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Unusal lung damage associated with pemetrexed in malignant pleural mesothelioma: A case report
Respiratory Medicine CME (2008) 1, 267e269
CASE REPORT
Unusal lung damage associated with pemetrexed in malignant pleural mesothelioma: A case report Giovenzio Genestreti a, Noemi Giovannini a, Dino Amadori a, Gian Luca Casoni b, Venerino Poletti b,* a b
Department of Oncology, Cancer Research Institute of Romagna (I.R.S.T.), Italy Thoracic Department, Morgagni-Pierantoni Hospital, Forlı`, Italy
Received 6 May 2008; accepted 1 July 2008
KEYWORDS Lung damage; Pemetrexed; Malignant pleural mesothelioma
Summary A 64-year-old male was diagnosed with malignant pleural mesothelioma (MPM) in June 2006 after complaining of dyspnoea and a persistent cough. In July 2006 the patient underwent talc pleurodesis and started first-line chemotherapy with cisplatin associated with pemetrexed (Alimta). At the end of the third chemotherapy cycle the disease was stable and no significant drug toxicity was recorded. The patient progressed through another three cycles under the same treatment schedule. Restaging at the end of the sixth cycle confirmed a stable disease and the patient started follow-up. In January 2007, further restaging showed disease progression and the patient was enrolled in a phase I clinical trial involving a continuous infusion of pemetrexed until at a dose of 100 mg m2 at day one. After 8 days the patient was referred to the Accident and Emergency Department for acute dyspnoea and a fever of 38.5 C. A high resolution CT-scan of the thorax showed diffuse, bilateral areas of ground glass attenuation with a patchy distribution. A 13-day broad-spectrum antibiotic therapy did not achieve any clinical and/or radiological improvement of respiratory abnormalities, and for this reason a bronchoscopy, with a fluoroscopic-guided transbronchial lung biopsy (TBB), and a bronchoalveolar lavage (BAL), were performed. BAL cultures for common bacteria, acid fast bacilli and fungi, as well as vial cultures and/or immunofluorescent tests for viruses (cytomegalovirus, adenovirus, herpes simplex virus, syncytial respiratory virus, influenzae and parainfluenzae viruses) and Legionellae, proved negative. Examination of BAL cytospin preparations, stained by both Diff-Quick and Papanicolaou methods, showed cuboidal hyperplastic/dysplastic cells (diffuse alveolar damage cells) whilst no malignant cells, viral inclusions, fungi, or Pneumocystis jiroveci cysts were identified. The TBB showed remnants of jaline membranes in the alveolar spaces along with granulation tissue partly obliterating the alveolar spaces, and slight
* Corresponding author. Department of Respiratory Diseases, Morgagni-Pierantoni Hospital, Via Forlanini 10, 47900 Forlı` (FC), Italy. Tel.: þ39 0543 735042; fax: þ39 0543 735039. E-mail addresses: [email protected], [email protected] (V. Poletti). 1755-0017/$34 ª 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.rmedc.2008.07.007
268
G. Genestreti et al. thickening of the interalveolar septa. Plump elongated reactive type II pneumocytes covering the alveolar septa were also numerous. A regimen of 200 mg methylprednisolone once a day was started and a partial remission of clinical and radiological abnormalities was achieved. Based on our clinical and radiological findings we therefore conclude a possible diagnosis of drug-induced toxicity by pemetrexed chemotherapy in continuous infusion. ª 2008 Elsevier Ltd. All rights reserved.
Case report A 64-year-old male was diagnosed with malignant pleural mesothelioma (MPM) in June 2006 after complaining of dyspnoea and a persistent cough. A chest X-ray showed right pleural effusion and a further series of exams, including high resolution computed tomography (HRCT), confirmed a biphasic MPM. The patient had a known history of hypertension, diabetes, abdominal aortic aneurism, and exposure to asbestos. In July 2006 the patient underwent talc pleurodesis and started first-line chemotherapy with cisplatin associated with pemetrexed (Alimta). At the end of the third chemotherapy cycle the disease was stable and no significant drug toxicity was recorded. For this reason, the patient progressed through another three cycles under the same treatment schedule. Restaging at the end of the sixth cycle confirmed a stable disease and the patient started follow-up. In January 2007, further restaging showed disease progression and the patient was enrolled in a phase I clinical trial involving a continuous infusion of pemetrexed at a dose of 100 mg m2 at day 1, every three weeks. Vitamin B6 and B12 supplements together with a premedication of prednisone were also included in the protocol to reduce the toxicity. The first cycle, performed on 13 February, 2007 at a dose of 150 mg (75% of the real dose), and the second cycle, carried out on 6 March, 2007 at the full dose (200 mg), did not induce any acute toxicity. On 14 March 2007 the patient was referred to the Accident and Emergency Department for acute dyspnoea and a fever of 38.5 C. On admission, a blood pressure of 140/90, a heart rate of 92 min1, and a SO2 of 78% were recorded, and a left anterior hemiblock was diagnosed by ECG. Laboratory exams revealed the following: leukocytes 2.89 106/mmc, neutrophils 1.04 106/mmc, platelets 1.01 105/mmc, haemoglobin 9.0 g/dl, glucose 139 mg/dl, creatinine 1.5 mg/dl, LDH 855 U/l, fibrinogen 630 mg/dl, and no pathogens were found in the peripheral blood haemoculture. A high resolution CT-scan of the thorax showed diffuse, bilateral areas of ground glass attenuation with a patchy distribution (Fig. 1). A 13-day broad-spectrum antibiotic therapy did not achieve any clinical and/or radiological improvement of respiratory abnormalities, and for this reason a bronchoscopy, with a fluoroscopic-guided transbronchial lung biopsy (TBB), and a bronchoalveolar lavage (BAL), were performed. BAL fluid analysis demonstrated 410 cells/mL3 with 52% macrophages, 12% lymphocytes, 35% neutrophils, 1% eosinophils and a reverse CD4/CD8 ratio (1:2). BAL cultures for common bacteria, acid fast bacilli and fungi, as well as vial cultures and/or immunofluorescent tests for viruses
(cytomegalovirus, adenovirus, herpes simplex virus, syncytial respiratory virus, influenzae and parainfluenzae viruses) and Legionellae, proved negative. Examination of BAL cytospin preparations, stained by both Diff-Quick and Papanicolaou methods, showed cuboidal hyperplastic/ dysplastic cells (diffuse alveolar damage cells) whilst no malignant cells, viral inclusions, fungi, or Pneumocystis jiroveci cysts were identified. The TBB showed remnants of jaline membranes in the alveolar spaces along with granulation tissue partly obliterating the alveolar spaces, and slight thickening of the interalveolar septa. Plump elongated reactive type II pneumocytes covering the alveolar septa were also numerous (Fig. 2). A regimen of 200 mg methylprednisolone once a day was started and a partial remission of clinical and radiological abnormalities was achieved. However the patient died after six months for progression of neoplastic disease. Pemetrexed is a multi-target folate inhibitor for the second-line treatment of non-small cell lung cancer (NSCLC),1 and MPM in combination or not with cisplatin.2,3 Neutropenia is the only common side effect of this welltolerated drug. Indeed, to the best of our knowledge, this is the first report of an adverse pulmonary reaction to be associated with this drug. Based on our clinical and radiological findings, the differential diagnosis of the
Figure 1 High resolution CT-scan of the thorax: diffuse, bilateral areas of ground glass attenuation with a patchy distribution.
Lung damage by pemetrexed in malignant pleural mesothelioma
269
spectrum antibiotics had failed to show any noticeable improvement. Based on these observations we therefore conclude that pemetrexed chemotherapy in continuous infusion may cause acute lung toxicity.
Conflict of interest statement The authors have no potential conflicts of interest.
Acknowledgements This report was supported by the GIPO (Gruppo Interdisciplinare di Pneumo-Oncologia). The Authors would also like to thank Dr. Ian Seymour for help with editing the manuscript. Figure 2 Histologic finding of TBB: remnants of jaline membranes in the alveolar spaces along with granulation tissue partly obliterating the alveolar spaces, and slight thickening of the interalveolar septa. Plump elongated reactive type II pneumocytes covering the alveolar septa were also numerous.
pulmonary changes could be narrowed down to a few pathologic conditions, i.e.: infections, malignancies, pulmonary alveolar haemorrhage, or drug-induced toxicity. An infectious aetiology was ruled out by extensive microbiological studies. The hypothesis of malignancies, either primary lung cancer (i.e. bronchioloalveolar carcinoma, and mucosa-associated lymphoid tissue (MALT) lymphoma), or metastatic mesothelioma involvement of the lung parenchyma was easily excluded by examining the lung biopsy.4e6 Furthermore, BAL and lung biopsy findings did not support the diagnosis of pulmonary alveolar haemorrhage. Together with the careful exclusion of these possible causes, several elements led to the suspicion that the lung damage was caused by drug-induced toxicity. Firstly, both cytological (BAL) and histological pulmonary findings, although not specific, appear to support the diagnosis of drug-induced toxicity.7 Secondly, for the prescription of corticosteroids, which achieved a progressive remission of clinico-radiological respiratory abnormalities after broad-
References 1. Hanna N, Shepherd FA, Fossella FV, Pereira JR, De Marinis F, Von Pawel J, et al. Randomized phase III trial of pemetrexed versus docetaxel in patients with non-small-cell lung cancer previously treated with chemotherapy. J Clin Oncol 2004;22:1589e97. 2. Vogelzang NJ, Rusthoven JJ, Symanowski J, Denham C, Kaukel E, Ruffie P, et al. Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma. J Clin Oncol 2003;21:2636e44. 3. Janne PA, Wozniak AJ, Belani CP, Keohan ML, Ross HJ, Polikoff JA, et al. Pemetrexed alone or in combination with cisplatin in previously treated malignant pleural mesothelioma: outcomes from a phase IIIB expanded access program. J Thorac Oncol 2006;1:506e12. 4. Lee KS, Kim Y, Han J, Ko EJ, Park CK, Primack SL. Bronchioloalveolar carcinoma: clinical, histopathologic, and radiologic findings. Radiographics 1997;17:1345e57. 5. McCulloch GL, Sinnatamby R, Stewart S, Goddard M, Flower CD. High-resolution computed tomographic appearance of MALToma of the lung. Eur Radiol 1998;8:1669e73. 6. Nagakawa T. CT of metastatic pulmonary tumors: morphology. HRCT and histological correlation. Nippon Igaku Gakka Zasshi 1996;56:1032e8. 7. Myers J. Pathology of drug-induced lung disease. In: Kazenstein ALA, editor. Katzenstein and Askin’s surgical pathology of non-neoplastic lung disease. Philadelphia: WB Saunders; 1997. p. 81e111.
CASE REPORT
Unusal lung damage associated with pemetrexed in malignant pleural mesothelioma: A case report Giovenzio Genestreti a, Noemi Giovannini a, Dino Amadori a, Gian Luca Casoni b, Venerino Poletti b,* a b
Department of Oncology, Cancer Research Institute of Romagna (I.R.S.T.), Italy Thoracic Department, Morgagni-Pierantoni Hospital, Forlı`, Italy
Received 6 May 2008; accepted 1 July 2008
KEYWORDS Lung damage; Pemetrexed; Malignant pleural mesothelioma
Summary A 64-year-old male was diagnosed with malignant pleural mesothelioma (MPM) in June 2006 after complaining of dyspnoea and a persistent cough. In July 2006 the patient underwent talc pleurodesis and started first-line chemotherapy with cisplatin associated with pemetrexed (Alimta). At the end of the third chemotherapy cycle the disease was stable and no significant drug toxicity was recorded. The patient progressed through another three cycles under the same treatment schedule. Restaging at the end of the sixth cycle confirmed a stable disease and the patient started follow-up. In January 2007, further restaging showed disease progression and the patient was enrolled in a phase I clinical trial involving a continuous infusion of pemetrexed until at a dose of 100 mg m2 at day one. After 8 days the patient was referred to the Accident and Emergency Department for acute dyspnoea and a fever of 38.5 C. A high resolution CT-scan of the thorax showed diffuse, bilateral areas of ground glass attenuation with a patchy distribution. A 13-day broad-spectrum antibiotic therapy did not achieve any clinical and/or radiological improvement of respiratory abnormalities, and for this reason a bronchoscopy, with a fluoroscopic-guided transbronchial lung biopsy (TBB), and a bronchoalveolar lavage (BAL), were performed. BAL cultures for common bacteria, acid fast bacilli and fungi, as well as vial cultures and/or immunofluorescent tests for viruses (cytomegalovirus, adenovirus, herpes simplex virus, syncytial respiratory virus, influenzae and parainfluenzae viruses) and Legionellae, proved negative. Examination of BAL cytospin preparations, stained by both Diff-Quick and Papanicolaou methods, showed cuboidal hyperplastic/dysplastic cells (diffuse alveolar damage cells) whilst no malignant cells, viral inclusions, fungi, or Pneumocystis jiroveci cysts were identified. The TBB showed remnants of jaline membranes in the alveolar spaces along with granulation tissue partly obliterating the alveolar spaces, and slight
* Corresponding author. Department of Respiratory Diseases, Morgagni-Pierantoni Hospital, Via Forlanini 10, 47900 Forlı` (FC), Italy. Tel.: þ39 0543 735042; fax: þ39 0543 735039. E-mail addresses: [email protected], [email protected] (V. Poletti). 1755-0017/$34 ª 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.rmedc.2008.07.007
268
G. Genestreti et al. thickening of the interalveolar septa. Plump elongated reactive type II pneumocytes covering the alveolar septa were also numerous. A regimen of 200 mg methylprednisolone once a day was started and a partial remission of clinical and radiological abnormalities was achieved. Based on our clinical and radiological findings we therefore conclude a possible diagnosis of drug-induced toxicity by pemetrexed chemotherapy in continuous infusion. ª 2008 Elsevier Ltd. All rights reserved.
Case report A 64-year-old male was diagnosed with malignant pleural mesothelioma (MPM) in June 2006 after complaining of dyspnoea and a persistent cough. A chest X-ray showed right pleural effusion and a further series of exams, including high resolution computed tomography (HRCT), confirmed a biphasic MPM. The patient had a known history of hypertension, diabetes, abdominal aortic aneurism, and exposure to asbestos. In July 2006 the patient underwent talc pleurodesis and started first-line chemotherapy with cisplatin associated with pemetrexed (Alimta). At the end of the third chemotherapy cycle the disease was stable and no significant drug toxicity was recorded. For this reason, the patient progressed through another three cycles under the same treatment schedule. Restaging at the end of the sixth cycle confirmed a stable disease and the patient started follow-up. In January 2007, further restaging showed disease progression and the patient was enrolled in a phase I clinical trial involving a continuous infusion of pemetrexed at a dose of 100 mg m2 at day 1, every three weeks. Vitamin B6 and B12 supplements together with a premedication of prednisone were also included in the protocol to reduce the toxicity. The first cycle, performed on 13 February, 2007 at a dose of 150 mg (75% of the real dose), and the second cycle, carried out on 6 March, 2007 at the full dose (200 mg), did not induce any acute toxicity. On 14 March 2007 the patient was referred to the Accident and Emergency Department for acute dyspnoea and a fever of 38.5 C. On admission, a blood pressure of 140/90, a heart rate of 92 min1, and a SO2 of 78% were recorded, and a left anterior hemiblock was diagnosed by ECG. Laboratory exams revealed the following: leukocytes 2.89 106/mmc, neutrophils 1.04 106/mmc, platelets 1.01 105/mmc, haemoglobin 9.0 g/dl, glucose 139 mg/dl, creatinine 1.5 mg/dl, LDH 855 U/l, fibrinogen 630 mg/dl, and no pathogens were found in the peripheral blood haemoculture. A high resolution CT-scan of the thorax showed diffuse, bilateral areas of ground glass attenuation with a patchy distribution (Fig. 1). A 13-day broad-spectrum antibiotic therapy did not achieve any clinical and/or radiological improvement of respiratory abnormalities, and for this reason a bronchoscopy, with a fluoroscopic-guided transbronchial lung biopsy (TBB), and a bronchoalveolar lavage (BAL), were performed. BAL fluid analysis demonstrated 410 cells/mL3 with 52% macrophages, 12% lymphocytes, 35% neutrophils, 1% eosinophils and a reverse CD4/CD8 ratio (1:2). BAL cultures for common bacteria, acid fast bacilli and fungi, as well as vial cultures and/or immunofluorescent tests for viruses
(cytomegalovirus, adenovirus, herpes simplex virus, syncytial respiratory virus, influenzae and parainfluenzae viruses) and Legionellae, proved negative. Examination of BAL cytospin preparations, stained by both Diff-Quick and Papanicolaou methods, showed cuboidal hyperplastic/ dysplastic cells (diffuse alveolar damage cells) whilst no malignant cells, viral inclusions, fungi, or Pneumocystis jiroveci cysts were identified. The TBB showed remnants of jaline membranes in the alveolar spaces along with granulation tissue partly obliterating the alveolar spaces, and slight thickening of the interalveolar septa. Plump elongated reactive type II pneumocytes covering the alveolar septa were also numerous (Fig. 2). A regimen of 200 mg methylprednisolone once a day was started and a partial remission of clinical and radiological abnormalities was achieved. However the patient died after six months for progression of neoplastic disease. Pemetrexed is a multi-target folate inhibitor for the second-line treatment of non-small cell lung cancer (NSCLC),1 and MPM in combination or not with cisplatin.2,3 Neutropenia is the only common side effect of this welltolerated drug. Indeed, to the best of our knowledge, this is the first report of an adverse pulmonary reaction to be associated with this drug. Based on our clinical and radiological findings, the differential diagnosis of the
Figure 1 High resolution CT-scan of the thorax: diffuse, bilateral areas of ground glass attenuation with a patchy distribution.
Lung damage by pemetrexed in malignant pleural mesothelioma
269
spectrum antibiotics had failed to show any noticeable improvement. Based on these observations we therefore conclude that pemetrexed chemotherapy in continuous infusion may cause acute lung toxicity.
Conflict of interest statement The authors have no potential conflicts of interest.
Acknowledgements This report was supported by the GIPO (Gruppo Interdisciplinare di Pneumo-Oncologia). The Authors would also like to thank Dr. Ian Seymour for help with editing the manuscript. Figure 2 Histologic finding of TBB: remnants of jaline membranes in the alveolar spaces along with granulation tissue partly obliterating the alveolar spaces, and slight thickening of the interalveolar septa. Plump elongated reactive type II pneumocytes covering the alveolar septa were also numerous.
pulmonary changes could be narrowed down to a few pathologic conditions, i.e.: infections, malignancies, pulmonary alveolar haemorrhage, or drug-induced toxicity. An infectious aetiology was ruled out by extensive microbiological studies. The hypothesis of malignancies, either primary lung cancer (i.e. bronchioloalveolar carcinoma, and mucosa-associated lymphoid tissue (MALT) lymphoma), or metastatic mesothelioma involvement of the lung parenchyma was easily excluded by examining the lung biopsy.4e6 Furthermore, BAL and lung biopsy findings did not support the diagnosis of pulmonary alveolar haemorrhage. Together with the careful exclusion of these possible causes, several elements led to the suspicion that the lung damage was caused by drug-induced toxicity. Firstly, both cytological (BAL) and histological pulmonary findings, although not specific, appear to support the diagnosis of drug-induced toxicity.7 Secondly, for the prescription of corticosteroids, which achieved a progressive remission of clinico-radiological respiratory abnormalities after broad-
References 1. Hanna N, Shepherd FA, Fossella FV, Pereira JR, De Marinis F, Von Pawel J, et al. Randomized phase III trial of pemetrexed versus docetaxel in patients with non-small-cell lung cancer previously treated with chemotherapy. J Clin Oncol 2004;22:1589e97. 2. Vogelzang NJ, Rusthoven JJ, Symanowski J, Denham C, Kaukel E, Ruffie P, et al. Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma. J Clin Oncol 2003;21:2636e44. 3. Janne PA, Wozniak AJ, Belani CP, Keohan ML, Ross HJ, Polikoff JA, et al. Pemetrexed alone or in combination with cisplatin in previously treated malignant pleural mesothelioma: outcomes from a phase IIIB expanded access program. J Thorac Oncol 2006;1:506e12. 4. Lee KS, Kim Y, Han J, Ko EJ, Park CK, Primack SL. Bronchioloalveolar carcinoma: clinical, histopathologic, and radiologic findings. Radiographics 1997;17:1345e57. 5. McCulloch GL, Sinnatamby R, Stewart S, Goddard M, Flower CD. High-resolution computed tomographic appearance of MALToma of the lung. Eur Radiol 1998;8:1669e73. 6. Nagakawa T. CT of metastatic pulmonary tumors: morphology. HRCT and histological correlation. Nippon Igaku Gakka Zasshi 1996;56:1032e8. 7. Myers J. Pathology of drug-induced lung disease. In: Kazenstein ALA, editor. Katzenstein and Askin’s surgical pathology of non-neoplastic lung disease. Philadelphia: WB Saunders; 1997. p. 81e111.