Published Ahead of Print on May 5, 2014 as 10.1200/JCO.2013.51.6930 The latest version is at http://jco.ascopubs.org/cgi/doi/10.1200/JCO.2013.51.6930
JOURNAL OF CLINICAL ONCOLOGY
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duration. She also had mild fatigue, 10-lb involuntary weight loss, and new hypoxemia that required the use of supplemental oxygen at night. On examination, she appeared well and her lungs were clear to auscultation. An initial computed tomography (CT) scan of the chest revealed a dominant 1.3 ⫻ 2.1– cm mixed solid and ground glass, spiculated mass in the right lower lobe (RLL) and bilateral nodular ground glass lesions with extensive septal thickening involving both lower lobes and the anterior aspects of both upper lobes (Figs 1A, 1C, and 1E). A positron emission tomography (PET)/CT scan confirmed
Downstaging of Non–Small-Cell Lung Cancer Through Identification of Reversible Drug Toxicity Case Report A 62-year-old woman, a former light smoker (⬍ 20 pack-year history; she had quit smoking 23 years before), presented with complaints of productive cough and dyspnea on exertion of 2-month
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E
F
Fig 1. Journal of Clinical Oncology, Vol 32, 2014
© 2014 by American Society of Clinical Oncology
Downloaded from jco.ascopubs.org on November 14, 2015. For personal use only. No other uses without permission. Copyright © 2014 American Society of Clinical Oncology. All rights reserved.
Copyright 2014 by American Society of Clinical Oncology
1
Browning et al
However, the superimposed finding of ground glass and nodular parenchymal abnormality in a bronchovascular and peripheral distribution with perilobular septal thickening was markedly reduced after discontinuing nitrofurantoin (Figs 1C to 1F; white arrows in Figs 1C and 1E). The patient reported significant improvement in her symptoms of dyspnea, cough, and fatigue after cessation of nitrofurantoin. Over the same time period, the elevated aminotransferase also significantly improved, with values just above the upper limit of normal. Because of the near resolution of the bilateral lung abnormalities, with the exception of the known RLL adenocarcinoma, clinical staging was revised from stage IV to stage I. The patient then underwent video-assisted thoracoscopic right lower lobectomy and mediastinal lymph node dissection. A 1.9-cm, invasive, well-differentiated adenocarcinoma with stromal response was confirmed (Fig 2A). Mediastinal and hilar lymph nodes were negative for malignancy, resulting in a pathologic staging of pT1a pN0 (stage IA). Pathologic examination of the resection specimen was also notable for the presence of patchy interstitial pneumonitis that was consistent with nitrofurantoin lung injury. A low-magnification image shows nitrofurantoin injury characterized by broad alveolar damage (Fig 2B). Higher magnification shows alveolar wall damage with loss of pneumocytes and exudate-associated alveolar wall damage (Fig 2C), and an area of exudate with fibroblast ingrowth that is indicative of injury (Fig 2D, black arrow).
the RLL mass with a standardized uptake value of 3.5. In addition, there were multiple other ground glass nodules in both lungs, including a 9 ⫻ 10 –mm nodule in the RLL (standardized uptake value, 1.5) and multiple smaller ground glass nodules in the left lower lobe, the largest measuring 7 ⫻ 7 mm, which were too small to evaluate on the PET portion of the study. There was also extensive nonhypermetabolic interstitial infiltrate in both lower lobes and the anterior aspects of both upper lobes. No disease outside of the chest was noted. Biopsy of the dominant RLL lesion revealed a thyroid transcription factor-1 positive, moderately differentiated adenocarcinoma consistent with a lung primary. The presence of bilateral spiculated and mixed density lung nodules, similar in morphology to the biopsy-proven RLL lesion, suggested a diagnosis of stage IV non–small-cell lung cancer. Past medical history was notable for recurrent urinary tract infections, for which the patient had been taking nitrofurantoin prophylaxis for 6 months at a dose of 100 mg per day. Laboratory evaluation revealed markedly elevated aminotransferases, with AST of 268 and ALT of 419, despite the absence of metastatic involvement of the liver on the staging investigations. Bilirubin was normal. Because of concerns about possible combined pulmonary and hepatic nitrofurantoin toxicity, it was recommended that the patient stop taking the prophylactic nitrofurantoin. A second biopsy of the RLL lung mass was performed to obtain additional tissue for molecular analysis. This biopsy again showed adenocarcinoma. The patient’s tumor was wild type for epidermal growth factor receptor, anaplastic lymphoma kinase, and KRAS. CT scanning of the chest was performed 3 weeks after the discontinuation of nitrofurantoin (Figs 1B, 1D, and 1F). The biopsy-proven RLL adenocarcinoma appeared stable (Figs 1A and 1B, black arrows).
Discussion Nitrofurantoin or trimethoprim/sulfamethoxazole is the recommended first-line treatment for uncomplicated cystitis, per the Infectious Disease Society of America 2010 clinical practice guidelines.1,2
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Fig 2. 2
© 2014 by American Society of Clinical Oncology
JOURNAL OF CLINICAL ONCOLOGY
Downloaded from jco.ascopubs.org on November 14, 2015. For personal use only. No other uses without permission. Copyright © 2014 American Society of Clinical Oncology. All rights reserved.
Diagnosis in Oncology
Nitrofurantoin is the third most commonly prescribed class of antibiotic for women with urinary tract infection, after quinolones and sulfa.3 For treatment of recurrent cystitis despite behavioral modifications, nitrofurantoin prophylaxis prescribed at a dose of 50 to 100 mg per day can reduce the risk of recurrent cystitis by 95%.1 Our patient experienced reversible pulmonary and hepatic toxicity as a result of nitrofurantoin, with probable causal association on the basis of the Naranjo probability scale.4 This toxicity, although rare, has been well described. The incidence of pulmonary toxicity is estimated to be between 0.0001% and 0.001%.5,6 In a review of 921 adverse reactions to nitrofurantoin in a Swedish registry, 48% of reactions were pulmonary, 42% allergic, 6% hepatic, and 11 patient cases were fatal.7 Pulmonary injury can be either acute or chronic, with acute reaction much more common than chronic.8 Acute pulmonary reactions to nitrofurantoin occur within weeks of initiating treatment, with the first symptoms presenting after a median of 7 days. The onset of chronic reactions occurs months after starting treatment, with a median of 17 months.8 Presenting symptoms of chronic nitrofurantoin pulmonary toxicity include gradual onset of dyspnea, cough, fatigue, and weight loss, all of which our patient experienced. In contrast, patients with acute pulmonary toxicity more commonly report fever and rash in addition to dyspnea and cough, with a sudden onset of symptoms.8 Lung infiltrates are seen on chest x-ray in 94% of patients with chronic nitrofurantoin toxicity.8 Nitrofurantoin lung toxicity can present with either a diffuse or basally predominant interstitial pattern, or less commonly, as a focal organizing pneumonia.9 Our patient had both basally predominant interstitial disease as well as likely areas of organizing pneumonia in the areas of nodularity that resolved after cessation of nitrofurantoin. Various findings of nitrofurantoin pulmonary toxicity have been described on CT, including bilateral ground glass attenuation, irregular linear opacities, consolidation, and fibrosis.10,11 Laboratory abnormalities that are commonly associated with chronic nitrofurantoin lung toxicity include eosinophilia, elevated aminotransferases, elevated lactate dehydrogenase, and elevated serum gamma globulin. Our patient did not have eosinophilia at diagnosis, but she had elevated aminotransferases. Lactate dehydrogenase and protein electrophoresis were not obtained. Treatment involves the cessation of nitrofurantoin, and in some cases, treatment with corticosteroids.10 Prompt recognition of drug toxicity had a dramatic impact on our patient’s care and allowed her to undergo curative-intent surgery for her lung cancer. The diagnosis of chronic nitrofurantoin pulmonary toxicity can be challenging because of the gradual onset of nonspecific respiratory symptoms. Although subsolid nodules are characteristic of adenocarcinoma, ground glass opacities have a broad differential diagnosis, and when multifocal and bilateral, consideration should be given to alternate or superimposed systemic or inflammatory processes such as drug toxicity, cryptogenic organizing pneumonia, or atypical infection. Other nononcologic drugs that are known to cause similar pul-
monary toxicity include amiodarone and gold salts.12,13 In terms of oncologic drugs, the cytotoxic agents busulfan, bleomycin, and methotrexate can also present with interstitial pneumonitis, fibrosis, or organizing pneumonia.9,12,14 The possibility of drug toxicity should be considered in any patient presenting with dyspnea while receiving nitrofurantoin or other drugs that are known to cause similar pulmonary toxicity, including in patients with a known cancer diagnosis.
Eiko Theodora Browning, Jason Michael Huckleberry, Willis Bon Barrow, and Nicole Lynn Restauri University of Colorado Denver, Aurora, CO
Douglas Jerome Kemme University of Colorado Health, Greeley, CO
Carlyne Debra Cool, Michael John Weyant, Wilbur A. Franklin, and D. Ross Camidge University of Colorado Denver, Aurora, CO
AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
The author(s) indicated no potential conflicts of interest. REFERENCES 1. Hooton TM: Clinical practice: Uncomplicated urinary tract infection. N Engl J Med 366:1028-1037, 2012 2. Gupta K, Hooton TM, Naber KG, et al: International clinical practice guidelines for the treatment of acute uncomplicated cystitis and pyelonephritis in women: A 2010 update by the Infectious Diseases Society of America and the European Society for Microbiology and Infectious Diseases. Clin Infect Dis 52:e103-e120, 2011 3. Kallen AJ, Welch HG, Sirovich BE: Current antibiotic therapy for isolated urinary tract infections in women. Arch Intern Med 166:635-639, 2006 4. Naranjo CA, Busto U, Sellers EM, et al: A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther 30:239-245, 1981 5. Cetti RJ, Venn S, Woodhouse CR: The risks of long-term nitrofurantoin prophylaxis in patients with recurrent urinary tract infection: A recent medicolegal case. BJU Int 103:567-569, 2009 6. Yalc¸in S, Sahin A, Yalc¸in B, et al: Nitrofurantoin toxicity to both liver and lungs. Liver 17:166-167, 1997 7. Holmberg L, Boman G, Bo¨ttiger LE, et al: Adverse reactions to nitrofurantoin: Analysis of 921 reports. Am J Med 69:733-738, 1980 8. Holmberg L, Boman G: Pulmonary reactions to nitrofurantoin: 447 cases reported to the Swedish Adverse Drug Reaction Committee 1966-1976. Eur J Respir Dis 62:180-189, 1981 9. Armstrong P, Wilson AG, Dee P, et al: Imaging of Diseases of the Chest (ed 3). London, United Kingdom, Mosby, 2000, pp 513-515 10. Mendez JL, Nadrous HF, Hartman TE, et al: Chronic nitrofurantoin-induced lung disease. Mayo Clin Proc 80:1298-1302, 2005 11. Padley SP, Adler B, Hansell DM, et al: High resolution computed tomography of drug-induced lung disease. Clin Radiol 46:232-236, 1992 12. Albert RK, Spiro SG, Jett JR: Clinical Respiratory Medicine (ed 2). St Louis, MO, Mosby, 2004, p 825-827 13. Cooper JA Jr, White DA, Matthay RA: Drug-induced pulmonary disease. Part 2: Noncytotoxic drugs. Am Rev Respir Dis 133:488-505, 1986 14. Cooper JA Jr, White DA, Matthay RA: Drug-induced pulmonary disease. Part 1: Cytotoxic drugs. Am Rev Respir Dis 133:321-340, 1986
DOI: 10.1200/JCO.2013.51.6930; published online ahead of print at www.jco.org on May 5, 2014
■ ■ ■
www.jco.org
© 2014 by American Society of Clinical Oncology
Downloaded from jco.ascopubs.org on November 14, 2015. For personal use only. No other uses without permission. Copyright © 2014 American Society of Clinical Oncology. All rights reserved.
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JOURNAL OF CLINICAL ONCOLOGY
D I A G N O S I S
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O N C O L O G Y
duration. She also had mild fatigue, 10-lb involuntary weight loss, and new hypoxemia that required the use of supplemental oxygen at night. On examination, she appeared well and her lungs were clear to auscultation. An initial computed tomography (CT) scan of the chest revealed a dominant 1.3 ⫻ 2.1– cm mixed solid and ground glass, spiculated mass in the right lower lobe (RLL) and bilateral nodular ground glass lesions with extensive septal thickening involving both lower lobes and the anterior aspects of both upper lobes (Figs 1A, 1C, and 1E). A positron emission tomography (PET)/CT scan confirmed
Downstaging of Non–Small-Cell Lung Cancer Through Identification of Reversible Drug Toxicity Case Report A 62-year-old woman, a former light smoker (⬍ 20 pack-year history; she had quit smoking 23 years before), presented with complaints of productive cough and dyspnea on exertion of 2-month
A
B
C
D
E
F
Fig 1. Journal of Clinical Oncology, Vol 32, 2014
© 2014 by American Society of Clinical Oncology
Downloaded from jco.ascopubs.org on November 14, 2015. For personal use only. No other uses without permission. Copyright © 2014 American Society of Clinical Oncology. All rights reserved.
Copyright 2014 by American Society of Clinical Oncology
1
Browning et al
However, the superimposed finding of ground glass and nodular parenchymal abnormality in a bronchovascular and peripheral distribution with perilobular septal thickening was markedly reduced after discontinuing nitrofurantoin (Figs 1C to 1F; white arrows in Figs 1C and 1E). The patient reported significant improvement in her symptoms of dyspnea, cough, and fatigue after cessation of nitrofurantoin. Over the same time period, the elevated aminotransferase also significantly improved, with values just above the upper limit of normal. Because of the near resolution of the bilateral lung abnormalities, with the exception of the known RLL adenocarcinoma, clinical staging was revised from stage IV to stage I. The patient then underwent video-assisted thoracoscopic right lower lobectomy and mediastinal lymph node dissection. A 1.9-cm, invasive, well-differentiated adenocarcinoma with stromal response was confirmed (Fig 2A). Mediastinal and hilar lymph nodes were negative for malignancy, resulting in a pathologic staging of pT1a pN0 (stage IA). Pathologic examination of the resection specimen was also notable for the presence of patchy interstitial pneumonitis that was consistent with nitrofurantoin lung injury. A low-magnification image shows nitrofurantoin injury characterized by broad alveolar damage (Fig 2B). Higher magnification shows alveolar wall damage with loss of pneumocytes and exudate-associated alveolar wall damage (Fig 2C), and an area of exudate with fibroblast ingrowth that is indicative of injury (Fig 2D, black arrow).
the RLL mass with a standardized uptake value of 3.5. In addition, there were multiple other ground glass nodules in both lungs, including a 9 ⫻ 10 –mm nodule in the RLL (standardized uptake value, 1.5) and multiple smaller ground glass nodules in the left lower lobe, the largest measuring 7 ⫻ 7 mm, which were too small to evaluate on the PET portion of the study. There was also extensive nonhypermetabolic interstitial infiltrate in both lower lobes and the anterior aspects of both upper lobes. No disease outside of the chest was noted. Biopsy of the dominant RLL lesion revealed a thyroid transcription factor-1 positive, moderately differentiated adenocarcinoma consistent with a lung primary. The presence of bilateral spiculated and mixed density lung nodules, similar in morphology to the biopsy-proven RLL lesion, suggested a diagnosis of stage IV non–small-cell lung cancer. Past medical history was notable for recurrent urinary tract infections, for which the patient had been taking nitrofurantoin prophylaxis for 6 months at a dose of 100 mg per day. Laboratory evaluation revealed markedly elevated aminotransferases, with AST of 268 and ALT of 419, despite the absence of metastatic involvement of the liver on the staging investigations. Bilirubin was normal. Because of concerns about possible combined pulmonary and hepatic nitrofurantoin toxicity, it was recommended that the patient stop taking the prophylactic nitrofurantoin. A second biopsy of the RLL lung mass was performed to obtain additional tissue for molecular analysis. This biopsy again showed adenocarcinoma. The patient’s tumor was wild type for epidermal growth factor receptor, anaplastic lymphoma kinase, and KRAS. CT scanning of the chest was performed 3 weeks after the discontinuation of nitrofurantoin (Figs 1B, 1D, and 1F). The biopsy-proven RLL adenocarcinoma appeared stable (Figs 1A and 1B, black arrows).
Discussion Nitrofurantoin or trimethoprim/sulfamethoxazole is the recommended first-line treatment for uncomplicated cystitis, per the Infectious Disease Society of America 2010 clinical practice guidelines.1,2
A
B
C
D
Fig 2. 2
© 2014 by American Society of Clinical Oncology
JOURNAL OF CLINICAL ONCOLOGY
Downloaded from jco.ascopubs.org on November 14, 2015. For personal use only. No other uses without permission. Copyright © 2014 American Society of Clinical Oncology. All rights reserved.
Diagnosis in Oncology
Nitrofurantoin is the third most commonly prescribed class of antibiotic for women with urinary tract infection, after quinolones and sulfa.3 For treatment of recurrent cystitis despite behavioral modifications, nitrofurantoin prophylaxis prescribed at a dose of 50 to 100 mg per day can reduce the risk of recurrent cystitis by 95%.1 Our patient experienced reversible pulmonary and hepatic toxicity as a result of nitrofurantoin, with probable causal association on the basis of the Naranjo probability scale.4 This toxicity, although rare, has been well described. The incidence of pulmonary toxicity is estimated to be between 0.0001% and 0.001%.5,6 In a review of 921 adverse reactions to nitrofurantoin in a Swedish registry, 48% of reactions were pulmonary, 42% allergic, 6% hepatic, and 11 patient cases were fatal.7 Pulmonary injury can be either acute or chronic, with acute reaction much more common than chronic.8 Acute pulmonary reactions to nitrofurantoin occur within weeks of initiating treatment, with the first symptoms presenting after a median of 7 days. The onset of chronic reactions occurs months after starting treatment, with a median of 17 months.8 Presenting symptoms of chronic nitrofurantoin pulmonary toxicity include gradual onset of dyspnea, cough, fatigue, and weight loss, all of which our patient experienced. In contrast, patients with acute pulmonary toxicity more commonly report fever and rash in addition to dyspnea and cough, with a sudden onset of symptoms.8 Lung infiltrates are seen on chest x-ray in 94% of patients with chronic nitrofurantoin toxicity.8 Nitrofurantoin lung toxicity can present with either a diffuse or basally predominant interstitial pattern, or less commonly, as a focal organizing pneumonia.9 Our patient had both basally predominant interstitial disease as well as likely areas of organizing pneumonia in the areas of nodularity that resolved after cessation of nitrofurantoin. Various findings of nitrofurantoin pulmonary toxicity have been described on CT, including bilateral ground glass attenuation, irregular linear opacities, consolidation, and fibrosis.10,11 Laboratory abnormalities that are commonly associated with chronic nitrofurantoin lung toxicity include eosinophilia, elevated aminotransferases, elevated lactate dehydrogenase, and elevated serum gamma globulin. Our patient did not have eosinophilia at diagnosis, but she had elevated aminotransferases. Lactate dehydrogenase and protein electrophoresis were not obtained. Treatment involves the cessation of nitrofurantoin, and in some cases, treatment with corticosteroids.10 Prompt recognition of drug toxicity had a dramatic impact on our patient’s care and allowed her to undergo curative-intent surgery for her lung cancer. The diagnosis of chronic nitrofurantoin pulmonary toxicity can be challenging because of the gradual onset of nonspecific respiratory symptoms. Although subsolid nodules are characteristic of adenocarcinoma, ground glass opacities have a broad differential diagnosis, and when multifocal and bilateral, consideration should be given to alternate or superimposed systemic or inflammatory processes such as drug toxicity, cryptogenic organizing pneumonia, or atypical infection. Other nononcologic drugs that are known to cause similar pul-
monary toxicity include amiodarone and gold salts.12,13 In terms of oncologic drugs, the cytotoxic agents busulfan, bleomycin, and methotrexate can also present with interstitial pneumonitis, fibrosis, or organizing pneumonia.9,12,14 The possibility of drug toxicity should be considered in any patient presenting with dyspnea while receiving nitrofurantoin or other drugs that are known to cause similar pulmonary toxicity, including in patients with a known cancer diagnosis.
Eiko Theodora Browning, Jason Michael Huckleberry, Willis Bon Barrow, and Nicole Lynn Restauri University of Colorado Denver, Aurora, CO
Douglas Jerome Kemme University of Colorado Health, Greeley, CO
Carlyne Debra Cool, Michael John Weyant, Wilbur A. Franklin, and D. Ross Camidge University of Colorado Denver, Aurora, CO
AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
The author(s) indicated no potential conflicts of interest. REFERENCES 1. Hooton TM: Clinical practice: Uncomplicated urinary tract infection. N Engl J Med 366:1028-1037, 2012 2. Gupta K, Hooton TM, Naber KG, et al: International clinical practice guidelines for the treatment of acute uncomplicated cystitis and pyelonephritis in women: A 2010 update by the Infectious Diseases Society of America and the European Society for Microbiology and Infectious Diseases. Clin Infect Dis 52:e103-e120, 2011 3. Kallen AJ, Welch HG, Sirovich BE: Current antibiotic therapy for isolated urinary tract infections in women. Arch Intern Med 166:635-639, 2006 4. Naranjo CA, Busto U, Sellers EM, et al: A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther 30:239-245, 1981 5. Cetti RJ, Venn S, Woodhouse CR: The risks of long-term nitrofurantoin prophylaxis in patients with recurrent urinary tract infection: A recent medicolegal case. BJU Int 103:567-569, 2009 6. Yalc¸in S, Sahin A, Yalc¸in B, et al: Nitrofurantoin toxicity to both liver and lungs. Liver 17:166-167, 1997 7. Holmberg L, Boman G, Bo¨ttiger LE, et al: Adverse reactions to nitrofurantoin: Analysis of 921 reports. Am J Med 69:733-738, 1980 8. Holmberg L, Boman G: Pulmonary reactions to nitrofurantoin: 447 cases reported to the Swedish Adverse Drug Reaction Committee 1966-1976. Eur J Respir Dis 62:180-189, 1981 9. Armstrong P, Wilson AG, Dee P, et al: Imaging of Diseases of the Chest (ed 3). London, United Kingdom, Mosby, 2000, pp 513-515 10. Mendez JL, Nadrous HF, Hartman TE, et al: Chronic nitrofurantoin-induced lung disease. Mayo Clin Proc 80:1298-1302, 2005 11. Padley SP, Adler B, Hansell DM, et al: High resolution computed tomography of drug-induced lung disease. Clin Radiol 46:232-236, 1992 12. Albert RK, Spiro SG, Jett JR: Clinical Respiratory Medicine (ed 2). St Louis, MO, Mosby, 2004, p 825-827 13. Cooper JA Jr, White DA, Matthay RA: Drug-induced pulmonary disease. Part 2: Noncytotoxic drugs. Am Rev Respir Dis 133:488-505, 1986 14. Cooper JA Jr, White DA, Matthay RA: Drug-induced pulmonary disease. Part 1: Cytotoxic drugs. Am Rev Respir Dis 133:321-340, 1986
DOI: 10.1200/JCO.2013.51.6930; published online ahead of print at www.jco.org on May 5, 2014
■ ■ ■
www.jco.org
© 2014 by American Society of Clinical Oncology
Downloaded from jco.ascopubs.org on November 14, 2015. For personal use only. No other uses without permission. Copyright © 2014 American Society of Clinical Oncology. All rights reserved.
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