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.^{1, 2, 3} 

The most common manifestation is interstitial lung disease (ILD)⁴ 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.^{1, 4}

Pathophysiology

Several pathophysiological mechanisms have been proposed for anti-cancer agent induced pulmonary toxicity:^{1, 2, 5, 6, 7}

• 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).⁴

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.^{2, 4} 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.¹ The anti-cancer agents with the highest reported incidence of pulmonary toxicities are bleomycin, carmustine, methotrexate, busulfan, and mitomycin.² Everolimus is associated with non-infectious pneumonitis in about 10% (range 2-36%) of patients.⁶ For anti-PD-1 checkpoint inhibitors such as pembrolizumab and nivolumab, symptomatic pneumonitis is estimated to affect up to 10.6% of patients⁸ and is more common for patients with non small cell lung cancer compared to other non-lung malignancies (7% vs 2%).⁵ The anti-CTLA-4 checkpoint inhibitor ipilimumab is rarely associated with symptomatic pneumonitis (1%).⁵ However, when combined with an anti-PD-1, the incidence is significantly higher (up to 10%).⁹ 

Onset/duration

Time of onset can vary from immediately after the first treatment, to several months or years after completion of treatment.² There have been reported cases of pulmonary toxicity developing decades after completion of treatment with carmustine.¹⁰ The most common manifestation that occurs months to years after treatment is pulmonary fibrosis.⁴

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)^{11, 12}
• gender- female (carmustine); male (EFGR inhibitors, methotrexate)^{3, 13}
• Asian ethnicity (trastuzumab deruxtecan)¹⁴
• history of smoking (bleomycin, EFGR inhibitors, methotrexate)^{3, 15}
• pre-existing lung disease³
• reduced kidney function (bleomycin)¹²
• cumulative drug dose (bleomycin, carmustine)^{12, 13}
• concomitant chemotherapy with known lung toxicity^{3, 12}
• concomitant or previous radiation therapy^{3, 3}
• high fraction of inspired oxygen*¹
• colony stimulating factors (bleomycin, cyclophosphamide)*¹⁶

* 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:^{1, 2}

• 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.^{1, 2} The following investigations may be considered in response to suspected pulmonary toxicity:^{1, 2, 4}

• 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

 Common Terminology Criteria for Adverse Events opens in a new tab or window (CTCAE) v5.0, 27 November 2017.

 Common Terminology Criteria for Adverse Events opens in a new tab or window (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.¹⁵ 

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.³ 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.³ 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.¹⁷ 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.¹⁸

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:^{15, 17, 19} 

• 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:^{2, 3}

• 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.^{3, 1}

** 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.^{3, 1}

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.

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.

1

Shannon, V.R. 2019. "Cancer Treatment-Related Lung Injury." In Oncologic Critical Care.

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Lung injury associated with cancer therapeutics is often the limiting factor that trumps otherwise successful cancer therapy. Thoracic radiation as well as cancer pharmacotherapeutics, including conventional chemotherapy, molecular targeted agents, and cancer immunotherapies, have been associated with a unique spectrum of histopathologic injury patterns that may involve the lung parenchyma, pleura, airways, and/or pulmonary vasculature. Injury patterns may be idiosyncratic, unpredictable, and highly variable from one agent class to the next. Variability in lung injury patterns within a specific therapeutic class of drugs also occurs, adding to the conundrum. Drug-induced toxicities to the thoracic cavity are infrequent, and early recognition of clinical clues portends a good outcome in most cases. Failure to recognize early clinical signs, however, may result in irreversible and potentially lethal consequences. This chapter provides an overview of our current knowledge of thoracic complications associated with cancer pharmacotherapies. The review is not intended to be a treatise of all cancer agents that adversely affect the lungs, but rather a discussion of established risk factors and histopathologic patterns of lung injury associated with broad classes of cancer agents. Optimal management strategies, based on existing clinical experience, will also be discussed. Complications associated with thoracic radiation are also reviewed. It is hoped that these discussions will facilitate early recognition and management of treatment-related thoracic complications and, ultimately, better patient outcomes.

2

Vahid, B. and P. E. Marik. 2008. "Pulmonary complications of novel antineoplastic agents for solid tumors." Chest. 133(2):528-538.

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Antineoplastic agent-induced pulmonary toxicity is an important cause of respiratory failure. Although the incidence of antineoplastic agent-induced pulmonary toxicity seems to be low, more cases can be expected, with increasing numbers of patients receiving the new generations of antineoplastic agents. Antineoplastic agents have previously been associated with bronchospasm, hypersensitivity reactions, venous thromboembolism, and pulmonary hemorrhage. Physicians should be aware of the clinical and radiographic presentations of the pulmonary toxicities associated with the newer antineoplastic agents. The approach to diagnosis, risk factors, and possible mechanisms of antineoplastic agent-induced pulmonary toxicity are discussed in this article

3

Skeoch, S., N. Weatherley, A. J. Swift, et al. 2018. "Drug-Induced Interstitial Lung Disease: A Systematic Review." J Clin Med 7(10).

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BACKGROUND: Drug-induced interstitial lung disease (DIILD) occurs as a result of numerous agents, but the risk often only becomes apparent after the marketing authorisation of such agents. METHODS: In this PRISMA-compliant systematic review, we aimed to evaluate and synthesise the current literature on DIILD. RESULTS: Following a quality assessment, 156 full-text papers describing more than 6000 DIILD cases were included in the review. However, the majority of the papers were of low or very low quality in relation to the review question (78%). Thus, it was not possible to perform a meta-analysis, and descriptive review was undertaken instead. DIILD incidence rates varied between 4.1 and 12.4 cases/million/year. DIILD accounted for 3⁻5% of prevalent ILD cases. Cancer drugs, followed by rheumatology drugs, amiodarone and antibiotics, were the most common causes of DIILD. The radiopathological phenotype of DIILD varied between and within agents, and no typical radiological pattern specific to DIILD was identified. Mortality rates of over 50% were reported in some studies. Severity at presentation was the most reliable predictor of mortality. Glucocorticoids (GCs) were commonly used to treat DIILD, but no prospective studies examined their effect on outcome. CCONCLUSIONS: Overall high-quality evidence in DIILD is lacking, and the current review will inform larger prospective studies to investigate the diagnosis and management of DIILD.

4

Abid, S. H., V. Malhotra and M. C. Perry. 2001. "Radiation-induced and chemotherapy-induced pulmonary injury." Curr Opin Oncol 13(4):242-248.

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The management of cancer has continued to advance with the development of new chemotherapeutic agents and improved techniques of radiation therapy. Although new therapeutic approaches have improved survival in cancer patients, each form of intervention has the potential to produce adverse effects on normal host tissues. Some of these toxicities may be accentuated with combined modality therapy. The use of chemotherapy and radiation therapy, alone or combined, can be associated with clinically significant pulmonary toxicity. Thepulmonary toxic effects of chemotherapy can be divided into (1) early onset, resulting in interstitial lung injury, and (2) late onset, with pulmonary fibrosis as a sequela. These toxic effects are frequently dose related but may be enhanced by radiation therapy. Similar to chemotherapy, radiation can produce acute or chronic lung injury depending on dose rate, duration, preexisting lung disease, and concomitant steroid use. Acute radiationinjury typically occurs 2 weeks to 3 months after treatment and is usually limited to the irradiated field. Mildinjury often resolves without treatment, whereas more serious injury results in fibrosis 6 to 12 months after treatment. Histopathologic evaluation of acute lung injury is no different from drug-induced injury, and damage to vascular endothelial cells and alveolar lining cells is seen. This article reviews and provides an update on the clinically important chemotherapy and radiation-induced pulmonary injuries, the pathologic mechanisms, where known, and the treatment advances that have occurred in this field.

5

Weber, JS, JC Yang, MB Atkins, et al. 2015. "Toxicities of Immunotherapy for the Practitioner." J Clin Oncol. 33(18):2092-9.

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The toxicities of immunotherapy for cancer are as diverse as the type of treatments that have been devised. These range from cytokine therapies that induce capillary leakage to vaccines associated with low levels of autoimmunity to cell therapies that can induce damaging cross-reactivity with normal tissue to checkpoint protein inhibitors that induce immune-related adverse events that are autoinflammatory in nature. The thread that ties these toxicities together is their mechanism-based immune nature and the T-cell-mediated adverse events seen. The basis for the majority of these adverse events is a hyperactivated T-cell response with reactivity directed against normal tissue, resulting in the generation of high levels of CD4 T-helper cell cytokines or increased migration of cytolytic CD8 T cells within normal tissues. The T-cell immune response is not tissue specific and may reflect a diffuse expansion of the T-cell repertoire that induces cross-reactivity with normal tissue, effectively breaking tolerance that is active with cytokines, vaccines, and checkpoint protein inhibitors and passive in the case of adoptive cell therapy. Cytokines seem to generate diffuse and nonspecific T-cell reactivity, whereas checkpoint protein inhibition, vaccines, and adoptive cell therapy seem to activate more specific T cells that interact directly with normal tissues, potentially causing specific organ damage. In this review, we summarize the toxicities that are unique to immunotherapies, emphasizing the need to familiarize the oncology practitioner with the spectrum of adverse events seen with newly approved and emerging modalities.

6

Albiges, L., F. Chamming's, B. Duclos, et al. 2012. "Incidence and management of mTOR inhibitor-associated pneumonitis in patients with metastatic renal cell carcinoma." Ann Oncol 23(8):1943-53.

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The administration of mammalian target of rapamycin (mTOR) inhibitors can give rise to a potentially life-threatening adverse event, often referred to as 'non-infectious pneumonitis' (NIP), which is characterized by non-infectious, non-malignant, and non-specific inflammatory infiltrates. Patients usually present with cough and/or dyspnoea. We provide a brief description of the mechanism of action of mTOR inhibitors and their overall safety in patients with metastatic renal cell carcinoma (mRCC) and review the literature on mTORinhibitor-associated NIP in patients with solid tumours. The review was used to derive questions on the diagnosis, management, and monitoring of mRCC patients with NIP, and to develop a decision tree for use in routine clinical practise. A key recommendation was the subdivision of grade 2 NIP into grades 2a and 2b, where grade 2a is closer to grade 1 and grade 2b to grade 3. This subdivision is important because it takes into account the nature and severity of clinical symptoms potentially related to NIP, either the onset of new symptoms or the worsening of existing symptoms, and thus determines the type and frequency of follow-up. It also helps to identify a subgroup of patients in whom treatment, if effective, may be continued without dose adjustment.

7

Barjaktarevic, I. Z., N. Qadir, A. Suri, et al. 2013. "Organizing pneumonia as a side effect of ipilimumab treatment of melanoma." Chest 143(3):858-861.

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Ipilimumab is one of the newly developed human monoclonal antibodies used in the treatment of metastaticmelanoma. Its primary mechanism of action is a specific blockade of cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), a T-cell receptor responsible for inhibition of lymphocyte activation. By blocking CTLA-4,ipilimumab enhances immune responses against tumor cells, but also exposes normal tissues to an increased risk of autoimmune phenomena as a potential side effect. In this report, we describe the case of a 58-year-old woman with metastatic melanoma who was treated with ipilimumab in the weeks prior to the onset of severe nonresolving dyspnea and cough. Extensive workup revealed organizing pneumonia as the cause of her hypoxemic respiratory failure and treatment with steroids led to a resolution of her pulmonary disease. To our knowledge, this is the first report of pulmonary toxicity caused by ipilimumab, which manifested on pathology as organizing pneumonia.

8

Naidoo, J., X. Wang, K. M. Woo, et al. 2017. "Pneumonitis in Patients Treated With Anti-Programmed Death-1/Programmed Death Ligand 1 Therapy." J Clin Oncol 35(7).

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Purpose Pneumonitis is an uncommon but potentially fatal toxicity of anti-programmed death-1 (PD-1)/ programmed death ligand 1 (PD-L1) monoclonal antibodies (mAbs). Clinical, radiologic, and pathologic features are poorly described. Methods Patients who received anti-PD-1/PD-L1 monotherapy or in combination with anti-cytotoxic T-cell lymphocyte-4mAb were identified at two institutions (Memorial Sloan Kettering Cancer Center: advanced solid cancers, 2009 to 2014, and Melanoma Institute of Australia: melanomas only, 2013 to 2015). Pneumonitis was diagnosed by the treating investigator; cases with confirmed malignant lung infiltration or infection were excluded. Clinical, radiologic, and pathologic features of pneumonitis were collected. Associations among pneumonitis incidence, therapy received, and underlyingmalignancywere examined with Fisher's exact test as were associations between pneumonitis features and outcomes. Results Of 915 patientswho received anti-PD-1/PD-L1mAbs, pneumonitis developed in 43 (5%; 95%CI, 3%to 6%; Memorial Sloan Kettering Cancer Center, 27 of 578 [5%]; Melanoma Institute of Australia, 16 of 337 [5%]). Time to onset of pneumonitis ranged from9 days to 19.2months. The incidence of pneumonitis was higher with combination immunotherapy versus monotherapy (19 of 199 [10%] v 24 of 716 [3%]; P , .01). Incidencewas similar in patientswithmelanoma and non-small-cell lung cancer (overall, 26 of 532 [5%] v nine of 209 [4%]; monotherapy, 15 of 417 v five of 152 [P = 1.0]; combination, 11 of 115 v four of 57 [P = .78]). Seventy-two percent (31 of 43) of caseswere grade 1 to 2, and 86%(37 of 43) improved/resolved with drug holding/immunosuppression. Five patients worsened clinically and died during the course of pneumonitis treatment; proximal cause of deathwas pneumonitis (n = 1), infection related to immunosuppression (n = 3), or progressive cancer (n = 1). Radiologic and pathologic features of pneumonitis were diverse. Conclusion Pneumonitis associated with anti-PD-1/PD-L1 mAbs is a toxicity of variable onset and clinical, radiologic, and pathologic appearances. It is more common when anti-PD-1/PD-L1 mAbs are combined with anti-cytotoxic T-cell lymphocyte-4 mAb. Most events are low grade and improve/ resolve with drug holding/immunosuppression. Rarely, pneumonitis worsens despite immunosuppression, and may result in infection and/or death.

9

Sears, C. R., T. Peikert, J. D. Possick, et al. 2019. "Knowledge Gaps and Research Priorities in Immune Checkpoint Inhibitor-related Pneumonitis. An Official American Thoracic Society Research Statement." Am J Respir Crit Care Med 200(6):e31-e43.

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RATIONALE: Immune checkpoint inhibitors (ICIs) have revolutionized cancer care but are associated with unique adverse events, including potentially life-threatening pneumonitis. The diagnosis of ICI-pneumonitis is increasing; however, the biological mechanisms, clinical and radiologic features, and the diagnosis and management have not been well defined. OBJECTIVES: To summarize evidence, identify knowledge and research gaps, and prioritize topics and propose methods for future research on ICI-pneumonitis. METHODS: A multidisciplinary group of international clinical researchers reviewed available data on ICI-pneumonitis to develop and refine research questions pertaining to ICI-pneumonitis. RESULTS: This statement identifies gaps in knowledge and develops potential research questions to further expand knowledge regarding risk, biologic mechanisms, clinical and radiologic presentation, and management of ICI-pneumonitis. CONCLUSIONS: Gaps in knowledge of the basic biological mechanisms of ICI-pneumonitis, coupled with a precipitous increase in the use of ICIs alone or combined with other therapies, highlight the importance in triaging research priorities for ICI-pneumonitis.

10

Lohani, S., B. R. O'Driscoll and A. A. Woodcock. 2004. "25-year study of lung fibrosis following carmustine therapy for brain tumor in childhood." Chest 126(3):1007.

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11

Jakubovic, B. D., A. Donovan, P. M. Webster, et al. 2013. "Methotrexate-induced pulmonary toxicity." Can Respir J 20(3):153-155.

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Methotrexate is a widely used medication with an array of recognized side effects. The present report describes a case of methotrexate-induced pneumonitis in a patient with psoriasis, and demonstrates the hallmark clinical and investigational findings that support this infrequently encountered diagnosis. The ensuing discussion reviews the pathogenesis, management and prevention of this adverse drug reaction.

12

O'Sullivan, J. M., R. A. Huddart, A. R. Norman, et al. 2003. "Predicting the risk of bleomycin lung toxicity in patients with germ-cell tumours." Ann Oncol 14(1):91-96.

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BACKGROUND: Bleomycin pulmonary toxicity (BPT) has been known since the early clinical trials of bleomycin in the 1960s. Postulated risk factors include cumulative bleomycin dose, reduced glomerular filtration rate (GFR), raised creatinine, older age and supplemental oxygen exposure. PATIENTS AND METHODS: From our prospectively collected testicular cancer research database, we reviewed 835 patients treated at the Royal Marsden NHS Trust (Sutton, UK) with bleomycin-containing regimens for germ-cell tumours between January 1982 and December 1999, to identify those with BPT. RESULTS: Fifty-seven (6.8%) patients had BPT, ranging from X-ray/CT (computed tomography) changes to dyspnoea. There were eight deaths (1% of patients treated) directly attributed to BPT. The median time from the start of bleomycin administration to documented lung toxicity was 4.2 months (range 1.2-8.2). On multivariate analysis, the factors independently predicting for increased risk of BPT were GFR <80 ml/min [hazard ratio (HR) 3.3], age >40 years (HR 2.3), stage IV disease at presentation (HR 2.6) and cumulative dose of bleomycin >300,000 IU (HR 3.5). CONCLUSIONS: Patients with poor renal function are at high risk of BPT, especially if they are aged >40 years, have stage IV disease at presentation or receive >300,000 IU of bleomycin. In such cases alternative drug regimens or dose restriction should be considered.

13

Alessandrino EP, Bernasconi P, Colombo A et al. 2000 "Pulmonary toxicity following carmustine-based preparative regimens and autologous peripheral blood progenitor cell transplantation in hematological malignancies".Bone Marrow Transplant. Feb;25(3):309-13.

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Sixty-five patients with hematological malignancies (25 multiple myeloma, 18 Hodgkin's disease, 22 non-Hodgkin's lymphomas) who received a carmustine-based regimen followed by autologous PBPC transplantation, were studied retrospectively to evaluate the incidence of post-transplant non-infective pulmonary complications (NIPCs), risk factors predictive of NIPCs, and response to steroids. Carmustine (BCNU) given i.v. at a dose of 600 mg/m2 was combined with etoposide and cyclophosphamide in 40 patients (BCV regimen) and with etoposide and melphalan in 25 patients (BEM regimen). Seventeen of 65 patients (26%) had one episode of NIPCs. The median time to NIPCs was 90 days (52-289). Factors that increased the risk of developing NIPCs on multivariate analysis were female sex (P < 0. 001) and BCV regimen (P < 0.05). All patients with NIPCs received prednisone at a dose of 1 mg/kg body weight for 10 days then tapered by 5 mg every two days; complete response to steroids was achieved in 15 of 17 patients; one unresponsive patient died of interstitial pneumonia. BCNU given at the dose of 600 mg/m2 is well tolerated when associated with melphalan and etoposide. In females and in patients receiving BCNU with cyclophosphamide, a BCNU dose reduction may be advisable. Bone Marrow Transplantation (2000) 25, 309-313.

14

Takano, T., D.R. Camidge, S. Modi, et al. 2020. " Risk factors for interstitial lung disease in patients treated with trastuzumab deruxtecan from two interventional studies." Ann Oncol 31: S357-S358.

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BACKGROUND: Trastuzumab deruxtecan (T-DXd; DS-8201) is a HER2-targeted antibody drug conjugate with demonstrated antitumor activity and manageable safety profile in HER2-expressing/mutated solid tumors. Interstitial lung disease (ILD) is an important identified risk for patients (pts) treated with T-DXd. We report incidence of independently adjudicated drug-related ILD events and explore potential risk factors. METHODS: A post hoc analysis was conducted of pooled data from 542 pts who received at least one dose of 1.6, 3.2, 5.4, 6.4, 7.4, or 8.0 mg/kg T-DXd in two open-label interventional studies in advanced solid tumors (NCT02564900) and breast cancer (BC) (NCT03248492) (data cutoff, August 1, 2019). Baseline characteristics, exposure, incidence, and time to onset were summarized. Potential risk factors were evaluated in a stepwise multivariable logistic regression model. RESULTS: 437 (80.6%) pts had BC; the remainder consisted of other tumors across all doses. 234 (43%) pts were from Japan. Median treatment duration was 8.4 months (range, 0.7-46.0). Overall, 16.8% (91/542) pts experienced an ILD (grade ≥ 3: 20/542, 3.7%), of which 18.1% (79/437) all grade ILD was reported in BC. Median time to onset was 208 days (range, 0-582) in the overall population and 134 days (range, 35-338) in the BC 5.4 mg/kg group. Potential risk factors associated with drug-related ILD were country (Japan vs. non-Japan; OR 3.6; 95% CI, 2.1-6.1) and tumor type (BC vs. other tumors; OR, 2.5; 95% CI, 1.2-5.0). Additional results will be presented, including for the non BC patients. CONCLUSIONS: In this population, higher incidence of ILD related to T-DXd treatment was observed among pts from Japan and those with BC. However, these results should be interpreted with caution given that the majority of patients in the analysis had BC.

15

Froudarakis, M., E. Hatzimichael, L. Kyriazopoulou, et al. 2013. "Revisiting bleomycin from pathophysiology to safe clinical use." Crit Rev Oncol Hematol. 87(1):90-100.

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Bleomycin is a key component of curative chemotherapy regimens employed in the treatment of curable cancers, such as Hodgkin lymphoma (HL) and testicular germ-cell tumours (GCT), yet its use may causebleomycin-induced lung injury (BILI), which is associated with significant morbidity and a mortality rate of 1-3%. Diagnosis of BILI is one of exclusion and physicians involved in the care of HL and GCT patients should be alerted. Pharmacogenomic studies could contribute towards the identification of molecular predictors ofbleomycin toxicity on the aim to optimize individual use of bleomycin. We review all existing data onbleomycin's most recent integrated chemical biology, molecular pharmacology and mature clinical data and provide guidelines for its safe clinical use.

16

Meadors, M., J. Floyd and M. Perry. 2006. "Pulmonary Toxicity of Chemotherapy." Seminars in oncology 33:98-105.

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Chemotherapy-induced pulmonary toxicity remains an elusive and sometimes difficult entity to diagnose. A myriad of new agents and the discovery of new classes of agents makes diagnosing this form of toxicity even more of a daunting task. The clinician should be ever vigilant in watching for the signs and symptoms of lung injury and be timely in adding chemotherapy-induced pulmonary toxicity into the differential diagnosis.

17

Watson, R. A., H. De La Pena, M. T. Tsakok, et al. 2018. "Development of a best-practice clinical guideline for the use of bleomycin in the treatment of germ cell tumours in the UK." Br J Cancer 119(9):1044-1051.

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Bleomycin, a cytotoxic chemotherapy agent, forms a key component of curative regimens for lymphoma and germ cell tumours. It can be associated with severe toxicity, long-term complications and even death in extreme cases. There is a lack of evidence or consensus on how to prevent and monitor bleomycin toxicity. We surveyed 63 germ cell cancer physicians from 32 cancer centres across the UK to understand their approach to using bleomycin. Subsequent guideline development was based upon current practice, best available published evidence and expert consensus. We observed heterogeneity in practice in the following areas: monitoring; route of administration; contraindications to use; baseline and follow-up investigations performed, and advice given to patients. A best-practice clinical guideline for the use of bleomycin in the treatment of germ cell tumours has been developed and includes recommendations regarding baseline investigations, the use of pulmonary function tests, route of administration, monitoring and patient advice. It is likely that existing heterogeneity in clinical practice of bleomycin prescribing has significant economic, safety and patient experience implications. The development of an evidence-based consensus guideline was supported by 93% of survey participants and aims to address these issues and homogenise practice across the UK.

18

Nuver, J., M. F. Lutke Holzik, M. van Zweeden, et al. 2005. "Genetic variation in the bleomycin hydrolase gene and bleomycin-induced pulmonary toxicity in germ cell cancer patients." Pharmacogenet Genomics 15(6):399-405.

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OBJECTIVE: Use of bleomycin as a cytotoxic agent is limited by its pulmonary toxicity. Bleomycin is mainly excreted by the kidneys, but can also be inactivated by bleomycin hydrolase (BMH). An 1450A >G polymorphic site in the BMH gene results in an amino acid substitution in the C-terminal domain of the protein. Deletion of this domain, including the polymorphic site, reduces enzymatic activity. We investigated the relation between the BMH genotype and the risk of bleomycin-induced pneumonitis (BIP). METHODS: From male germ cell cancer patients, treated with bleomycin-containing chemotherapy at the University Hospital Groningen, The Netherlands, between 1977 and 2003, data were collected on age, cumulative bleomycin dose, pretreatment creatinine clearance, pulmonary metastases, lung function parameters, and occurrence of BIP. BIP was defined as: death due to BIP, or presence of clinical and/or radiographic signs of BIP during or following treatment. Polymerase chain reaction and restriction fragment length polymorphism were used to determine the BMH genotype. RESULTS: BIP developed in 38 (11%) of 340 patients; four of these cases were fatal. BMH genotype distribution did not differ between patients with and those without BIP. Patients with BIP were older and had a lower pretreatment creatinine clearance. Changes in pulmonary function tests were similar in patients with different genotypes. CONCLUSIONS: The BMH genotype was not associated with the development of BIP nor with changes in pulmonary function tests. Since renal function is important for bleomycin pharmacokinetics, variations in renal clearance may have obscured significant effects of the BMH genotype.

19

Della Latta, V., A. Cecchettini, S. Del Ry, et al. 2015. "Bleomycin in the setting of lung fibrosis induction: From biological mechanisms to counteractions." Pharmacol Res 97:122-130.

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Bleomycin (BLM) is a drug used to treat different types of neoplasms. BLM's most severe adverse effect is lung toxicity, which induces remodeling of lung architecture and loss of pulmonary function, rapidly leading to death. While its clinical role as an anticancer agent is limited, its use in experimental settings is widespread since BLM is one of the most widely used drugs for inducing lung fibrosis in animals, due to its ability to provoke a histologic lung pattern similar to that described in patients undergoing chemotherapy. This pattern is characterized by patchy parenchymal inflammation, epithelial cell injury with reactive hyperplasia, epithelial-mesenchymal transition, activation and differentiation of fibroblasts to myofibroblasts, basement membrane and alveolar epithelium injuries. Several studies have demonstrated that BLM damage is mediated by DNA strand scission producing single- or double-strand breaks that lead to increased production of free radicals. Up to now, the mechanisms involved in the development of pulmonary fibrosis have not been fully understood; several studies have analyzed various potential biological molecular factors, such as transforming growth factor beta 1, tumor necrosis factor alpha, components of the extracellular matrix, chaperones, interleukins and chemokines. The aim of this paper is to review the specific characteristics of BLM-induced lung fibrosis in different animal models and to summarize modalities and timing of in vivo drug administration. Understanding the mechanisms of BLM-induced lung fibrosis and of commonly used therapies for counteracting fibrosis provides an opportunity for translating potential molecular targets from animal models to the clinical arena.

20

Li, L., H. Mok, P. Jhaveri, et al. 2018. "Anticancer therapy and lung injury: molecular mechanisms." Expert Rev Anticancer Ther 18(10):1041-1057.

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INTRODUCTION: Chemotherapy and radiation therapy are two mainstream strategies applied in the treatment of cancer that is not operable. Patients with hematological or solid tumor malignancies substantially benefit from chemotherapeutic drugs and/or ionizing radiation delivered to the site of malignancy. However, considerable adverse effects, including lung inflammation and fibrosis, are associated with the use of these treatment modalities. AREAS COVERED: As we move towards the era of precision health, we are compelled to understand the molecular basis of chemoradiation-induced pathological lung remodeling and to develop effective treatment strategies that mitigate the development of chronic lung disease (i.e. fibrosis) in cancer patients. The review discusses chemotherapeutic agents that are reported to induce or associate with acute and/or chronic lung injury. EXPERT COMMENTARY: There is a need to molecularly understand how chemotherapeutic drugs induce or associate with respiratory toxicities and whether such characteristics are inherently related to their anti-tumor effect or are collateral. Once such mechanisms have been identified and/or fully characterized, they may be able to guide disease-management decisions including effective intervention strategies for the adverse effects. In the meantime, radiation oncologists should be judicious on the dose of radiation delivered to the lungs, the volume of lung irradiated, and concurrent use of chemotherapeutic drugs.

21

Castro, M., M. H. Veeder, J. A. Mailliard, et all. 1996. "A prospective study of pulmonary function in patients receiving mitomycin." Chest 109(4):939-944.

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Mitomycin is a chemotherapeutic agent that is used to treat a variety of solid tumors. Pulmonary toxic reactions from this agent can be life threatening. We prospectively investigated the utility of pulmonary function tests (PFTs) in monitoring for the occurrence of pulmonary toxicity due to mitomycin. PFTs were obtained at baseline and after three cycles of mitomycin therapy. We analyzed the clinical course, radiologic studies, and PFT results in 133 patients with metastatic squamous cell carcinoma of the lung randomized to treatment with either mitomycin, vinblastine, and cisplatin or mitomycin alone as part of a prospective treatment protocol of the North Central Cancer Treatment Group (NCCTG). The diffusing capacity (DCO) was available in only 40 patients after the third cycle due to a high rate of progression and death from their underlying disease. After three cycles of chemotherapy, there was an average decline in the DCO of 14% (p<0.0001) and no changes were observed in expiratory flows. No differences were noted between treatment arms. A significant decline in the DCO (defined as a>20% change after correcting for hemoglobin) was noted in 11 of 40 patients (28%). This decline in the DCO was not associated with a worse prognosis (p=0.77). Seven patients (5%) developed severe pulmonary toxic reactions attributed to chemotherapy, including noncardiogenic pulmonary edema, interstitial pneumonitis, and pleural effusions. Corticosteroid therapy resulted in temporary subjective improvement in three patients. The Dco did not correlate with the development of pulmonary toxic reactions in these seven patients. In conclusion, (1) the incidence of clinically significant pulmonary toxic reactions from mitomycin is relatively low (5%), (2) mitomycin therapy resulted in a greater than 20% decline in the DCO in approximately one-fourth of patients receiving three cycles of chemotherapy, and (3) the use of serial PFTs in patients receiving mitomycin was not shown to be predictive of pulmonary toxicity.

22

Linette, D. C., K. H. McGee and J. A. McFarland. 1992. "Mitomycin-induced pulmonary toxicity: case report and review of the literature." Ann Pharmacother 26(4):481-484.

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OBJECTIVE: This report describes a case of mitomycin-induced pulmonary toxicity and reviews the incidence of this adverse effect, reported patterns of toxicity and associated dosages of the drug, and the use of corticosteroids in the management of pulmonary toxicity. DATA SOURCES: Information about our patient was obtained in part from the medical chart; we had also treated him personally in the past. We conducted a MEDLINE search of the English language literature (restricted to human studies) from 1966 to 1991 and manually searched Index Medicus for current information. STUDY SELECTION: All case reports that described pulmonary toxicity possibly associated with mitomycin were reviewed. DATA EXTRACTION: Studies were evaluated for the dosages of mitomycin given to patients, the nature and onset of symptoms, management course, and corticosteroid use. DATA SYNTHESIS: Our case is similar to others describedin the literature. The incidence of mitomycin-induced pulmonary toxicity has been reported to range from 2 to 38 percent. Concurrent vinca alkaloid administration may potentiate the risk of an acute pulmonary insult secondary to mitomycin use. The toxicity is usually of slow onset and the average total dosage of drug implicated is 78 mg. A formal evaluation of corticosteroid treatment has not been performed, but various authors have reported success with different regimens. CONCLUSIONS: The incidence of pulmonary toxicity associated with mitomycin is unpredictable, but more likely to occur at higher dosages. Treatment with corticosteroids is encouraged to improve pulmonary response.

23

Megan, M.D., F. Maldonado and A.H. Limper. 2016. "Drug-Induced Pulmonary Disease." In Murray and Nadel's Textbook of Respiratory Medicine. 6 Edition.

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24

O'Driscoll, B. R., P. S. Hasleton, P. M. Taylor, et al. 1990. "Active lung fibrosis up to 17 years after chemotherapy with carmustine (BCNU) in childhood." N Engl J Med 323(6):378-382.

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BACKGROUND: Carmustine (BCNU) is an anticancer drug known to produce pulmonary fibrosis as a side effect within three years of treatment. It is not known whether pulmonary fibrosis can appear later. METHODS: To investigate the clinical range of this side effect, we studied the survivors among 31 children treated with carmustine for brain tumors between 1972 and 1976. Fourteen had died of their tumor; of the remaining 17, 6 had died of lung fibrosis--2 within 3 years of treatment and 4 from 8 to 13 years after treatment. This report focuses primarily on the 11 survivors, 8 of whom were available for detailed study 13 to 17 years (mean, 14) after treatment. RESULTS: Of the eight survivors studied, six had abnormal chest radiographs showing predominantly upper-zone fibrotic changes. These patients also had abnormal CT scans, showing a previously undescribed pattern of upper-zone fibrosis. All the survivors studied had restrictive spirometric defects (mean [+/- SD] vital capacity, 54 +/- 19 percent of the predicted value). Bronchoalveolar-lavage fluid contained abnormal proportions of specific macrophage subgroups. Light and electron microscopy in six patients revealed interstitial fibrosis and elastosis with damage to epithelial and endothelial cells. Four patients had symptoms (shortness of breath, cough, or both). CONCLUSIONS: Carmustine chemotherapy in childhood causes lung fibrosis that may remain asymptomatic for many years or become symptomatic at any time.

25

Bristol-Myers Squibb Pty Ltd. CeeNU product information. 2020.

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26

Ozkan, M., R. A. Dweik and M. Ahmad. 2001. "Drug-induced lung disease." Cleve Clin J Med 68(9):782-785, 789-795.

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Drug-induced lung disease is a major source of iatrogenic injury. We review the various drugs known to induce injury and the various patterns of injury seen.

27

Celgene Pty Ltd. – ONUREG product information. 2022.

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28

Celgene Pty Ltd. – VIDAZA product information. 2022.

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29

Barlesi, F., P. Villani, C. Doddoli, et al. 2004. "Gemcitabine-induced severe pulmonary toxicity." Fundam.Clin Pharmacol. 18(1):85-91.

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Gemcitabine is a relatively new deoxycytidine analog (2',2'-difluorodeoxycytidine) with structural similarities to cytosine arabinoside (Ara-C). Activity of gemcitabine is demonstrated in the treatment of many solid tumors, like pancreas, ovarian and nonsmall cell lung cancer (NSCLC). Although gemcitabine is considered as a drug with a good safety profile, cases of gemcitabine-induced severe pulmonary toxicity (GISPT) were reported as for Ara-C. We performed a systematic review of reported cases on the GISPT. Twenty-nine clinical trials especially interesting NSCLC patients (21) and 21 reported cases recording 40 patients were analyzed. The incidence of the GISPT varies from 0 to 5%. The clinical presentation is a subacute clinical syndrome and is frequently nonspecific. The predominant radiographic pattern on chest X-ray are reticulo-nodular interstitial infiltrates. It was postulated that the physio-pathological mechanism of the GISPT was an inflammatory reaction of the alveolar capillary wall cytokine-mediated, which created an abnormal permeability of its membrane. After the differential diagnosis were ruled out, the discontinuation of the drug and the early initiation of steroids and diuretics are the most frequently performed treatments. Under these conditions, the outcome was favorable in a delay of few days generally for a majority of patients but 20% of patients died. Some risk factors, as a previous pulmonary disease or a previous thoracic irradiation, for the occurrence of the GISPT were proposed. GISPT is rare but sometimes fatal. Its a necessity to increase awareness about it to enhanced an early and suitable management of patients developing such a toxicity after gemcitabine administration

30

Limper, A. H. 2004. "Chemotherapy-induced lung disease." Clin Chest Med 25(1):53-64.

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The lung has significant susceptibility to injury from a variety of chemotherapeutic agents. The clinician must be familiar with classic chemotherapeutic agents with well-described pulmonary toxicities and must also be vigilant about a host of new agents that may exert adverse effects on lung function. The diagnosis of chemotherapy-associated lung disease remains an exclusionary process, particularly with respect to considering usual and atypical infections, as well as recurrence of the underlying neoplastic process in these immune compromised patients. In many instances, chemotherapy-associated lung disease may respond to withdrawal of the offending agent and to the judicious application of corticosteroid therapy.

31

sanofi-aventis Pty Ltd. JEVTANA product information. 2018.

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32

Pierre Fabre Australia Pty Limited. NAVELBINE product information. 2020.

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33

Pharmaco (Australia) Ltd. VESANOID product information. 2020.

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34

Arsenic trioxide product information: Micromedex Online: IBM Micromedex (accessed 2021).

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35

Genentech USA, Inc (per FDA). ALECENSA product information. 2017.

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36

ARIAD Pharmaceuticals, Inc (per FDA). ALUNBRIG product information. 2017.

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37

Pfizer Labs (per FDA). XALKORI product information. 2021.

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38

Pfizer Australia Pty Ltd. – LORVIQUA product information. 2021.

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39

Bristol-Myers Squibb Australia Pty Ltd. – EMPLICITI product information. 2023.

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40

Peerzada, M. M., T. P. Spiro and H. A. Daw. 2010. "Pulmonary toxicities of biologics: a review." Anticancer Drugs 21(2):131-139.

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With the advancement of research in cancer treatment more and more drugs are being introduced for the treatment of cancer. In this review study, we have tried to look at some of the relatively newly introduced drugs, commonly referred to as biologics. The aim of this study was to review the very rare but fatal pulmonary toxicities (mostly interstitial lung disease) caused by these drugs. The drugs that were reviewed are rituximab, cetuximab, bevacizumab, alemtuzumab, and trastuzumab. This review basically aims at presenting a basic introduction (mechanism of action and indications of use) of these drugs followed by a summary of the incidence, various clinical presentations, diagnosis, treatment options, and outcome of patients around the world who presented with pulmonary toxicities caused by these drugs.

41

Genzyme Corporation (per FDA). LEMTRADA intravenous injection product information. 2014.

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42

Bristol-Myers Squibb Pty Ltd. SPRYCEL product information. 2017.

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43

Seattle Genetics, Inc (per FDA). ADCETRIS product information. 2011.

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44

U.S. Food and Drug Administration. 2019. "FDA warns about rare but severe lung inflammation with Ibrance, Kisqali, and Verzenio for breast cancer: FDA Drug Safety Communication".

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45

Lilly USA LLC (per FDA). VERZENIO product information. 2019.

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46

Pfizer Labs (per FDA). IBRANCE product information. 2019.

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47

Novartis Pharmaceuticals Corporation (per FDA). KISQALI product information. 2019.

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48

Barber, N. A. and A. K. Ganti. 2011. "Pulmonary toxicities from targeted therapies: a review." Target Oncol 6(4):235-243.

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Pulmonary toxicity is rarely seen with most commonly used targeted therapies. The endothelial growth factor receptor (EGFR) small-molecule tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib can cause interstitial lung disease (ILD). BCR-ABL tyrosine kinase inhibitors imatinib and dasatinib can cause pleural effusions. Infusion-related bronchospasm is common with the monoclonal antibodies to EGFR cetuximab and panitumumab, and case reports of bronchiolitis and pulmonary fibrosis have been described. Up to one-sixth of patients taking mammalian target of rapamycin (mTOR) inhibitors get a reversible interstitial pneumonitis. Bevacizumab, the monoclonal antibody to vascular endothelial growth factor (VEGF), has been associated with hemoptysis and pulmonary embolism particularly in patients with squamous cell lung cancer. Infusion-related bronchospasms, acute respiratory distress syndrome (ARDS), and interstitial pneumonitis can be seen with the anti-lymphocyte monoclonal antibodies rituximab, ofatumumab, and alemtuzumab. While most pulmonary toxicities from these therapies are mild and resolve promptly with dose reduction or discontinuation, it is important for the clinician to recognize these potential toxicities when faced with treatment-related complications. Discerning these pulmonary adverse effects may help in making decisions on diagnostic testing and therapy, particularly for those with pulmonary and cardiovascular co-morbidities.

49

Boehringer Ingelheim Pty Ltd. GIOTRIF product information. 2020.

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50

Satoh, T., A. Gemma, S. Kudoh, et al. 2014. "Incidence and clinical features of drug-induced lung injury in patients with advanced colorectal cancer receiving cetuximab: results of a prospective multicenter registry." Jpn J Clin Oncol 44(11):1032-1039.

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OBJECTIVE: We investigated the incidence and clinical features of drug-induced lung injury during cetuximab therapy in Japanese patients with colorectal cancer in a prospective multicenter registry based on a central registration system. METHODS: We investigated and followed up patients with or suspected of having drug-induced lung injury among 2006 patients with cetuximab-treated colorectal cancer. A subcommittee of medical oncologists, pulmonologists and a radiologist evaluated and discussed each case of drug-induced lung injury that occurred during cetuximab therapy. RESULTS: Sixty-six patients were identified and further examinations of drug-induced lung injury were conducted during the registration period. We analyzed time to onset, patient characteristics and factors associated with mortality. Cetuximab-related drug-induced lung injury occurred in 24 (1.2%) patients, and was rated as Grade 3 or worse in 15 (0.7%) patients. Fourteen patients received steroid pulse therapy. Ten patients with drug-induced lung injury died, of whom eight received steroid pulse therapy. The incidence of drug-induced lung injury was significantly higher in elderly patients, and in patients with prior interstitial lung disease. There was no particular trend in the time to onset. Patients with early onset of drug-induced lung injury (within 90 days) after starting cetuximab therapy had higher mortality than patients with later onset (over 90 days). CONCLUSIONS: The incidence of drug-induced lung injury in cetuximab-treated patients was 1.2%. Because drug-induced lung injury is potentially serious, it is important to promptly initiate appropriate treatments. Considering that early onset drug-induced lung injury during cetuximab therapy is associated with a poor prognosis, close monitoring is mandatory for these patients.

51

Yoshioka, H., K. Komuta, F. Imamura, et al. 2014. "Efficacy and safety of erlotinib in elderly patients in the phase IV POLARSTAR surveillance study of Japanese patients with non-small-cell lung cancer." Lung Cancer 86(2):201-206.

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OBJECTIVES: More tolerable treatment options are needed for the large number of elderly patients with non-small-cell lung cancer (NSCLC). An analysis of the phase IV POLARSTAR surveillance study examined the safety and efficacy of erlotinib in elderly Japanese patients with previously treated NSCLC. MATERIAL AND METHODS: From December 2007 to October 2009, all erlotinib-treated patients with unresectable, recurrent/advanced NSCLC in Japan were enrolled. Efficacy and safety data were stratified by age (<75 years, 75–84 years, ≥85 years). Kaplan–Meier methodology was used to estimate median progression-free survival (PFS). Safety data were collected with a focus on interstitial lung disease (ILD). RESULTS: A total of 9907 patients were eligible for safety assessment (<75 years, n = 7848; 75–84 years, n = 1911; ≥85 years, n = 148) and 9651 for efficacy assessment (<75 years, n = 7701; 75–84 years, n = 1815; ≥85 years, n = 135). Other baseline characteristics were balanced. The incidence of ILD (all grades) was 4.2% (<75 years), 5.1% (75–84 years), and 3.4% (≥85 years). The mortality rate due to ILD was ≤1.7% in all age groups. Other toxicities (including rash) were similar between age groups. The median PFS was 65 days (95% confidence interval [CI], 62–68) for patients aged <75 years, 74 days (95% CI, 69–82) for patients aged 75–84 years, and 72 days (95% CI, 56–93) for patients aged ≥85 years. CONCLUSIONS: Efficacy and tolerability of erlotinib for elderly patients was not numerically inferior to that reported in younger patients. Erlotinib could be considered for elderly patients with recurrent/advanced NSCLC.

52

Takano, T., Y. Ohe, M. Kusumoto, et al. 2004. "Risk factors for interstitial lung disease and predictive factors for tumor response in patients with advanced non-small cell lung cancer treated with gefitinib." Lung Cancer 45(1):93-104.

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A high incidence of interstitial lung disease (ILD) has been reported in patients with non-small cell lung cancer (NSCLC) treated with gefitinib in Japan. We retrospectively analyzed 112 patients with advanced NSCLC who received gefitinib monotherapy. Univariate and multivariate analyses were used to identify risk factors for gefitinib-related ILD and predictive factors for tumor response to gefitinib. The incidence of ILD was 5.4%, and it was higher in the patients with pre-existing pulmonary fibrosis (33% versus 2%; P < 0.001). The results of a multivariate analysis showed that pulmonary fibrosis was a significant risk factor for ILD (odds ratio: 177, 95% confidence interval: 4.53-6927, P = 0.006). The response rate was 33% in the 98 evaluable patients and higher in women (53% versus 23%; P = 0.003), patients with adenocarcinoma (38% versus 6%; P = 0.010), never-smokers (63% versus 18%; P < 0.001), and the patients with no history of thoracic radiotherapy (39% versus 13%; P = 0.015). The results of a multivariate analysis showed that the predictors of tumor response were no history of smoking and no history of thoracic radiotherapy. Never-smokers had a significantly longer survival time than smokers (P = 0.007). Although gefitinib therapy confers a clinical benefit on patients with advanced NSCLC, especially on women, patients with adenocarcinoma, never-smokers, and patients with no history of thoracic radiotherapy, it also poses a high risk of ILD, especially to patients with pulmonary fibrosis. The risk-benefit ratio must be carefully considered.

53

Cohen, M. H., G. A. Williams, R. Sridhara, et al. 2003. "FDA drug approval summary: gefitinib (ZD1839) (Iressa) tablets." Oncologist 8(4):303-306.

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On May 5, 2003, gefitinib (Iressa), ZD1839) 250-mg tablets received accelerated approval by the U.S. Food and Drug Administration as monotherapy treatment for patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) after failure of both platinum-based and docetaxel chemotherapies. Information provided in this summary includes efficacy and safety results of relevant clinical trials. Effectiveness was demonstrated in a randomized, double-blind, phase II, multicenter trial comparing two oral doses of gefitinib (250 mg/day versus 500 mg/day). Two hundred sixteen patients were enrolled. The 142 patients who were refractory to or intolerant of a platinum and docetaxel comprised the evaluable population for the efficacy analysis. A partial tumor response occurred in 14% (9 of 66) of patients receiving gefitinib 250 mg/day and in 8% (6 of 76) of patients receiving gefitinib 500 mg/day. The overall objective response rate for both doses combined was 10.6% (15 of 142 patients) (95% confidence interval 6.0%-16.8%). Responses were more frequent in females and in nonsmokers. The median duration of response was 7.0 months (range 4.6-18.6+ months). Other submitted data included the results of two large trials conducted in chemotherapy-naive, stage III and IV NSCLC patients. Patients were randomized to receive gefitinib (250 mg or 500 mg daily) or placebo, in combination with either gemcitabine plus cisplatin (n = 1,093) or carboplatin plus paclitaxel (n = 1,037). Results from those studies showed no benefit (response rate, time to progression, or survival) from adding gefitinib to chemotherapy. Consequently, gefinitib is only recommended for use as monotherapy. Common adverse events associated with gefitinib treatment included diarrhea, rash, acne, dry skin, nausea, and vomiting. Most toxicities were Common Toxicity Criteria grade 1 or 2. Interstitial lung disease (ILD) has been observed in patients receiving gefitinib. Worldwide, the incidence of ILD is about 1% (2% in the Japanese postmarketing experience and about 0.3% in a U.S. expanded access program). Approximately one-third of the cases were fatal. Physicians should promptly evaluate new or worsening pulmonary symptoms. If ILD is confirmed, appropriate management includes discontinuation of gefitinib. Gefitinib was approved under accelerated approval regulations on the basis of a surrogate end point response rate. No controlled gefitinib trials, to date, demonstrate a clinical benefit, such as improvement in disease-related symptoms or greater survival. Accelerated approval regulations require the sponsor to conduct further studies to verify that gefitinib therapy produces such a benefit.

54

AstraZeneca Pty Ltd. – TAGRISSO product information. 2023.

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55

Giusti, R. M., K. Shastri, A. M. Pilaro, et al. 2008. "U.S. Food and Drug Administration approval: panitumumab for epidermal growth factor receptor-expressing metastatic colorectal carcinoma with progression following fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy regimens." Clin Cancer Res 14(5):1296-1302.

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PURPOSE: To describe the Food and Drug Administration review and marketing approval considerations for panitumumab (Vectibix) for the third-line treatment of patients with epidermal growth factor receptor-expressing metastatic colorectal carcinoma. EXPERIMENTAL DESIGN: Food and Drug Administration reviewed a single, open-label, multicenter trial in which 463 patients with epidermal growth factor receptor-expressing metastatic colorectal cancer who had progressed on or following treatment with a regimen containing a fluoropyrimidine, oxaliplatin, and irinotecan were randomized (1:1) to receive best supportive care (BSC) with or without panitumumab (6 mg/kg every other week) administered until disease progression or intolerable toxicity. Progression and response were confirmed by an independent review committee masked to treatment assignment. At progression, patients in the BSC-alone arm were eligible to receive panitumumab. RESULTS: Although median progression-free survival (PFS) was similar in both treatment arms ( approximately 8 weeks), the mean PFS was approximately 50% longer among patients receiving panitumumab than among those receiving BSC alone (96 versus 60 days, respectively) and the objective response rate in patients receiving panitumumab was 8%. However, no difference in overall survival was shown between the two study arms. CONCLUSIONS: Panitumumab received accelerated approval based on improvement in PFS and an independently confirmed response rate of 8%, similar to that observed with other active agents at this advanced stage of disease. Confirmation of clinical benefit will be required for full approval.

56

Astellas Pharma Australia Pty Ltd. PADCEV product information. 2022.

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57

Astellas Pharma Australia Pty Ltd. XOSPATA product information. 2020.

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58

Pfizer Australia Pty Ltd. – MYLOTARG product information. 2022.

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59

Genentech, Inc. HERCEPTIN product information. 2016.

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60

AstraZeneca Pty Ltd. Trastuzumab deruxtecan product information. 2022.

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61

Genentech Inc (per FDA). KADCYLA product information. 2019.

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62

Amgen Australia Pty Ltd. – LUMAKRAS product information. 2020.

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63

Paik, P. K., E. Felip, R. Veillon, et al. 2020. "Tepotinib in Non-Small-Cell Lung Cancer with MET Exon 14 Skipping Mutations." N Engl J Med 383(10):931-943.

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BACKGROUND: A splice-site mutation that results in a loss of transcription of exon 14 in the oncogenic driver MET occurs in 3 to 4% of patients with non-small-cell lung cancer (NSCLC). We evaluated the efficacy and safety of tepotinib, a highly selective MET inhibitor, in this patient population. METHODS: In this open-label, phase 2 study, we administered tepotinib (at a dose of 500 mg) once daily in patients with advanced or metastatic NSCLC with a confirmed MET exon 14 skipping mutation. The primary end point was the objective response by independent review among patients who had undergone at least 9 months of follow-up. The response was also analyzed according to whether the presence of a MET exon 14 skipping mutation was detected on liquid biopsy or tissue biopsy. RESULTS: As of January 1, 2020, a total of 152 patients had received tepotinib, and 99 patients had been followed for at least 9 months. The response rate by independent review was 46% (95% confidence interval [CI], 36 to 57), with a median duration of response of 11.1 months (95% CI, 7.2 to could not be estimated) in the combined-biopsy group. The response rate was 48% (95% CI, 36 to 61) among 66 patients in the liquid-biopsy group and 50% (95% CI, 37 to 63) among 60 patients in the tissue-biopsy group; 27 patients had positive results according to both methods. The investigator-assessed response rate was 56% (95% CI, 45 to 66) and was similar regardless of the previous therapy received for advanced or metastatic disease. Adverse events of grade 3 or higher that were considered by investigators to be related to tepotinib therapy were reported in 28% of the patients, including peripheral edema in 7%. Adverse events led to permanent discontinuation of tepotinib in 11% of the patients. A molecular response, as measured in circulating free DNA, was observed in 67% of the patients with matched liquid-biopsy samples at baseline and during treatment. CONCLUSIONS: Among patients with advanced NSCLC with a confirmed MET exon 14 skipping mutation, the use of tepotinib was associated with a partial response in approximately half the patients. Peripheral edema was the main toxic effect of grade 3 or higher. (Funded by Merck [Darmstadt, Germany]; VISION ClinicalTrials.gov number, NCT02864992.).

64

Novartis Pharmaceuticals Corporation (per FDA). RYDAPT product information. 2021.

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65

Gilead Sciences Inc (per FDA). ZYDELIG product information. 2018.

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66

Gilead Sciences, Inc. ZYDELIG product information. 2016.

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67

Janssen-Cilag Pty Ltd. VELCADE product information. 2019.

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68

Onyx Pharmaceuticals, Inc. KYPROLIS product information. 2020.

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69

Antengene (Aus) Pty Ltd. – XPOVIO product information. 2023.

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70

Genentech Inc. AVASTIN product information. 2016.

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

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