Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Interstitial lung disease in patients with non-small-cell lung cancer: causes, mechanisms and management

This article has been updated

The incidence of lung cancer has markedly increased in the past few decades and is still increasing in many countries worldwide. Lung cancer is a leading cause of death in many developed countries, and approximately 140 000 new cases are identified each year in the US alone (Green, 2004). The majority of patients with non-small-cell lung cancer (NSCLC) are diagnosed with advanced disease and cannot undergo radical surgical treatment. Typically, patients from this large group are offered best supportive care or palliative treatment regimens incorporating various combinations of chemotherapy and radiotherapy.

Progress in palliative care for lung cancer has been slow; however, advances have been made due to better utilisation of drugs (i.e. timing, duration of treatment), choice of drugs for first-line therapy and subsequent regimens, and optimal combination and timing with radiation therapy (Spiro and Porter, 2002). Chemotherapy or chemoradiation therapy is the treatment of choice for unresected lung cancer in many countries (Spiro and Porter, 2002) and may be accepted as a treatment option for resected lung cancer in the future (Arriagada et al, 2004). There is the general agreement that properly used chemotherapy regimens have increased life expectancy and improved the quality of life of patients with lung cancer.

However, chemotherapy benefits can be at the expense of adverse effects in different organ systems, including the lung (Foucher et al, 2003; Limper, 2004). Several novel compounds, such as irinotecan (Masuda et al, 1992; Foucher et al, 2003), gemcitabine (Pavlakis et al, 1997), paclitaxel (Goldberg and Vannice, 1995) and docetaxel (Merad et al, 1997), have been associated with the development of sometimes severe lung disease in about 3–5% of patients with lung cancer (Kunitoh et al, 1996; Merad et al, 1997; Wang et al, 2001; Erasmus et al, 2002; Lilly, 2003). The assessment of drug causality in patients with lung cancer who develop interstitial lung disease (ILD) is difficult compared with other respiratory reactions to drugs. The diagnosis of drug-associated lung disease is against the background of the underlying neoplastic lung disease, adverse effects of other drugs, colony-stimulating factors, oxygen or radiation therapy and opportunistic infections. Patients with lung cancer are often sequentially exposed to different chemotherapy regimens and the risk of drug-induced disease may increase correlatively. Clarifying the respective role of these factors is often impossible.

Gefitinib (‘Iressa’) is a new type of targeted treatment for NSCLC. It is an inhibitor of the epidermal growth factor receptor (EGFR) signalling pathway that acts intracellularly at the level of the EGFR tyrosine kinase. Two phase II monotherapy trials (‘Iressa’ Dose Evaluation in Advanced Lung cancer [IDEAL] 1 and 2) have reported unprecedented antitumour activity and symptom relief in pretreated patients with advanced metastatic NSCLC (Fukuoka et al, 2003; Kris et al, 2003). Furthermore, recent evidence in patients with NSCLC points to a specific gain in function in patients who bear somatic mutations in the tyrosine kinase domain of the EGFR (Lynch et al, 2004; Paez et al, 2004). These mutations exert a dominant oncogenic effect that correlates with the clinical response to gefitinib, contrasted with the low response rate seen in patients lacking these mutations (Lynch et al, 2004; Paez et al, 2004). However, in addition to patients with a clinical response, an additional 35% of patients experience stable disease or symptom improvement with gefitinib (Fukuoka et al, 2003; Kris et al, 2003) and further molecular studies are clearly required to identify predictive markers in this group of patients. The prevalence of this mutation is also different in Japanese NSCLC patients, as opposed to NSCLC patients from the US (Paez et al, 2004), which may explain the greater response rate of Japanese patients to gefitinib.

Although gefitinib is not associated with many of the general adverse effects of broadly acting cytotoxic chemotherapeutic agents, recent reports from Japan have indicated that a proportion of patients treated with gefitinib experienced severe ILD (Ieki et al, 2003; Inoue et al, 2003; Okamoto and Suga, 2003; Rabinowits et al, 2003; Sumter et al, 2003). Evaluation of drug causality is also difficult here. Tolerability data from the compassionate use of gefitinib in the ‘Iressa’ Expanded Access Programme support the favourable safety profile reported in phase I and II trials, and incidence figures for ILD in the West are not dissimilar to those reported for gefitinib- vs placebo-exposed patients with NSCLC (Giaccone et al, 2002; Herbst et al, 2004). Whether the mutations of the EGFR signalling domain referred to above also modulate the occurrence of adverse pulmonary effects of gefitinib, or interfere with repair processes of the pulmonary epithelium (Suzuki et al, 2003), is unknown at this time.

This experience of ILD in patients with NSCLC has posed a number of important questions relating to definition, diagnosis, management and mechanisms. A group of experts in the field of NSCLC and lung disease discussed these issues at a symposium held in Seattle in May 2003. The content of the presentations is discussed within this supplement. Hopefully, the knowledge of gefitinib may provide new insights into the field of ILD and chemotherapy-associated lung disease in the way it has in the treatment of cancer.

Change history

  • 16 November 2011

    This paper was modified 12 months after initial publication to switch to Creative Commons licence terms, as noted at publication

References

  1. Arriagada R, Bergman B, Dunant A, Le Chevalier T, Pignon JP, Vansteenkiste J, International Adjuvant Lung Cancer Trial Collaborative Group (2004) Cisplatin-based adjuvant chemotherapy in patients with completely resected non-small-cell lung cancer. N Engl J Med 350: 351–360

    Article  Google Scholar 

  2. Erasmus JJ, McAdams HP, Rossi SE (2002) Drug-induced lung injury. Semin Roentgenol 37: 72–81

    Article  Google Scholar 

  3. Foucher P, Camus P, and the GEPPI (2003) Pneumotox on line. The drug-induced lung diseases. Available at http://www.pneumotox.com Accessed 10/03

  4. Fukuoka M, Yano S, Giaccone G, Tamura T, Nakagawa K, Douillard J-Y, Nishiwaki Y, Vansteenkiste J, Kudoh S, Rischin D, Eek R, Horai T, Noda K, Takata I, Smit E, Averbuch S, Macleod A, Feyereislova A, Dong R-P, Baselga J (2003) Multi-institutional randomized phase II trial of gefitinib for previously treated patients with advanced non-small-cell lung cancer. J Clin Oncol 21: 2237–2246

    CAS  Article  Google Scholar 

  5. Giaccone G, Johnson DH, Manegold C, Scagliotti GV, Rosell R, Wolf M, Rennie P, Ochs J, Averbuch S, Fandi A (2002) A phase III clinical trial of ZD1839 (‘Iressa’) in combination with gemcitabine and cisplatin in chemotherapy-naive patients with advanced non-small-cell lung cancer (INTACT 1). Ann Oncol 13(Suppl 5): 2 (abstr. 4)

    Article  Google Scholar 

  6. Goldberg HL, Vannice SB (1995) Pneumonitis related to treatment with paclitaxel. J Clin Oncol 13: 534–535

    CAS  Article  Google Scholar 

  7. Green MR (2004) Targeting targeted therapy. N Engl J Med 350: 2191–2193

    CAS  Article  Google Scholar 

  8. Herbst RS, Giaccone G, Schiller JH, Natale RB, Miller V, Manegold C, Scagliotti G, Rosell R, Oliff I, Reeves JA, Wolf MK, Krebs AD, Averbuch SD, Ochs JS, Grous J, Fandi A, Johnson DH (2004) Gefitinib in combination with paclitaxel and carboplatin in advanced non-small-cell lung cancer: a phase III trial – INTACT 2. J Clin Oncol 22: 785–794

    CAS  Article  Google Scholar 

  9. Ieki R, Saitoh E, Shibuya M (2003) Acute lung injury as a possible adverse drug reaction related to gefitinib. Eur Respir J 22: 179–181

    CAS  Article  Google Scholar 

  10. Inoue A, Saijo Y, Maemondo M, Gomi K, Tokue Y, Kimura Y, Ebina M, Kikuchi T, Moriya T, Nukiwa T (2003) Severe acute interstitial pneumonia and gefitinib. Lancet 361: 137–139

    Article  Google Scholar 

  11. Kris MG, Natale RB, Herbst RS, Lynch Jr TJ, Prager D, Belani CP, Schiller JH, Kelly K, Spiridonidis H, Sandler A, Albain KS, Cella D, Wolf MK, Averbuch SD, Ochs JJ, Kay AC (2003) Efficacy of gefitinib, an inhibitor of the epidermal growth factor receptor tyrosine kinase, in symptomatic patients with non-small cell lung cancer. A randomized trial. JAMA 290: 2149–2158

    CAS  Article  Google Scholar 

  12. Kunitoh H, Watanabe K, Onoshi T, Furuse K, Niitani H, Taguchi T (1996) Phase II trial of docetaxel in previously untreated advanced non-small-cell lung cancer: a Japanese cooperative study. J Clin Oncol 14: 1649–1655

    CAS  Article  Google Scholar 

  13. Lilly (2003) Gemcitabine prescribing information. Available at http://pi.lilly.com/gemzar.pdf Accessed 4/23/99

  14. Limper AH (2004) Chemotherapy-induced lung disease. Clin Chest Med 25: 53–64

    Article  Google Scholar 

  15. Lynch TJ, Bell DW, Sordella R, Gurubhagavatula S, Okimoto RA, Brannigan BW, Harris PL, Haserlat SM, Supko JG, Haluska FG, Louis DN, Christiani DC, Settleman J, Haber DA (2004) Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 350: 2129–2139

    CAS  Article  Google Scholar 

  16. Masuda N, Fukuoka M, Kusunoki Y, Matsui K, Takifuji N, Kudoh S, Negoro S, Nishioka M, Nakagawa K, Takada M (1992) CPT-11: a new derivative of camptothecin for the treatment of refractory or relapsed small-cell lung cancer. J Clin Oncol 10: 1225–1229

    CAS  Article  Google Scholar 

  17. Merad M, Le Cesne A, Baldeyrou P, Mesurolle B, Le Chevalier T (1997) Docetaxel and interstitial pulmonary injury. Ann Oncol 8: 191–194

    CAS  Article  Google Scholar 

  18. Okamoto I, Suga M (2003) Pulmonary toxicity due to chemotherapy how is the risk and benefit from ZD1839 treatment against non-small cell lung cancer? Intern Med 42: 926–927

    Article  Google Scholar 

  19. Paez JG, Janne PA, Lee JC, Tracy S, Greulich H, Gabriel S, Herman P, Kaye FJ, Linderman N, Boggon TJ, Naoki K, Sasaki H, Fujii Y, Eck MJ, Sellers WR, Johnson BE, Meyerson M (2004) EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 304: 1497–1500

    CAS  Article  Google Scholar 

  20. Pavlakis N, Bell DR, Millward MJ, Levi JA (1997) Fatal pulmonary toxicity resulting from treatment with gemcitabine. Cancer 80: 286–291

    CAS  Article  Google Scholar 

  21. Rabinowits G, Herchenhorn D, Rabinowits M, Weatge D, Torres W (2003) Fatal pulmonary toxicity in a patient treated with gefitinib for non-small cell lung cancer after previous hemolytic–uremic syndrome due to gemcitabine. Anticancer Drugs 14: 665–668

    CAS  Article  Google Scholar 

  22. Spiro SG, Porter JC (2002) Lung cancer – where are we today? Current advances in staging and nonsurgical treatment. Am J Respir Crit Care Med 166: 1166–1196

    Article  Google Scholar 

  23. Sumter K, Harper-Wynne C, O'Brien M (2003) Severe acute interstitial pneumonia and gefitinib. Lung Cancer 43: 367–368

    Article  Google Scholar 

  24. Suzuki H, Aoshiba K, Yokohori N, Nagai A (2003) Epidermal growth factor receptor tyrosine kinase inhibition augments a murine model of pulmonary fibrosis. Cancer Res 63: 5054–5059

    CAS  PubMed  Google Scholar 

  25. Wang G-S, Yan K-Y, Perng R-P (2001) Life-threatening hypersensitivity pneumonitis induced by docetaxel (taxotere). Br J Cancer 85: 1247–1250

    CAS  Article  Google Scholar 

Download references

Acknowledgements

We thank Mark Walker, PhD, for providing editorial support during preparation of the supplement. ‘Iressa’ is a trademark of the AstraZeneca group of companies.

Author information

Affiliations

Authors

Corresponding author

Correspondence to P Camus.

Rights and permissions

From twelve months after its original publication, this work is licensed under the Creative Commons Attribution-NonCommercial-Share Alike 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/

Reprints and Permissions

About this article

Cite this article

Camus, P. Interstitial lung disease in patients with non-small-cell lung cancer: causes, mechanisms and management. Br J Cancer 91, S1–S2 (2004). https://doi.org/10.1038/sj.bjc.6602060

Download citation

Further reading

Search

Quick links