Pulmonary toxicity associated with anti-cancer agents

Definition

Many anti-cancer agents can cause damage to the lungs, airways, pleura, and pulmonary circulation. Pulmonary toxicities induced by systemic anti-cancer agents can vary in severity ranging from minor to life threatening. Toxicity patterns are highly variable from one agent class to the next and may be accentuated by combined-modality therapy.^rrr 

The most common manifestation is interstitial lung disease (ILD)^r and can be categorised based on either clinical criteria or pathological findings, and may include acute, subacute or chronic presentation with ILD. The specific ILD patterns which are seen associated with anti-cancer agents are varied and may progress to pulmonary fibrosis.^rr

Pathophysiology

Several pathophysiological mechanisms have been proposed for anti-cancer agent induced pulmonary toxicity:^rrrrr

• direct chemical injury to pneumocytes or alveolar capillary endothelium, with subsequent cytokine release and inflammatory cell recruitment
• capillary leak and pulmonary oedema due to systemic release of cytokines by anti-cancer agents (e.g. gemcitabine)
• oxidative injury secondary to free oxygen radicals (e.g. bleomycin, mitomycin)
• epidermal growth factor receptor (EGFR)-mediated disruption to alveolar repair mechanisms potentiating lung injury from other causes such as sepsis and radiation therapy (e.g. EGFR inhibitors)
• activation of lymphocytes causing cell-mediated lung injury (e.g. idiosyncratic drug-induced hypersensitivity, mTOR inhibitors, immune checkpoint inhibitors)
• opportunistic infection through immune suppression/activation (e.g. immune checkpoint inhibitors, proteasome inhibitors).^r

Incidence/prevalence

The incidence of systemic anti-cancer therapy induced pulmonary toxicity according to the literature has been reported as high as 20%, dependent on the agent. However, in clinical practice toxicity is uncommon for most anti-cancer agents.^rr The anti-cancer agents within one therapeutic class may produce pulmonary toxicity patterns with widely varying frequencies. Thus, estimates of the incidence of lung injury caused by individual agents vary broadly.^r The anti-cancer agents with the highest reported incidence of pulmonary toxicities are bleomycin, carmustine, methotrexate, busulfan, and mitomycin.^r Everolimus is associated with non-infectious pneumonitis in about 10% (range 2-36%) of patients.^r For anti-PD-1 checkpoint inhibitors such as pembrolizumab and nivolumab, symptomatic pneumonitis is estimated to affect up to 10.6% of patients^r and is more common for patients with non small cell lung cancer compared to other non-lung malignancies (7% vs 2%).^r The anti-CTLA-4 checkpoint inhibitor ipilimumab is rarely associated with symptomatic pneumonitis (1%).^r However, when combined with an anti-PD-1, the incidence is significantly higher (up to 10%).^r 

Onset/duration

Time of onset can vary from immediately after the first treatment, to several months or years after completion of treatment.^r There have been reported cases of pulmonary toxicity developing decades after completion of treatment with carmustine.^r The most common manifestation that occurs months to years after treatment is pulmonary fibrosis.^r

Risk factors

Risk factors for developing anti-cancer agent induced pulmonary toxicity may include:

• age (bleomycin: increased risk for ages > 40 years, carmustine: increased risk for ages < 6 years)^rr
• gender- female (carmustine); male (EFGR inhibitors, methotrexate)^rr
• Asian ethnicity (trastuzumab deruxtecan)^r
• history of smoking (bleomycin, EFGR inhibitors, methotrexate)^rr
• pre-existing lung disease^r
• reduced kidney function (bleomycin)^r
• cumulative drug dose (bleomycin, carmustine)^rr
• concomitant chemotherapy with known lung toxicity^rr
• concomitant or previous radiation therapy^rr
• high fraction of inspired oxygen*^r
• colony stimulating factors (bleomycin, cyclophosphamide)*^r

* Available evidence is inconsistent, largely anecdotal and has not been confirmed in randomised clinical trials.

Pulmonary toxicity can be unpredictable; development in young patients and those treated with low doses has been observed.

Symptoms and signs

Clinical presentation can be variable, unpredictable and non-specific. Many patients will present with asymptomatic pulmonary infiltrates, or with one or more of the following:^rr

• dyspnoea and decreased exercise tolerance
• non-productive cough
• haemoptysis
• increased sputum production
• hypoxaemia  
• pleuritic or substernal chest pain
• fine inspiratory crackles
• acute respiratory failure and acute respiratory distress syndrome (ARDS)
• low-grade fever
• tachycardia
• weight loss.

Investigations and diagnosis

Universal criteria for the diagnosis of anti-cancer agent induced pulmonary toxicity have not been defined. There is no single diagnostic test or biopsy that can confirm the diagnosis of anti-cancer agent induced pulmonary toxicity. Generally, diagnosis is dependent upon an appropriate history of drug exposure, histological evidence of lung injury and the elimination of other possible conditions that may have similar signs and symptoms, e.g. infection, cardiogenic pulmonary oedema, radiation induced lung injury, pulmonary embolus, and metastatic disease.^rr The following investigations may be considered in response to suspected pulmonary toxicity:^rrr

• chest X-ray and/or computed tomography (CT) scan (may show a diffuse reticulonodular pattern, bilateral acinar or reticular infiltrates and pleural effusions)
• pulmonary function test (PFT) [typically a decrease in diffusing capacity for carbon monoxide (DLCO), total lung capacity and forced vital capacity]
• bronchoscopy/bronchoalveolar lavage (BAL) to exclude infection, alveolar haemorrhage or lymphangitic carcinomatosis
• lung biopsy to exclude infection, tumour progression, and other pulmonary diseases.

Grading

Grade	Pneumonitis
1	Asymptomatic; clinical or diagnostic observations only; intervention not indicated
2	Symptomatic; medical intervention indicated; limiting instrumental ADL
3	Severe symptoms; limiting self care ADL; oxygen indicated
4	Life-threatening respiratory compromise; urgent intervention indicated (e.g. tracheotomy or intubation)

 Common Terminology Criteria for Adverse Events (CTCAE) v5.0, 27 November 2017.

Grade	Pulmonary fibrosis
1	Radiologic pulmonary fibrosis <25% of lung volume associated with hypoxia
2	Evidence of pulmonary hypertension; radiographic pulmonary fibrosis 25 - 50% associated with hypoxia
3	Severe hypoxia; evidence of right-sided heart failure; radiographic pulmonary fibrosis >50 - 75%
4	Life-threatening consequences (e.g. hemodynamic/pulmonary complications); intubation with ventilatory support indicated; radiographic pulmonary fibrosis >75% with severe honeycombing

 Common Terminology Criteria for Adverse Events (CTCAE) v5.0, 27 November 2017.

Prevention

While anti-cancer agent induced pulmonary toxicity is well recognised in the literature, there is limited information regarding its prevention. Prevention methods include identification of individual patient risk factors, monitoring for signs and symptoms, and maximum cumulative dosing.^r 

The role of radiological investigations in screening and early detection of anti-cancer agent induced pulmonary toxicity is unclear and remains inconsistent in practice. Baseline chest X-ray or CT may be completed and form part of staging.^r However,  25 to 75% of chest radiographs are normal in cases of clinically suspected ILDs. CT assessments have been non-specific for anti-cancer agent induced pulmonary toxicity, as the numerous patterns of interstitial changes are commonly seen in other ILDs.^r Pulmonary physiology is also important in the assessment of suspected cases but again lacks specificity. There are currently no guidelines for routine PFTs in either prevention or monitoring for anti-cancer agent induced pulmonary toxicity and their use remains largely institution based. PFTs should be considered an inexpensive and useful tool for supporting CT findings where there is diagnostic uncertainty surrounding pulmonary symptoms.^r There is no established genetic screening. Bleomycin hydrolase is implicated in bleomycin pulmonary toxicity, however genetic variations in the bleomycin hydrolase gene have not been proven to predict occurrence.^r

Bleomycin

Bleomycin is one of the most well recognised anti-cancer agents to cause pulmonary toxicity. There is a lack of consensus regarding the approach to prevention of bleomycin induced pulmonary toxicity, however the following considerations have been discussed in the literature:^rrr 

• Baseline chest CT for patients > 40 years of age.
• PFTs (DLCO and lung capacity) may be completed at baseline and repeated if pulmonary toxicity is suspected.
• Consider chest X-ray prior to each cycle of bleomycin.
• Monitor for new clinical symptoms (e.g. cough, dyspnoea) prior to, and after, each dose of bleomycin.
• Patient education on symptom detection and reporting to support early initiation of investigations and treatment.
• Maximum cumulative dose of bleomycin should not exceed 400,000 international units (IU) and should be documented and reviewed prior to each dose.
• Consideration should be given for the completion of a post-treatment CT chest in patients who receive a cumulative dose of bleomycin > 300,000 IU. Note: Whilst cumulative dose is a risk factor for pulmonary toxicity, it is not entirely dose-dependent and ILD has been reported in patients receiving low doses.
• Monitor kidney function prior to each dose of bleomycin, particularly if administered with other renally toxic agents.
• Due to the suspicion that concurrent colony stimulating factors may increase the risk of pulmonary toxicity, the relative risks and benefits should be considered before administering these agents in combination with bleomycin.

Treatment

There are limited established guidelines for the treatment of anti-cancer agent induced pulmonary toxicity. Management is largely empiric rather than evidence based. The main components of management include:^rr

• pulmonary status investigations (including CT and PFTs)
• assessment of risk factors
• prompt drug withholding/discontinuation*
• corticosteroids (intravenous or oral)**
• supportive care measures therapy (e.g. supplemental oxygen)
• early referral to a respiratory physician may be considered.

* Permanent drug discontinuation or reintroduction should be carefully considered following toxicity and may be dependent upon the agent, individual patient factors, severity of toxicity and treatment intent.^rr

** Evidence-based guidelines informing the optimal timing, dose, and duration of corticosteroid therapy do not exist. It is reasonable to commence prompt corticosteroid dosing in the early and inflammatory stages to reduce the risk of pulmonary fibrosis, however an infectious aetiology should always be excluded prior to initiation of treatment.^rr

The following tables provide information on a number of anti-cancer agents that may cause pulmonary toxicity. However this is not a definitive list and should be used as a guide only.

Agent	Syndromes	Incidence	Specific risk factors	Management
Antitumour antibiotics
Bleomycinrrr	Interstitial lung disease (ILD) nonspecific interstitial pneumonitis  interstitial pneumonia eosinophilic pneumonia  eosinophilic alveolitis organising pneumonia  non-cardiogenic pulmonary oedema diffuse alveolar damage (e.g. ARDS) pulmonary fibrosis Pulmonary vascular disease pulmonary hypertension pulmonary veno-occlusive disease  Airway disease (infusion reaction/bronchospasm) Acute chest pain syndrome	Ranges from 6.8–21%, mortality rate up to 48%r	Age (> 40 years) Cumulative dose > 300,000 IU Pre-existing lung disease Kidney dysfunction Previous chest radiation High concentration oxygen History of smoking G-CSF Support	Pulmonary status investigations Assess for risk factors Withhold/discontinue drug Corticosteroids may provide benefit
Dactinomycin (actinomycin D)r	ILD  pneumonitis pulmonary fibrosis	-	Previous chest radiation
Mitomycin-Crr	ILD nonspecific interstitial pneumonitis  non-cardiogenic pulmonary oedema diffuse alveolar damage (e.g. ARDS) pulmonary Fibrosis Pulmonary vascular disease pulmonary hypertension pulmonary veno-occlusive disease Pleural disease pleural effusions pleural haemorrhage Airway disease (infusion reaction/bronchospasm)	Ranges from 4-12%, fatal cases reportedrr	Cumulative dose ≥ 20 mg/m2 Previous chest radiation Previous or concomitant use of other pulmonary toxic agents High concentration oxygen
Alkylating agents
Busulfanrr	ILD nonspecific interstitial pneumonitis  eosinophilic pneumonia  organising pneumonia diffuse alveolar damage (e.g. ARDS) pulmonary fibrosis (late onset) Pulmonary vascular disease pulmonary hypertension Pleural disease pleural fibrosis	Ranges from 2.5-43%, mortality rate 80%r	High cumulative dose  Previous chest radiation Previous/concomitant use of other pulmonary toxic agents High concentration oxygen	Pulmonary status investigations Assess for risk factors Withhold/discontinue drug Corticosteroids may provide benefit
Carmustiner	ILD nonspecific interstitial pneumonitis  eosinophilic pneumonia  organising pneumonia pulmonary fibrosis (early and late onset)	Ranges from 20-30%r	Age (< 6 years) Female gender Cumulative dose > 50,000 IU Pre-existing lung disease Previous chest radiation Previous/concomitant use of other pulmonary toxic agents High concentration oxygen
Lomustiner	ILD pulmonary fibrosis	Ranges from 2-20%r	High dose
Chlorambucilr	ILD nonspecific interstitial pneumonitis  organising pneumonia pulmonary fibrosis	Rare,r fatal cases reported	-
Cyclophosphamiderrr	ILD nonspecific interstitial pneumonitis (acute and delayed onset) eosinophilic pneumonia  organising pneumonia diffuse alveolar damage (e.g. ARDS) pulmonary fibrosis Pulmonary vascular disease pulmonary hypertension Pleural disease pleural effusions pleural fibrosis Airway disease (infusion reaction/bronchospasm)	1%,r fatal cases reported	High cumulative dose Previous chest radiation Previous/concomitant use of other pulmonary toxic agents High concentration oxygen G-CSF Support
Antimetabolites
Azacitidinerr	ILD: pneumonitis bacterial/fungal pneumonia Differentiation Syndrome (reported in patients receiving injectable azacitidine) respiratory distress pulmonary infiltrates pulmonary oedema pleural effusions pericardial effusions Opportunistic infections (Pneumocystis jirovecii)			Pulmonary status investigations Assess for risk factors Consider high-dose IV corticosteroids and haemodynamic monitoring at first onset of signs/symptoms suggestive of differentiation syndrome. Consider temporary discontinuation of injectable azacitidine until resolution of symptoms of differentiation syndrome and caution if drugs is resumed.
Gemcitabinerrr	ILD nonspecific interstitial pneumonitis eosinophilic pneumonia  diffuse alveolar damage (e.g. ARDS) non-cardiogenic pulmonary oedema pulmonary fibrosis Radiation recall pneumonitis Pleural disease pleural effusions Airway disease (infusion reaction/bronchospasm)	Ranges from 1.1–3.9%, mortality rate up to 22%r	Older age  Pre-existing lung disease Previous chest radiation Previous/concomitant use of other pulmonary toxic agents	Pulmonary status investigations Assess for risk factors Assess capillary leak syndrome Withhold/discontinue drug Corticosteroids may provide benefit
Methotrexaterrrr	ILD nonspecific interstitial pneumonitis (acute and delayed onset) eosinophilic pneumonia  organising pneumonia hypersensitivity pneumonitis  diffuse alveolar damage (e.g. ARDS) pulmonary fibrosis Pleural disease pleural effusions Airway disease (infusion reaction/bronchospasm) Opportunistic infections (Pneumocystis jirovecii)	Ranges from 0.06-15%, mortality rate 10–33%r	Older age Male gender Kidney dysfunction Hypoalbuminemia Concomitant use of drugs that reduce methotrexate excretion History of smoking	Pulmonary status investigations Assess for risk factors Withhold/discontinue drug Corticosteroids may provide benefit May consider prophylaxis for pneumocystis jirovecii
Microtubule targeting agents
Cabazitaxelr	ILD nonspecific interstitial pneumonitis diffuse alveolar damage (e.g. ARDS)	Ranges from 2.4-11.9%r	-	Pulmonary status investigations Assess for risk factors Withhold/discontinue drug Corticosteroids may provide benefit Pre-treatment with corticosteroids and antihistamines. See Premedication for prophylaxis of taxane hypersensitivity reactions
Vinorelbiner	ILD   interstitial pneumonia pulmonary oedema diffuse alveolar damage (e.g. ARDS)	Rare, fatal cases reportedr		Pulmonary status investigations Assess for risk factors Withhold/discontinue drug Corticosteroids may provide benefit
Miscellaneous cytotoxic agents
All-trans retinoic acid (ARTA)rr Arsenic trioxiderr​	ILD nonspecific interstitial pneumonitis diffuse alveolar damage (e.g. ARDS) Pleural disease pleural effusions pleural fibrosis Differentiation Syndrome (non-cardiogenic pulmonary oedema)	Differentiation syndrome: 25% for ARTA,r 16-23% for arsenic trioxider	BMI > 35 kg/m2 Elevated white cell count > 50 x 109	Pulmonary status investigations Assess for risk factors Withhold/discontinue drug (in case of differentiation syndrome temporarily withhold the drug only in severe cases) Prophylactic corticosteroids. See APML differentiation syndrome
Irinotecanrr	ILD: nonspecific interstitial pneumonitis	0.74%, mortality rate 24%r	Pre-existing lung disease Previous chest radiation Previous/concomitant use of other pulmonary toxic agents	Pulmonary status investigations Assess for risk factors Withhold/discontinue drug Corticosteroids may provide benefit
Immune Checkpoint Inhibitors
Anti-PD-1/PD-L-1 agents Anti-CTLA-4  agentsrr e.g. atezolizumab, avelumab, cemiplimab, durvalumab,  ipilimumab, nivolumab,  pembrolizumab	ILD nonspecific interstitial pneumonitis  eosinophilic pneumonia  organising pneumonia hypersensitivity pneumonitis  diffuse alveolar damage (e.g. ARDS) Opportunistic infections (Pneumocystis jirovecii)	Anti-PD-1/PD-L-1: 3.6-10.6%, mortality rate 8.0-9.4%rr Anti-CTLA-4: 1.1%r Anti-PD-1+Anti-CTLA-4: up to 10%r	-	See Management of immune-related adverse events (irAEs)
Targeted therapies
ALK Inhibitorsr e.g. alectinib, brigatinib, ceritinib, crizotinib, lorlatinib	ILD nonspecific interstitial pneumonitis	Alectinib: 1.3% ILD, 4.6% pneumonia, 1.2% pulmonary embolism, fatal cases reportedr Brigatinib: ranges from 4-9%r Ceritinib: ranges from 3-4%, fatal cases reportedr Crizotinib: ranges from 0.8-2.9%; 1.5% severe, life-threatening or fatalr Lorlatinib: 1.9% pneumonitis, grade 3-4: 0.6%r	-	Pulmonary status investigations Assess for risk factors Withhold/discontinue drug Corticosteroids may provide benefit
Elotuzumabr	ILD atypical pneumonia bronchopneumonia lobar pneumonia pneumococcal /fungal/influenza pneumonia	Pneumonia: 20.1%; grade 3-4: 14.2%
Anti-lymphocyte Monoclonal Antibodiesrr e.g. alemtuzumab	ILD nonspecific interstitial pneumonitis  diffuse alveolar damage (e.g. ARDS)	Alemtuzumab: dyspnoea 8-14%, pneumonitis 0.5%, case reports of pulmonary alveolar haemorrhager	Higher dose  Pre-existing lung disease Larger tumour burden
Bcr-Abl Tyrosine Kinase Inhibitorsrr e.g. dasatinib	ILD nonspecific interstitial pneumonitis  pulmonary oedema Pleural disease pleural effusion	Dasatinib: pulmonary oedema 1-4%, pleural effusion 20-28%, pulmonary hypertension 2-5%r	Pre-existing lung disease Pre-existing cardiovascular disease
Brentuximab vendotinr	ILD: nonspecific interstitial pneumonitis  diffuse alveolar damage (e.g. ARDS)	Pneumonitis 2%, pneumothorax 2%, pulmonary embolism 2%, fatal cases reportedr	-
CDK 4/6 Inhibitorsr e.g. abemaciclib, palbociclib, ribociclib	ILD: nonspecific interstitial pneumonitis	Abemaciclib: ranges from 0.6-3.3% (various grades), fatal cases reportedr Palbociclib: ranges from 0.1-1% (various grades), fatal cases reportedr Ribociclib: ranges from 0.3-1.1% (various grades), fatal cases reportedr	-
EGFR Inhibitorsrrr e.g. afatinib, cetuximab, erlotinib, gefitinib, osimertinib, panitumumab	ILD: nonspecific interstitial pneumonitis  interstitial pneumonia diffuse alveolar damage (e.g. ARDS) pulmonary fibrosis	Afatinib: 0.7%, fatal cases reportedr Cetuximab: ranges from 2.5-20% (varies geographically)r Erlotinib: ranges from 0.8-4%, 30% fatality rater Gefitinib: ranges from 0.2-6% (varies geographically), 31-45% fatality raterr Osimertinib: 3.8%, grade ≥3: 1.1%r Panitutumab: <1%, fatal cases reportedr	Older age Male gender Asian ethnicity Pre-existing lung disease Previous chest radiation Previous/concomitant use of other pulmonary toxic agents History of smoking
Enfortumab vedotin	ILD: nonspecific interstitial pneumonitis diffuse alveolar damage (e.g. ARDS)  aspiration pneumonia	Pneumonitis 2-4%, fatal cases reportedr	-
FLT3 Tyrosine Kinase inhibitorsr e.g. gilteritinib	Differentiation Syndrome (non-cardiogenic pulmonary oedema)	3%, fatal cases reportedr	-	Pulmonary status investigations Assess for risk factors Withhold/discontinue drug Prophylactic corticosteroids. See APML differentiation syndrome
Gemtuzumab ozogamicinr	ILD: nonspecific interstitial pneumonitis pulmonary alveolar haemorrhage  Opportunistic infections (Pneumocystis jirovecii and pulmonary mycosis)	Fatal cases reported
HER-2 inhibitorsrr e.g. trastuzumab, trastuzumab deruxtecan, trastuzumab emtansine	ILD: nonspecific interstitial pneumonitis  organising pneumonia diffuse alveolar damage (e.g. ARDS) pulmonary fibrosis Pulmonary vascular disease pulmonary hypertension  Pleural disease pleural effusion Acute pulmonary oedema	Trastuzumab: ranges from 0.2-14.3%, fatal cases reportedr Trastuzumab deruxtecan: all grades: 11%, grade 3-4: 0.8%, mortality: 1.1%r Trastuzumab emtansine: ranges from 0.8 to 1.2, fatal cases reportedr	Pre-existing lung disease Previous chest radiation Previous/concomitant use of other pulmonary toxic agents Poor functional status	Pulmonary status investigations Assess for risk factors Withhold/discontinue drug Corticosteroids may provide benefit
KRAS inhibitors e.g. sotorasib	ILD: nonspecific interstitial pneumonitis pneumonia respiratory failure	ILD/pneumonitis: 0.8%,r fatal cases reported Pneumonia: 8%, fatal cases reported Respiratory failure: 0.8%, fatal
MET Tyrosine Kinase Inhibitors e.g. tepotinib	ILD: nonspecific interstitial pneumonitis pneumonia acute respiratory failure Pleural disease pleural effusion	Pneumonitis: 1.3%,  fatal cases reported Pneumonia: 5.3% Pleural effusion:15%, grade ≥3: 5.9%r	-
Midostaurin	ILD  pneumonitis  organising pneumonia diffuse alveolar damage (e.g. ARDS) Pulmonary vascular disease pulmonary oedema Pleural disease pleural effusions	ILD: 1%,r fatal cases reported Pneumonia: 2-10%, fatal cases reported Pneumonitis: up to 11%, fatal cases reported Pulmonary oedema : 3% Pleural effusion: 6-13%	-
mTOR inhibitorsrr e.g. everolimus, temsirolimus	ILD: nonspecific interstitial pneumonitis  organising pneumonia diffuse alveolar damage (e.g. ARDS) Opportunistic infections (pneumocystis jirovecii)	Everolimus: 53.9% radiographic, 13.5% clinicalr Temsirolimus: 29% radiographic, 6% clinicalr	Pre-existing lung disease
PI3K inhibitorsr e.g. idelalisib	ILD: nonspecific interstitial pneumonitis pneumonia Opportunistic infections (pneumocystis jirovecii)	Pneumonia: 25-30%r Fatal pneumocystis jirovecii pneumonia or cytomegalovirus: < 1%r Pneumonitis: 4%,r fatal cases reported
Proteasome Inhibitorsrr e.g. bortezomib, carfilzomib	ILD: pneumonitis  ARDS Pulmonary vascular disease pulmonary hypertension	Rare, fatal cases reportedrr
Selinexorr	pneumonia atypical pneumonia lung infection lower respiratory tract infection aspiration pneumonia pneumocystis jirovecii pneumonia influenza pneumonia viral pneumonia	Pneumonia: 26% (includes fatal event)
VEGF inhibitorsr e.g. bevacizumab	ILD: diffuse alveolar damage and hemoptysis. Pulmonary vascular disease  pulmonary veno-occlusive disease	4-31% pulmonary hemorrhage, 25-30% dyspnoea, 1-1.8% bronchopleural fistulas,r fatal cases reported	Pre-existing hemoptysis Squamous cell lung cancer histology

Educate patient:

• about the risk of developing a pulmonary toxicity (including acute and delayed onset)
• to report symptoms of pulmonary toxicity (e.g. cough, dyspnoea, chest pain, decreased exercise tolerance)
• to go to the nearest hospital emergency department if the patient becomes short of breath or develops chest pain
• to avoid high flow oxygen (bleomycin)
• about smoking cessation strategies.

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Opioid conversion ratios Guidance document. Safer Care Victoria. February 2021.

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Faculty of Pain Medicine ANZCA. Opioid-dose equivalence. Melbourne: FPM, 2021.

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Version 3

Date	Summary of changes
01/11/2023	Document reviewed internally. Risk factors updated to include Asian ethnicity. Investigation and diagnosis updated. Trastuzumab deruxtcan, azacitidine, lorlatinib, osimertinib, elotuzumab, gemtuzumab ozogamicin and selinexor added to the list of anti-cancer agents that may cause pulmonary toxicity. Version increased to V.3. Next review in 2 years.
10/05/2024	New flag added to reflect regular addition of drugs to the document.

Version 2

Date	Summary of changes
13/10/2021	Protocol reviewed electronically by Medical Oncology and Haematology Reference Committees. Background, assessment and management sections updated. Version increased to V.2. Next review in 2 years.
26/09/2023	Enfortumab vedotin, sotorasib and tepotinib added to the list of anti-cancer agents that may cause pulmonary toxicity.

Version 1

Date	Summary of changes
18/07/2017	Document approved on eviQ. Version number V.1.
24/04/2018	CTCAE information updated to v5.0 published November 27, 2017.