- Email: [email protected]
Cetuximab-Associated Pulmonary Toxicity
Case Report
Cetuximab-Associated Pulmonary Toxicity Wei Chua,1 Matthew Peters,2 Robert Loneragan,3 Stephen Clarke1 Abstract There is increasing evidence for the use of epidermal growth factor receptor (EGFR) inhibitors in head and neck, non–small-cell lung, and colorectal cancers. We report the case of a 78-year-old man with metastatic colorectal cancer (CRC) involving liver and lung who received cetuximab plus irinotecan as third-line treatment. Two months later, he presented with signs and symptoms consistent with bronchiolotis obliterans organizing pneumonia secondary to cetuximab. Reports of cetuximab-associated pulmonary toxicity are rare, although there have been extensive reports of interstitial fibrosis with the use of other EGFR inhibitors such as gefitinib and erlotinib. There are many causes of pulmonary infiltrates in patients treated for advanced CRC, and this case highlights the importance of considering drug toxicity. Clinical Colorectal Cancer, Vol. 8, No. 2, 118-120, 2009; DOI: 10.3816/CCC.2009.n.019 Keywords: 5-Fluorouracil, Epidermal growth factor inhibitors, Oxaliplatin, Pulmonary fibrosis
Introduction There is increasing evidence for the use of epidermal growth factor receptor (EGFR) inhibitors in head and neck, non–smallcell lung, and colorectal cancers. Cunningham et al1 reported that cetuximab had efficacy as a single agent and more importantly, was able to reverse resistance to irinotecan in patients with metastatic colorectal cancer (CRC) who were irinotecan refractory.
Case Report We report the case of a 78-year-old man with mCRC involving liver and lung who received cetuximab plus irinotecan as third-line treatment after disease progression on bevacizumab, 5-fluorouracil (5-FU) and oxaliplatin followed by 5-FU, and irinotecan. He was a former smoker who had stopped smoking about 60 years before his cancer diagnosis and worked in the building industry for many years. After 6 weeks of cetuximab treatment, computed tomography (CT) scans showed a reduction in the size of liver and lung lesions (Figure 1A). There was also stable long-standing minor pulmonary fibrosis consistent with his previous occupational exposure as a builder. However, he did not report any known preexisting lung disease. Two months after starting cetuximab, he presented with cough and breathlessness worsening over 7 days. Examination of the 1Department
of Medical Oncology, Concord Repatriation General Hospital, Australia of Respiratory Medicine, Concord Repatriation General Hospital, Australia 3Department of Radiology, Concord Repatriation General Hospital, Australia 2Department
Submitted: May 26, 2008; Revised: Aug 29, 2008; Accepted: Oct 9, 2008 Address for correspondence: Wei Chua, MBBS, Department of Medical Oncology, Concord Repatriation General Hospital, Hospital Rd, Concord, NSW 2139, Australia Fax: 612-9767-5764; e-mail: [email protected]
chest revealed new fine crackles and scattered squeaks. His jugular venous pressure was not raised, and there were no additional heart sounds. A CT pulmonary angiogram excluded pulmonary embolism; however, there were new bilateral patchy ground-glass changes (Figure 1B). Differential diagnosis at presentation included infection or a drug reaction. He was commenced on intravenous cefotaxime and azithromycin. Treatment with cetuximab was ceased. Bronchoscopy showed no focal abnormalities, and bronchoalveolar lavage was negative for infective organisms on microscopy and culture. There was no history of previous cardiac disease and insufficient clinical or radiologic evidence to suggest congestive cardiac failure. He also failed to respond to a trial of diuretics. Radiologic findings did not support lymphangitis carcinomatosis as a cause of his symptoms. Spirometry and lung volumes were moderately restricted, and diffusing capacity reduced consistent with interstitial lung disease (ILD). Antibiotics were stopped after 6 days because of a lack of symptomatic improvement. Because lung biopsy was considered too hazardous, he was empirically commenced on oral prednisone 50 mg daily. His symptoms improved steadily, and he was discharged on a reducing schedule of prednisone. A high-resolution CT chest performed 3 weeks after hospital admission showed marked improvement in the ground-glass changes, consistent with his symptomatic improvement (Figure 1C). Unfortunately, he died 4 months later from respiratory failure because of progressive lung metastases despite further chemotherapy with mitomycin C and oral capecitabine. We believe the clinical course and laboratory and radiologic findings are most consistent with bronchiolitis obliterans organizing pneumonia secondary to cetuximab. Unfortunately, a definitive diagnosis was not possible because the patient was too unwell to
This summary may include the discussion of investigational and/or unlabeled uses of drugs and/or devices that may not be approved by the FDA. Electronic forwarding or copying is a violation of US and International Copyright Laws. Authorization to photocopy items for internal or personal use, or the internal or personal use of specific clients, is granted by CIG Media Group, LP, ISSN #1533-0028, provided the appropriate fee is paid directly to Copyright Clearance Center, 222 Rosewood Drive, Danvers, MA 01923 USA. www.copyright.com 978-750-8400.
118
| Clinical Colorectal Cancer
April 2009
have a lung biopsy, and an autopsy was not performed. Based on the available information, we feel that the reaction was probably related to cetuximab. Severe complications of ILD have been reported in only 3 of 774 (< 0.5%) of patients with advanced CRC and 1 of 796 (< 0.5%) of patients with head and neck cancer receiving cetuximab in clinical trials resulting in 1 death from the colon cancer group.2 Two patients had pre-existing fibrotic lung disease, and the onset of symptoms occurred between the fourth and eleventh doses of treatment.2 Leard et al reported fatal diffuse alveolar damage in 2 lung transplantation patients treated with cetuximab for metastatic cutaneous squamous cell carcinoma.2 However, it was unclear if these patients were at an increased risk because of an interaction between cetuximab and immunosuppressive agents such as sirolimus or possible increased EGFR expression in transplanted lungs, which have been reported in animal studies.3 Interstitial lung disease is a recognized complication of other EGFR inhibitors such as gefitinib and erlotinib. Detailed analysis of gefitinib’s drug safety database by the US Food and Drug Administration, reports from 2 phase III trials, expanded-access schemes, and retrospective reviews estimates the worldwide incidence of interstitial fibrosis secondary to gefitinib or erlotinib at 0.3% to 1.1% with consistently higher rates in Japanese patients of 2%-10%.4-10 True mortality rates from these studies are unclear but have been reported at 1.6% in one study.8 The most common symptoms are fever, dyspnea, and cough, with the median duration of treatment before onset of symptoms ranging from 18 to 29 days.7,8 However development of ILD could occur as early as within 3 days of drug initiation, and there have been reports of ILD after drug reintroduction or switching from gefitinib to erlotinib.11,12 A retrospective study of 1976 patients treated with gefitinib examined the chest radiography and CT findings of patients who developed ILD concluded the imaging findings induced by gefitinib as similar to those of pulmonary toxicity induced by conventional chemotherapeutic agents.13 Preexisting pulmonary fibrosis, male sex, previous thoracic irradiation, and poor performance status have been reported as risk factors for gefitinib-induced ILD.8,9 Mortality rates in patients who develop ILD range from 33% to 50%, and poor prognostic features include the presence of preexisting pulmonary fibrosis, short interval from the initiation of gefitinib treatment to the onset of ILD, and acute interstitial pneumonia pattern seen on CT scan.8,9 Treatment strategies including symptomatic management and cessation of the EGFR inhibitor, and corticosteroids have been used with varying success. Specific serum markers of pulmonary fibrosis such as surfactant protein (SP)-A, SP-D, and KL-6 have been developed and evaluated for ILD; however, its use has been limited in patients with gefitinib induced ILD. A case report of 3 patients whose pretreatment sera was examined for these surfactant proteins exhibited high concentrations of at least one of these markers with subsequent increases in all except for SP-A in 1 patient with the occurrence of acute lung injury.10 Prospectively identified biologic markers are needed, and development of newer techniques such as proteomics on sputum or blood might be a useful tool for early diagnosis of ILD in the future.14 The mechanisms of EGFR inhibitor–induced ILD are poorly understood. Current evidence suggests that pulmonary fibrosis is
Figure 1 Computed Tomography of the Chest A
B
C
Computed tomography of the chest (A) after 6 weeks of cetuximab treatment, (B) demonstrating new bilateral patchy ground glass changes with onset of respiratory symptoms, and (C) showing resolution of ground glass changes after 3 weeks of steroid treatment.
a fibrotic rather than an inflammatory disease, with aberrant tissue remodeling by fibroblasts leading to irreversible parenchymal fibrosis.15 In idiopathic pulmonary fibrosis, it is thought that regenera-
Clinical Colorectal Cancer April 2009
| 119
Cetuximab-Induced Interstitial Lung Disease tion of injured epithelium is mediated by upregulation of EGFR and EGFR ligands, leading to proliferation of alveolar type II cells and ultimately focal hyperplasia.14 Suzuki et al16 hypothesized that EGFR inhibitors in patients with pulmonary fibrosis might promote fibrogenesis and demonstrated that gefitinib augmented bleomycin-induced pulmonary fibrosis in a murine model. EGFR inhibitors might impair healing of the epithelium and thereby exacerbate any existing lung injury.10,11 In contrast, 2 other animal studies have showed that EGFR inhibition led to attenuation of lung fibrosis.17,18 Ishii et al17 demonstrated that gefitinib prevented pulmonary fibrosis at 3 different doses on a bleomycin-induced lung fibrosis in mice, supporting their hypothesis that inhibition of EGFR signaling prevents pulmonary fibrosis. Reports of cetuximab-associated pulmonary toxicity are rare, although there have been extensive reports of interstitial fibrosis outside clinical trials and in expanded access programs with the use of other EGFR inhibitors such as gefitinib11,19-22 and erlotinib.11 Preexisting pulmonary fibrosis has been described as a risk factor for development of gefitinb-induced ILD8 and was likely a significant factor here. There are many causes of pulmonary infiltrates in patients treated for advanced CRC, and this case highlights the importance of considering drug toxicity.
Disclosures The authors have no relevant relationships to disclose.
References 1. Cunningham D, Humblet Y, Siena S, et al. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med 2004; 351:337-45. 2. Erbitux (cetuximab) Product Information: ImClone Systems Incorporated; New York, NY 10014. Available at: http://www.erbitux.com. Accessed: March 4, 2009. 3. Leard LE, Cho BK, Jones KD, et al. Fatal diffuse alveolar damage in two lung transplant patients treated with cetuximab. J Heart Lung Transplant 2007; 26:1340-4. 4. Cohen MH, Williams GA, Sridhara R, et al. FDA Drug Approval Summary:
120
| Clinical Colorectal Cancer
April 2009
Gefitinib (ZD 1839) (Iressa) tablets. Oncologist 2003; 8:303-6. 5. Giaccone G, Herbst RS, Manegold C, et al. Gefitinib in combination with gemcitabine and cisplatin in advanced non-small cell lung cancer: a phase III trial- INTACT 1. J Clin Oncol 2004; 22:777-84. 6. Herbst RS, Giaconne G, Schiller JH, et al. Gefitinib in combination with paclitaxel and carboplatin in advanced non-small cell lung cancer: a phase III trialINTACT 2. J Clin Oncol 2004; 22:785-94. 7. Ando M, Okamoto I, Yamamoto N, et al. Predictive factors for interstitial lung disease, antitumour response, and survival in non-small cell lung cancer patients treated with gefitinib. J Clin Oncol 2006; 24:2549-55. 8. Takano T, One Y, Kusumoto M, et al. Risk factors for interstitial lung disease and predictive factors for tumour response in patients with advanced non-small cell lung cancer treated with gefitinib. Lung Cancer 2004; 45:93-104. 9. Hotta K, Harita S, Bessho A, et al. Interstitial lung disease (ILD) during gefitinib treatment in Japanese patients with non-small cell lung cancer (NSCLC): Okayama Lung Cancer Study Group. Proc Am Soc Clin Oncol 2004; 23:629 (Abstract 7063). 10. Inomata S, Takahashi H, Nagata M, et al. Acute lung injury as an adverse event of gefitinib. Anticancer Drugs 2004; 15:461-7. 11. Tammaro KA, Baldwin PD, Lundberg AS. Interstitial lung disease following erlotinib in a patient who previously tolerated gefitinic. J Oncol Pharm Pract 2005; 11:127-30. 12. Camus P, Kudoh S, Ebina M. Interstitial lung disease associated with drug therapy. Br J Cancer 2004; 91(suppl 2):S18-S23. 13. Endo M, Johkoh T, Kimura K, et al. Imaging of gefitinib-related interstitial lung disease: Multi-institutional analysis by the West Japan Thoracic Oncology Group. Lung Cancer 2006; 52:135-40. 14. Higenbottom T, Kuwano K, Nemery B et al. Understanding the mechanisms of drug-associated interstitial lung disease. Br J Cancer 2004; 91(suppl 2):S31-S37. 15. Selman M, King TE, Pardo A. Idiopathic pulmonary fibrosis: prevaling and evolving hypotheses about its pathogenesis and implications for therapy. Ann Intern Med 2001; 134:136-51. 16. Suzuki H, Aoshiba K, Yokohari N, et al. Epidermal growth factor tyrosine kinase inhibition augments a murine model of pulmonary fibrosis. Cancer Res 2003; 63:5054-9. 17. Ishii Y, Fujimoto S, Fukuda T. Gefitinib prevents bleomycin-induced lung fibrosis in mice. Am J Respir Crit Care Med 2006; 174:550-6. 18. Rice AB, Moomaw CR, Morgan DL, et al. Specific inhibitors of platelet-derived growth factor or epidermal growth factor receptor tyrosine kinase reduce pulmonary fibrosis in rats. Am J Pathol 1999; 155:213-21. 19. Saijo A, Maemondo M, Gomi K, et al. Severe acute interstitial pneumonia and gefitinib. Lancet 2003; 361:137-9. 20. Nagaria NC, Cogswell J, Choe JK, et al. Side effects and good effects from new chemotherapeutic agents. Case 1. Gefitinib-induced interstitial fibrosis. J Clin Oncol 2005; 23:2423-4. 21. Kitajima H, Takahasho H, Harada K, et al. Gefitinib-induced interstitial lung disease showing improvement after cessation: disassociation of serum markers. Respirology 2006; 11:217-20. 22. Kataoka K, Taniguchi H, Hasegawa Y, et al. Interstitial lung disease associated with gefitinib. Respir Med 2006; 100:698-704.
Cetuximab-Associated Pulmonary Toxicity Wei Chua,1 Matthew Peters,2 Robert Loneragan,3 Stephen Clarke1 Abstract There is increasing evidence for the use of epidermal growth factor receptor (EGFR) inhibitors in head and neck, non–small-cell lung, and colorectal cancers. We report the case of a 78-year-old man with metastatic colorectal cancer (CRC) involving liver and lung who received cetuximab plus irinotecan as third-line treatment. Two months later, he presented with signs and symptoms consistent with bronchiolotis obliterans organizing pneumonia secondary to cetuximab. Reports of cetuximab-associated pulmonary toxicity are rare, although there have been extensive reports of interstitial fibrosis with the use of other EGFR inhibitors such as gefitinib and erlotinib. There are many causes of pulmonary infiltrates in patients treated for advanced CRC, and this case highlights the importance of considering drug toxicity. Clinical Colorectal Cancer, Vol. 8, No. 2, 118-120, 2009; DOI: 10.3816/CCC.2009.n.019 Keywords: 5-Fluorouracil, Epidermal growth factor inhibitors, Oxaliplatin, Pulmonary fibrosis
Introduction There is increasing evidence for the use of epidermal growth factor receptor (EGFR) inhibitors in head and neck, non–smallcell lung, and colorectal cancers. Cunningham et al1 reported that cetuximab had efficacy as a single agent and more importantly, was able to reverse resistance to irinotecan in patients with metastatic colorectal cancer (CRC) who were irinotecan refractory.
Case Report We report the case of a 78-year-old man with mCRC involving liver and lung who received cetuximab plus irinotecan as third-line treatment after disease progression on bevacizumab, 5-fluorouracil (5-FU) and oxaliplatin followed by 5-FU, and irinotecan. He was a former smoker who had stopped smoking about 60 years before his cancer diagnosis and worked in the building industry for many years. After 6 weeks of cetuximab treatment, computed tomography (CT) scans showed a reduction in the size of liver and lung lesions (Figure 1A). There was also stable long-standing minor pulmonary fibrosis consistent with his previous occupational exposure as a builder. However, he did not report any known preexisting lung disease. Two months after starting cetuximab, he presented with cough and breathlessness worsening over 7 days. Examination of the 1Department
of Medical Oncology, Concord Repatriation General Hospital, Australia of Respiratory Medicine, Concord Repatriation General Hospital, Australia 3Department of Radiology, Concord Repatriation General Hospital, Australia 2Department
Submitted: May 26, 2008; Revised: Aug 29, 2008; Accepted: Oct 9, 2008 Address for correspondence: Wei Chua, MBBS, Department of Medical Oncology, Concord Repatriation General Hospital, Hospital Rd, Concord, NSW 2139, Australia Fax: 612-9767-5764; e-mail: [email protected]
chest revealed new fine crackles and scattered squeaks. His jugular venous pressure was not raised, and there were no additional heart sounds. A CT pulmonary angiogram excluded pulmonary embolism; however, there were new bilateral patchy ground-glass changes (Figure 1B). Differential diagnosis at presentation included infection or a drug reaction. He was commenced on intravenous cefotaxime and azithromycin. Treatment with cetuximab was ceased. Bronchoscopy showed no focal abnormalities, and bronchoalveolar lavage was negative for infective organisms on microscopy and culture. There was no history of previous cardiac disease and insufficient clinical or radiologic evidence to suggest congestive cardiac failure. He also failed to respond to a trial of diuretics. Radiologic findings did not support lymphangitis carcinomatosis as a cause of his symptoms. Spirometry and lung volumes were moderately restricted, and diffusing capacity reduced consistent with interstitial lung disease (ILD). Antibiotics were stopped after 6 days because of a lack of symptomatic improvement. Because lung biopsy was considered too hazardous, he was empirically commenced on oral prednisone 50 mg daily. His symptoms improved steadily, and he was discharged on a reducing schedule of prednisone. A high-resolution CT chest performed 3 weeks after hospital admission showed marked improvement in the ground-glass changes, consistent with his symptomatic improvement (Figure 1C). Unfortunately, he died 4 months later from respiratory failure because of progressive lung metastases despite further chemotherapy with mitomycin C and oral capecitabine. We believe the clinical course and laboratory and radiologic findings are most consistent with bronchiolitis obliterans organizing pneumonia secondary to cetuximab. Unfortunately, a definitive diagnosis was not possible because the patient was too unwell to
This summary may include the discussion of investigational and/or unlabeled uses of drugs and/or devices that may not be approved by the FDA. Electronic forwarding or copying is a violation of US and International Copyright Laws. Authorization to photocopy items for internal or personal use, or the internal or personal use of specific clients, is granted by CIG Media Group, LP, ISSN #1533-0028, provided the appropriate fee is paid directly to Copyright Clearance Center, 222 Rosewood Drive, Danvers, MA 01923 USA. www.copyright.com 978-750-8400.
118
| Clinical Colorectal Cancer
April 2009
have a lung biopsy, and an autopsy was not performed. Based on the available information, we feel that the reaction was probably related to cetuximab. Severe complications of ILD have been reported in only 3 of 774 (< 0.5%) of patients with advanced CRC and 1 of 796 (< 0.5%) of patients with head and neck cancer receiving cetuximab in clinical trials resulting in 1 death from the colon cancer group.2 Two patients had pre-existing fibrotic lung disease, and the onset of symptoms occurred between the fourth and eleventh doses of treatment.2 Leard et al reported fatal diffuse alveolar damage in 2 lung transplantation patients treated with cetuximab for metastatic cutaneous squamous cell carcinoma.2 However, it was unclear if these patients were at an increased risk because of an interaction between cetuximab and immunosuppressive agents such as sirolimus or possible increased EGFR expression in transplanted lungs, which have been reported in animal studies.3 Interstitial lung disease is a recognized complication of other EGFR inhibitors such as gefitinib and erlotinib. Detailed analysis of gefitinib’s drug safety database by the US Food and Drug Administration, reports from 2 phase III trials, expanded-access schemes, and retrospective reviews estimates the worldwide incidence of interstitial fibrosis secondary to gefitinib or erlotinib at 0.3% to 1.1% with consistently higher rates in Japanese patients of 2%-10%.4-10 True mortality rates from these studies are unclear but have been reported at 1.6% in one study.8 The most common symptoms are fever, dyspnea, and cough, with the median duration of treatment before onset of symptoms ranging from 18 to 29 days.7,8 However development of ILD could occur as early as within 3 days of drug initiation, and there have been reports of ILD after drug reintroduction or switching from gefitinib to erlotinib.11,12 A retrospective study of 1976 patients treated with gefitinib examined the chest radiography and CT findings of patients who developed ILD concluded the imaging findings induced by gefitinib as similar to those of pulmonary toxicity induced by conventional chemotherapeutic agents.13 Preexisting pulmonary fibrosis, male sex, previous thoracic irradiation, and poor performance status have been reported as risk factors for gefitinib-induced ILD.8,9 Mortality rates in patients who develop ILD range from 33% to 50%, and poor prognostic features include the presence of preexisting pulmonary fibrosis, short interval from the initiation of gefitinib treatment to the onset of ILD, and acute interstitial pneumonia pattern seen on CT scan.8,9 Treatment strategies including symptomatic management and cessation of the EGFR inhibitor, and corticosteroids have been used with varying success. Specific serum markers of pulmonary fibrosis such as surfactant protein (SP)-A, SP-D, and KL-6 have been developed and evaluated for ILD; however, its use has been limited in patients with gefitinib induced ILD. A case report of 3 patients whose pretreatment sera was examined for these surfactant proteins exhibited high concentrations of at least one of these markers with subsequent increases in all except for SP-A in 1 patient with the occurrence of acute lung injury.10 Prospectively identified biologic markers are needed, and development of newer techniques such as proteomics on sputum or blood might be a useful tool for early diagnosis of ILD in the future.14 The mechanisms of EGFR inhibitor–induced ILD are poorly understood. Current evidence suggests that pulmonary fibrosis is
Figure 1 Computed Tomography of the Chest A
B
C
Computed tomography of the chest (A) after 6 weeks of cetuximab treatment, (B) demonstrating new bilateral patchy ground glass changes with onset of respiratory symptoms, and (C) showing resolution of ground glass changes after 3 weeks of steroid treatment.
a fibrotic rather than an inflammatory disease, with aberrant tissue remodeling by fibroblasts leading to irreversible parenchymal fibrosis.15 In idiopathic pulmonary fibrosis, it is thought that regenera-
Clinical Colorectal Cancer April 2009
| 119
Cetuximab-Induced Interstitial Lung Disease tion of injured epithelium is mediated by upregulation of EGFR and EGFR ligands, leading to proliferation of alveolar type II cells and ultimately focal hyperplasia.14 Suzuki et al16 hypothesized that EGFR inhibitors in patients with pulmonary fibrosis might promote fibrogenesis and demonstrated that gefitinib augmented bleomycin-induced pulmonary fibrosis in a murine model. EGFR inhibitors might impair healing of the epithelium and thereby exacerbate any existing lung injury.10,11 In contrast, 2 other animal studies have showed that EGFR inhibition led to attenuation of lung fibrosis.17,18 Ishii et al17 demonstrated that gefitinib prevented pulmonary fibrosis at 3 different doses on a bleomycin-induced lung fibrosis in mice, supporting their hypothesis that inhibition of EGFR signaling prevents pulmonary fibrosis. Reports of cetuximab-associated pulmonary toxicity are rare, although there have been extensive reports of interstitial fibrosis outside clinical trials and in expanded access programs with the use of other EGFR inhibitors such as gefitinib11,19-22 and erlotinib.11 Preexisting pulmonary fibrosis has been described as a risk factor for development of gefitinb-induced ILD8 and was likely a significant factor here. There are many causes of pulmonary infiltrates in patients treated for advanced CRC, and this case highlights the importance of considering drug toxicity.
Disclosures The authors have no relevant relationships to disclose.
References 1. Cunningham D, Humblet Y, Siena S, et al. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med 2004; 351:337-45. 2. Erbitux (cetuximab) Product Information: ImClone Systems Incorporated; New York, NY 10014. Available at: http://www.erbitux.com. Accessed: March 4, 2009. 3. Leard LE, Cho BK, Jones KD, et al. Fatal diffuse alveolar damage in two lung transplant patients treated with cetuximab. J Heart Lung Transplant 2007; 26:1340-4. 4. Cohen MH, Williams GA, Sridhara R, et al. FDA Drug Approval Summary:
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| Clinical Colorectal Cancer
April 2009
Gefitinib (ZD 1839) (Iressa) tablets. Oncologist 2003; 8:303-6. 5. Giaccone G, Herbst RS, Manegold C, et al. Gefitinib in combination with gemcitabine and cisplatin in advanced non-small cell lung cancer: a phase III trial- INTACT 1. J Clin Oncol 2004; 22:777-84. 6. Herbst RS, Giaconne G, Schiller JH, et al. Gefitinib in combination with paclitaxel and carboplatin in advanced non-small cell lung cancer: a phase III trialINTACT 2. J Clin Oncol 2004; 22:785-94. 7. Ando M, Okamoto I, Yamamoto N, et al. Predictive factors for interstitial lung disease, antitumour response, and survival in non-small cell lung cancer patients treated with gefitinib. J Clin Oncol 2006; 24:2549-55. 8. Takano T, One Y, Kusumoto M, et al. Risk factors for interstitial lung disease and predictive factors for tumour response in patients with advanced non-small cell lung cancer treated with gefitinib. Lung Cancer 2004; 45:93-104. 9. Hotta K, Harita S, Bessho A, et al. Interstitial lung disease (ILD) during gefitinib treatment in Japanese patients with non-small cell lung cancer (NSCLC): Okayama Lung Cancer Study Group. Proc Am Soc Clin Oncol 2004; 23:629 (Abstract 7063). 10. Inomata S, Takahashi H, Nagata M, et al. Acute lung injury as an adverse event of gefitinib. Anticancer Drugs 2004; 15:461-7. 11. Tammaro KA, Baldwin PD, Lundberg AS. Interstitial lung disease following erlotinib in a patient who previously tolerated gefitinic. J Oncol Pharm Pract 2005; 11:127-30. 12. Camus P, Kudoh S, Ebina M. Interstitial lung disease associated with drug therapy. Br J Cancer 2004; 91(suppl 2):S18-S23. 13. Endo M, Johkoh T, Kimura K, et al. Imaging of gefitinib-related interstitial lung disease: Multi-institutional analysis by the West Japan Thoracic Oncology Group. Lung Cancer 2006; 52:135-40. 14. Higenbottom T, Kuwano K, Nemery B et al. Understanding the mechanisms of drug-associated interstitial lung disease. Br J Cancer 2004; 91(suppl 2):S31-S37. 15. Selman M, King TE, Pardo A. Idiopathic pulmonary fibrosis: prevaling and evolving hypotheses about its pathogenesis and implications for therapy. Ann Intern Med 2001; 134:136-51. 16. Suzuki H, Aoshiba K, Yokohari N, et al. Epidermal growth factor tyrosine kinase inhibition augments a murine model of pulmonary fibrosis. Cancer Res 2003; 63:5054-9. 17. Ishii Y, Fujimoto S, Fukuda T. Gefitinib prevents bleomycin-induced lung fibrosis in mice. Am J Respir Crit Care Med 2006; 174:550-6. 18. Rice AB, Moomaw CR, Morgan DL, et al. Specific inhibitors of platelet-derived growth factor or epidermal growth factor receptor tyrosine kinase reduce pulmonary fibrosis in rats. Am J Pathol 1999; 155:213-21. 19. Saijo A, Maemondo M, Gomi K, et al. Severe acute interstitial pneumonia and gefitinib. Lancet 2003; 361:137-9. 20. Nagaria NC, Cogswell J, Choe JK, et al. Side effects and good effects from new chemotherapeutic agents. Case 1. Gefitinib-induced interstitial fibrosis. J Clin Oncol 2005; 23:2423-4. 21. Kitajima H, Takahasho H, Harada K, et al. Gefitinib-induced interstitial lung disease showing improvement after cessation: disassociation of serum markers. Respirology 2006; 11:217-20. 22. Kataoka K, Taniguchi H, Hasegawa Y, et al. Interstitial lung disease associated with gefitinib. Respir Med 2006; 100:698-704.