shortness of breath pathway¹

(Reproduced with kind permission of UKONS¹)

Always make sure that the Acute oncology Team are informed of the patient's assessment and/or admission as soon as possible.

Immediate advice is available from the Acute Oncology Service or the 24-hour Oncology on call rota.

Withhold SACT, including oral therapy, until you have discussed with the Acute Oncology or Site Specific Team.

Wide differential diagnosis: disease progression, infection (including SARS-Cov-2), lymphangitis, pulmonary oedema, pulmonary emboli, sarcoidosis.

Immune-related pneumonitis pathway¹

1. Abridged from: NHS Lothian Immunotherapy toxicity management guidelines v7.0. S Clive & C Barrie. Last reviewed: 22.11.2021.

The following content is abridged from: Edinburgh Cancer Centre. Tyrosine kinase inhibitor-related pneumonitis for solid tumours and haematology (S\Tox\20) v1.0. 

Please also note that there are separate guidelines for:

• Immunotherapy related pneumonitis with different management of pneumonitis, including higher steroid doses.
• Trastuzumab deruxtecan (T-DXd) related ILD/pneumonitis, which is associated with a 1% mortality rate and again may require much higher doses of steroids - see section below

This guideline should NOT be used to guide management of pneumonitis for any patient on an immune checkpoint inhibitor, or Trastzuzumab-deruxtecan – please refer to the links above for appropriate management advice

Assessment and immediate management

Please ensure that SARS-CoV-2 (Covid-19) has been ruled out.  

General medicine physicians who encounter these patients eg as acute admissions are encouraged to discuss their management with oncology or haematology teams.

Grade 1

• Asymptomatic – radiological changes only (CT scan)
• Observations including pulse oximetry, pulmonary function tests.

Grade 2

• Mild to moderate new onset of symptoms limiting instrumental activities of daily living (ADL) (e.g. shortness of breath, cough, fever, chest pain).   
• Bloods, observations including pulse oximetry, pulmonary function tests. High Resolution CT chest.   
• Consider hospital admission. Investigations to exclude pulmonary infection (especially COVID-19). 
• Seek specialist respiratory advice.

 Grade 3

• Severe new onset of symptoms limiting self care, or hypoxia or acute respiratory distress syndrome 
• Urgent hospital admission 
• Seek specialist respiratory advice. 

Ongoing management and TKI management

Grade 1

• Interrupt therapy if on an antibody drug conjugate (refer to list in appendix). Refer to SACT protocol or SPC for details.
• Continue therapy if on a TKI.
• Monthly clinical review and pulmonary function tests.   
• 2-monthly cross sectional imaging of the chest.

Grade 2

• Withhold TKI.   
• If infection excluded commence high dose steroid (e.g. prednisolone 50mg OD with PPI cover).  
• Seek specialist respiratory advice as above.   
• Taper steroid dose as symptoms improve.   
• If symptoms settle to grade 1 on steroids within 3 weeks and no alternative treatment option available for the patient, discuss risk-benefits of re-introducing TKI at same dose.   
• Steroids need to continue for the duration of TKI therapy. 
• Monthly clinical review and pulmonary function tests. 2-monthly cross sectional imaging of the chest. 

Grade 3

• Permanently discontinue TKI therapy. 
• Manage with high dose steroids, e.g. prednisolone 50mg daily with PPI cover. Refer to ECC steroid safety bundles (accessible on intranet) for management of patients on steroids, and if on steroids for over four weeks, see PJP Prophylaxis Guidance.
• Seek specialist respiratory advice as above.  
• Taper dose as symptoms improve.   
• Repeat PFTs and cross sectional imaging of the chest to monitor improvement. 

If a patient develops radiological changes potentially consistent with ILD/pneumonitis OR develops an acute onset of new or worsening pulmonary or other related signs/symptoms such as dyspnoea, cough, or fever, ILD/pneumonitis MUST be excluded and T-DXd should be interrupted pending further evaluation.

Assessment and immediate management

Patients are usually having 6-9 weekly surveillance chest CT scans so may be diagnosed radiologically.

Grade 1

• Asymptomatic – radiological changes only (CT scan)

Grade 2

• Mild to moderate new onset of symptoms limiting instrumental ADL (e.g. shortness of breath, cough, fever, chest pain)

Grade 3 or 4 (potentially life-threatening)

• Severe new onset of symptoms limiting self-care, hypoxia/requirement for oxygen supplementation or acute respiratory distress syndrome/life-threatening compromise
• Requires urgent hospital admission

Investigations should include:

• Urgent High-resolution CT followed by CTPA with narrow slices (0.5 – 1mm)
• Blood culture and full blood count (FBC)
• Viral throat swab including SARS-CoV-2 (Covid-19)
• Pulmonary function tests and pulse oximetry (SpO2)
• Arterial blood gases, if clinically indicated.
• Consider bronchoscopy and bronchoalveolar lavage
• Low threshold to refer to specialist respiratory physician

Differential diagnoses include Pneumonia; Alveolar haemorrhage; Radiation-induced lung injury; Cardiac impairment; COVID-19 or seasonal infections; Pulmonary embolism; Metastatic disease or lymphangitis.

Ongoing management

Grade 1

The administration of T-DXd must be interrupted for any ILD/pneumonitis event, regardless of grade

• Review patient and check pulse oximetry at rest and after a brisk walk
• Recommend starting systemic steroids (at least 0.5 mg/kg/day prednisone or equivalent) followed by gradual taper over at least 4 weeks, unless clear clinical rationale not to.
• Monitor and closely follow up patient again within 3-5 days to ensure no progression of symptoms. Ensure patient is seen face-to-face for review if not giving steroids.
• Follow-up with repeat HRCT imaging at 4 weeks (or sooner if worsening symptoms). If not giving steroids for any reason, repeat CT earlier at 1-2 weeks
• If abnormal diagnostic observations at any stage or development of symptoms despite initiation of initial corticosteroids, then follow grade 2 guidelines

T-DXd rechallenge (after grade 1 event only):

This must only be a consultant decision.

For grade 1 events, T-DXd can be restarted only if the event is fully resolved to grade 0:

• If resolved in ≤ 28 days from day of onset, could consider maintaining dose
• If resolved in > 28 days from day of onset, reduce dose one level

However, if the event of Grade 1 ILD/pneumonitis first occurs beyond day 22 and has not resolved within 49 days from the last infusion, T-DXd should be discontinued.

*If patient remains asymptomatic, then patient should still be considered as grade 1 even if steroid treatment is given.

Grade 2

• Permanently discontinue T-DXd therapy.
• Promptly start and treat with systemic steroids (eg at least 1 mg/kg/day prednisolone or equivalent) for at least 14 days or until complete resolution of clinical and chest CT findings, then followed by a gradual taper over at least 4 weeks
• Monitor symptoms closely
• Re-image with a CT scan of the chest as clinically indicated, after 2-4 weeks
• If worsening or no improvement in clinical or diagnostic observations in 5 days, consider increasing dose of steroids (eg, 2 mg/kg/day prednisolone or equivalent) and administration may be switched to intravenous methylprednisolone, see grade 3/4 for dosing
• Reconsider additional work-up for alternative aetiology.
• Escalate care as clinically indicated
• Refer to ECC steroid safety bundles (accessible on intranet) for management of patients on steroids, and if on steroids for over four weeks, see PJP Prophylaxis Guidance.

Grade 3/4

• Permanently discontinue T-DXd therapy
• Urgent hospitalisation required
• Promptly initiate empirical high-dose methylprednisolone IV treatment (500–1000 mg/day for 3 days), followed by at least 1.0 mg/kg/day of prednisolone (or equivalent) for at least 14 days or until complete resolution of clinical and chest CT findings, then followed by a gradual taper over at least 4 weeks
• Refer to respiratory physician for specialist opinion +/- High Dependency Unit support if required
• Re-image as clinically indicated within 2-4 weeks
• If still no improvement within 3 to 5 days, reconsider additional work-up for alternative aetiologies
• Consider other immunosuppressants eg infliximab or mycophenolate mofetil as per local practice under respiratory physician guidance
• If systemic steroids equivalent to prednisolone ≥20mg/day are recommended over a period >4 weeks, Pneumocystis jirovecii pneumonia (PJP) prophylaxis with co-trimoxazole cover should be provided (eg 960mg daily or three times a week, for the duration of steroid treatment)³
• Refer to ECC steroid safety bundles (accessible on intranet) for management of patients on steroids, and if on steroids for over four weeks, see PJP Prophylaxis Guidance.

• UKONS Oncology Nursing Society. Acute oncology initial management guidelines. v.4.0. Publication date: 13.02.2023. Available from: https://ukons.org/news-events/acute-oncology-initial-management-guidelines-latest-version/
• Supplement to: Modi S, Saura C, Yamashita T, et al. Trastuzumab deruxtecan in previously treated HER2-positive breast cancer. N Engl J Med 2020;382:610-21. p17-18
• Sandra M. Swain et al. Multidisciplinary clinical guidance on trastuzumab deruxtecan (T-DXd)–related interstitial lung disease/pneumonitis—Focus on proactive monitoring, diagnosis, and management. Cancer Treatment Reviews, Volume 106, 2022, 102378
• Optimizing treatment management of trastuzumab deruxtecan in clinical practice of breast cancer. Rugo et al, ESMO Open 2022. Volume 7 - Issue 4 – 2022. p1-12
• UKBCG Document: UK Guidance for the monitoring and management of ENHERTU®-related ILD iPDF
• An Official American Thoracic Society Statement: Treatment of Fungal Infections in Adult Pulmonary and Critical Care Patients. Am J Respir Crit Care Med, 183 (1) (2011), pp. 96-128