Side effects of systemic cancer therapy - drug induced interstitial lung disease

Overview

Drug-induced interstitial lung disease (DI-ILD): a diagnosis of exclusion, but one to reach early
*Any new cough or breathlessness in a patient on systemic anticancer therapy is DI-ILD until proven otherwise*
Presents anywhere from days (hypersensitivity) to years (fibrosis) after exposure

Pattern	Typical culprits
Organising pneumonia	Checkpoint inhibitors, bleomycin, rituximab
NSIP	Methotrexate, checkpoint inhibitors
Hypersensitivity pneumonitis	Methotrexate, bleomycin
Diffuse alveolar damage / ARDS	Bleomycin, busulfan, gemcitabine, the pattern that kills
UIP-like fibrosis	Bleomycin, busulfan, nitrosoureas, amiodarone
Eosinophilic pneumonia	Daptomycin, NSAIDs, some TKIs

Bleomycin ~10% (fatal in ~1-2%)
Trastuzumab deruxtecan (T-DXd) ~10-15%, fatal in ~2% - the most important contemporary cause
Checkpoint inhibitor pneumonitis ~3-5% single agent, ~7-10% combination; higher in lung cancer
EGFR TKIs ~1-2% (higher in Japanese populations); osimertinib ~3-4%
mTOR inhibitors (everolimus, temsirolimus) ~10-15%
Methotrexate ~1-5%; gemcitabine, taxanes, cyclophosphamide less commonly

Direct cytotoxic injury to alveolar epithelium and endothelium
- Dose-dependent, predictable, cumulative
- Bleomycin, busulfan, nitrosoureas
Immune-mediated / idiosyncratic
- Not dose-related, unpredictable
- Checkpoint inhibitors, methotrexate, TKIs, ADCs

Bleomycin hydrolase inactivates bleomycin, and lung and skin have the least of it - explains organ selectivity
Iron-dependent free radical generation -> DNA strand breaks -> alveolar epithelial injury
-> inflammatory pneumonitis -> progressive fibrosis
Risk factors: cumulative dose >300-400 units, age >40, renal impairment (reduced clearance), smoking, mediastinal radiotherapy, and high FiO2
- *High inspired oxygen during anaesthesia or resuscitation may precipitate fatal pulmonary toxicity, potentially for life* - flag it in the record and to every anaesthetist

Busulfan - alkylating agent; "busulfan lung" with late fibrosis
Methotrexate - hypersensitivity pattern, may occur at low doses, can recur on re-challenge
Amiodarone (non-oncological but the classic comparison)

Exclude the mimics first - the differential is the whole exercise

Infection - bacterial, viral, PJP (esp. if on steroids or fludarabine/rituximab), fungal, atypical
Lymphangitis carcinomatosa or progressive malignancy
Pulmonary embolism
Cardiogenic pulmonary oedema (fluid load, cardiotoxicity)
Radiation pneumonitis (within the radiation field, 4-12 weeks post; recall reaction with subsequent chemotherapy)
Transfusion-related lung injury, diffuse alveolar haemorrhage

HRCT chest - defines the pattern; ground-glass, consolidation, reticulation, traction bronchiectasis
Bronchoscopy with BAL - primarily to exclude infection; lymphocytosis supports drug/immune aetiology
Lung function: restrictive pattern with a low DLCO; DLCO falls earliest
Blood: FBE (eosinophilia), CRP, cultures, respiratory viral PCR, beta-D-glucan
Echo/BNP to exclude cardiac cause
Lung biopsy rarely needed
Bleomycin surveillance: baseline and serial DLCO; a >25% fall from baseline warrants cessation

A. Stop the drug

Permanent discontinuation in moderate or severe disease - the single most important step
Continue at grade 1 only with close monitoring and specialist input

B. Corticosteroids

Grade	Management
1 (radiographic only, asymptomatic)	Hold the drug, repeat HRCT in 3-4 weeks, monitor
2 (symptomatic, limiting instrumental ADLs)	Withhold; prednisolone 1-2 mg/kg/day; HRCT; consider bronchoscopy; permanently discontinue if recurrent
3-4 (severe, hypoxic, life-threatening)	Permanent discontinuation; admit; IV methylprednisolone 1-2 mg/kg/day (up to 1 g in fulminant disease); respiratory referral

Taper slowly over at least 6-8 weeks - rebound is common with rapid weaning
Cover with empirical antibiotics until infection is excluded, and PJP prophylaxis if prednisolone >=20 mg for >4 weeks
Refractory at 48-72 hours -> add infliximab, mycophenolate, cyclophosphamide or IVIG

C. Agent-specific

Bleomycin - stop permanently; *flag lifelong oxygen caution* (avoid FiO2 >30% unless clinically essential); monitor DLCO
T-DXd - grade 1 may be re-challenged after full radiological resolution at a reduced dose; grade >=2 is permanent discontinuation
EGFR TKI pneumonitis - stop the TKI, high-dose steroids; do not re-challenge with the same agent
Checkpoint inhibitor pneumonitis - as per irAE protocols
Methotrexate - stop; folinic acid does not prevent pneumonitis

D. Supportive

Oxygen (with caution after bleomycin), non-invasive ventilation, pulmonary rehabilitation
Smoking cessation
Vaccination

Bleomycin (BEP for germ cell tumour, ABVD for Hodgkin), busulfan - the classic fibrosis-inducing pair
Nitrosoureas (carmustine, lomustine), mitomycin C
Methotrexate, cyclophosphamide, gemcitabine, taxanes, cytarabine
Trastuzumab deruxtecan and other antibody-drug conjugates
EGFR TKIs (gefitinib, erlotinib, osimertinib), ALK inhibitors, mTOR inhibitors (everolimus, temsirolimus)
Checkpoint inhibitors; CAR-T
Rituximab, brentuximab vedotin
Radiotherapy - additive risk; radiation recall pneumonitis
Non-oncological comparators: amiodarone, nitrofurantoin, methotrexate for RA, sulfasalazine

Hypersensitivity and organising pneumonia patterns: usually reversible with cessation and steroids
Fibrotic patterns (bleomycin, busulfan, nitrosoureas): often irreversible and may progress despite stopping the drug
Diffuse alveolar damage carries mortality up to 50%
Bleomycin pulmonary toxicity: fatal in ~1-2% of exposed patients; survivors may have permanent restrictive defect
Recurrence on re-challenge is common and often more severe
Long term: exertional limitation, reduced DLCO, secondary pulmonary hypertension, susceptibility to further lung injury
Document the culprit drug as an allergy/adverse reaction so it is never given again

14 more sections, plus exam facts

Premium unlocks every note across every specialty, and the full exam fact library behind it.