Jpn J Clin Oncol 2014;44(5)497– 500 doi:10.1093/jjco/hyu023 Advance Access Publication 28 March 2014
Diffuse Alveolar Hemorrhage as a Fatal Adverse Effect of Bevacizumab: An Autopsy Case Satoshi Ikeda1,*, Akimasa Sekine1, Terufumi Kato1, Masahiro Yoshida1, Ryo Ogata1, Tomohisa Baba1, Kiyotaka Nagahama2, Koji Okudela2 and Takashi Ogura1 1
Department of Respiratory Medicine, Kanagawa Cardiovascular and Respiratory Center, Yokohama and 2Department of Pathology, Yokohama-city Graduate University School of Medicine, Yokohama, Japan
Received September 30, 2013; accepted February 18, 2014
A 71-year-old female with Stage IIIB primary adenocarcinoma was administered a three-drug combination therapy consisting of docetaxel, cisplatin and bevacizumab as a first-line treatment based on the Phase II clinical trial. On the 32nd day after the fourth course of chemotherapy, the patient developed bloody sputum. She was found dead at home on the 34th day. Autopsy revealed a diffuse alveolar hemorrhage without diffuse alveolar damage. Endothelial cells of the small arteries and capillaries were swollen and desquamated, indicating that alveolar capillaries were injured. The similar pathological changes in blood vessels were also observed in the kidney and the digestive tract. Because diffuse alveolar hemorrhage caused by cisplatin and docetaxel has never been reported apart from interstitial pneumonitis, bevacizumab is the most suspicious drug for diffuse alveolar hemorrhage in our case. Chest physicians and oncologists should be aware that although it is very rare, diffuse alveolar hemorrhage can develop during any course of chemotherapy with bevacizumab. Key words: bevacizumab – diffuse alveolar hemorrhage – adverse effect
CASE REPORT We present the case of a 71-year-old female with stage IIIB primary adenocarcinoma. Although she never smoked, she presented with hoarseness in her voice. Chest computed tomography showed a mass located in the left upper lobe, with metastasis to the left hilum, bilateral mediastinum and left subclavian lymph nodes. Invasion into major blood vessels and cavitation were absent (Fig. 1). Chemoradiotherapy could not be performed because of extensive radiation field. Therefore, three-drug combination chemotherapy with docetaxel (60 mg/m 2), cisplatin (80 mg/m 2) and bevacizumab (15 mg/kg) was administered as a first-line treatment based on the Phase II clinical trial (UMIN 000004368). After the fourth course of chemotherapy, partial remission resulting in cavity formation was observed. The patient had not experienced hemorrhagic adverse effect including nasal bleeding, and coagulopathy was not observed by blood examination during
four-cycle chemotherapy. However, on the 32nd day after the fourth course of chemotherapy, the patient developed bloody sputum, but she stayed at home on her decision. On the 34th day, the patient was found lying unconscious with massive hemoptysis. When the ambulance team arrived, the patient was already in cardiopulmonary arrest and was confirmed dead on arrival at the hospital. Autopsy revealed a diffuse alveolar hemorrhage (DAH) that primarily affected bilateral lower lobes of her lung. Although a cavity formation in the tumor lesion was found, the definite source of bleeding and injuries to the major vessels were not detected (Fig. 2). Microscopic examination showed that DAH consisted of fresh red blood cells and also contained a few hemosiderin-burdened macrophages, suggesting that there could have been chronic mild alveolar hemorrhage before the onset of DAH (Fig. 3A). Hyaline membrane suggestive of diffuse alveolar damage was absent. Endothelial
# The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: [email protected]
Downloaded from http://jjco.oxfordjournals.org/ at Simon Fraser University on June 5, 2015
*For reprints and all correspondence: Satoshi Ikeda, Department of Respiratory Medicine, Kanagawa Cardiovascular and Respiratory Center, Tomioka-Higashi 6-16-1, Kanazawa-ku, Yokohama, Japan. E-mail: [email protected]
498
Diffuse alveolar hemorrhage by bevacizumab
cells of the small – medium-sized muscular arteries and capillaries were often swollen and occasionally desquamated (Fig. 3B and C). The sub-endothelial space was occasionally enlarged due to fibroedematous changes (Fig. 3C and D; autopsied lung from another unrelated disease served as a negative control). The similar pathological changes in blood vessels were also observed in the kidney and the digestive tract (Fig. 4).
DISCUSSION
Figure 1. Chest computed tomography (CT) scans before treatment. A tumor can be observed in the left upper lobe, and mediastinal and hilar lymph nodes were enlarged.
Figure 2. Macroscopic examination. Diffuse pulmonary hemorrhage was predominantly observed in both lower lobes. A cavity was found in the tumor lesion. However, no definitive bleeding source was identified in the central airways, major blood vessels and tumor lesion.
Downloaded from http://jjco.oxfordjournals.org/ at Simon Fraser University on June 5, 2015
Bevacizumab is a humanized monoclonal antibody that inhibits vascular endothelial growth factor (VEGF) (1). Bevacizumab is rarely associated with severe pulmonary hemorrhage, which could potentially be life threatening. The risk
factors previously reported are major blood vessel and bronchial vessel infiltration, encasement and abutting (2). However, these findings and the definite source of bleeding could not be detected on autopsy, although the cavitary lesion of the tumor was at first considered to be related to the bleeding. Considering the fact that DAH caused by cisplatin and docetaxel has never been reported apart from interstitial pneumonitis, bevacizumab is the most suspicious drug for DAH in our case. To the best of our knowledge, there has been only one report presenting a case affected by DAH after an injection of only 1.25 mg/body bevacizumab into the eyeball (3). In this report, DAH was diagnosed solely through the examination of bronchial lavage fluid; the potential cause of DAH was not investigated. In the present case, autopsy revealed DAH as well as small artery and capillary injuries, although major vessels were intact. Moreover, the similar pathological changes in blood vessels were observed in the kidney and the digestive tract. Thus, DAH in the present case could be considered as a specific adverse effect primarily caused by inhibition of VEGF. VEGF not only stimulates endothelial cell proliferation but also promotes endothelial survival and helps maintain vascular integrity (4). Therefore, the inhibition of VEGF with bevacizumab may make alveolar capillaries fragile. Moreover, autopsy findings in the present case would support this hypothesis. In clinical practice, situations in which bevacizumab is used are increasing. The retrospective analysis by Nadler et al. (5) reported that the maintenance therapy using bevacizumab was effective to treat lung cancer. On the other hand, the meta-analysis by Ranpura et al. (6) reported the association of increased treatment-related mortality with bevacizumab. The important thing in our case is that DAH developed after the
Jpn J Clin Oncol 2014;44(5)
499
Figure 4. Microscopic appearance of the kidney autopsied is shown. A marked hyalinization in a sub-endothelial space of a small artery is found (arrows). Left panel, HE stain; right panel, Periodic Acid-Methenamine-silver stain. Magnification is 400 each.
fourth course of chemotherapy with bevacizumab, indicating that accumulation of capillary injuries is necessary for developing DAH. Therefore, chest physicians and oncologists should be aware that DAH could develop during any course of chemotherapy with bevacizumab.
Acknowledgements This patient was included in the clinical trial conducted by Thoracic Oncology Research Group (TORG). The trial number is TORG 1016 (UMIN 000004368).
Downloaded from http://jjco.oxfordjournals.org/ at Simon Fraser University on June 5, 2015
Figure 3. Microscopic examination. Representative photographs from microscopic examination are presented. Fresh red blood cells were filled in the alveolar spaces (A, Hematoxylin and eosin (HE) stain, 40). Endothelial cells of the capillaries (B, arrows, HE stain, 400) and small – medium-sized muscular arteries (C, HE stain, 400) were swollen and occasionally desquamated. The sub-endothelial space of muscular arteries was occasionally enlarged due to fibroedematous changes (C, arrow heads, HE stain, 400). Autopsied lung from another unrelated disease served as a negative control (D, HE stain, 400).
500
Diffuse alveolar hemorrhage by bevacizumab
Conflict of interest statement None declared.
References 1. Grothey A, Galanis E. Targeting angiogenesis: progress with anti-VEGF treatment with large molecules. Nat Rev Clin Oncol 2009;6:507 –18. 2. Reck M, Barlesi F, Crino L, et al. Predicting and managing the risk of pulmonary haemorrhage in patients with NSCLC treated with bevacizumab: a consensus report from a panel of experts. Ann Oncol 2012;23:1111–20.
3. Seto R, Yamada H, Wada H, Osawa M, Nagao T, Nakano Y. Diffuse alveolar haemorrhage may be associated with intravitreal injection of bevacizumab in a patient with systemic risk factors. BMJ Case Rep 2011; doi:10.1136/bcr.08.2010.3224. 4. Kilickap S, Abali H, Celik I. Bevacizumab, bleeding, thrombosis, and warfarin. J Clin Oncol 2003;21:35 –42. 5. Nadler E, Yu E, Ravelo A, Sing A, Forsyth M, Gruschkus S. Bevacizumab treatment to progression after chemotherapy: outcomes from a U.S. community practice network. Oncologist 2011;16:486– 96. 6. Ranpura V, Hapani S, Wu S. Treatment-related mortality with bevacizumab in cancer patients: a meta-analysis. JAMA 2011;305: 487 –94.
Downloaded from http://jjco.oxfordjournals.org/ at Simon Fraser University on June 5, 2015
Diffuse Alveolar Hemorrhage as a Fatal Adverse Effect of Bevacizumab: An Autopsy Case Satoshi Ikeda1,*, Akimasa Sekine1, Terufumi Kato1, Masahiro Yoshida1, Ryo Ogata1, Tomohisa Baba1, Kiyotaka Nagahama2, Koji Okudela2 and Takashi Ogura1 1
Department of Respiratory Medicine, Kanagawa Cardiovascular and Respiratory Center, Yokohama and 2Department of Pathology, Yokohama-city Graduate University School of Medicine, Yokohama, Japan
Received September 30, 2013; accepted February 18, 2014
A 71-year-old female with Stage IIIB primary adenocarcinoma was administered a three-drug combination therapy consisting of docetaxel, cisplatin and bevacizumab as a first-line treatment based on the Phase II clinical trial. On the 32nd day after the fourth course of chemotherapy, the patient developed bloody sputum. She was found dead at home on the 34th day. Autopsy revealed a diffuse alveolar hemorrhage without diffuse alveolar damage. Endothelial cells of the small arteries and capillaries were swollen and desquamated, indicating that alveolar capillaries were injured. The similar pathological changes in blood vessels were also observed in the kidney and the digestive tract. Because diffuse alveolar hemorrhage caused by cisplatin and docetaxel has never been reported apart from interstitial pneumonitis, bevacizumab is the most suspicious drug for diffuse alveolar hemorrhage in our case. Chest physicians and oncologists should be aware that although it is very rare, diffuse alveolar hemorrhage can develop during any course of chemotherapy with bevacizumab. Key words: bevacizumab – diffuse alveolar hemorrhage – adverse effect
CASE REPORT We present the case of a 71-year-old female with stage IIIB primary adenocarcinoma. Although she never smoked, she presented with hoarseness in her voice. Chest computed tomography showed a mass located in the left upper lobe, with metastasis to the left hilum, bilateral mediastinum and left subclavian lymph nodes. Invasion into major blood vessels and cavitation were absent (Fig. 1). Chemoradiotherapy could not be performed because of extensive radiation field. Therefore, three-drug combination chemotherapy with docetaxel (60 mg/m 2), cisplatin (80 mg/m 2) and bevacizumab (15 mg/kg) was administered as a first-line treatment based on the Phase II clinical trial (UMIN 000004368). After the fourth course of chemotherapy, partial remission resulting in cavity formation was observed. The patient had not experienced hemorrhagic adverse effect including nasal bleeding, and coagulopathy was not observed by blood examination during
four-cycle chemotherapy. However, on the 32nd day after the fourth course of chemotherapy, the patient developed bloody sputum, but she stayed at home on her decision. On the 34th day, the patient was found lying unconscious with massive hemoptysis. When the ambulance team arrived, the patient was already in cardiopulmonary arrest and was confirmed dead on arrival at the hospital. Autopsy revealed a diffuse alveolar hemorrhage (DAH) that primarily affected bilateral lower lobes of her lung. Although a cavity formation in the tumor lesion was found, the definite source of bleeding and injuries to the major vessels were not detected (Fig. 2). Microscopic examination showed that DAH consisted of fresh red blood cells and also contained a few hemosiderin-burdened macrophages, suggesting that there could have been chronic mild alveolar hemorrhage before the onset of DAH (Fig. 3A). Hyaline membrane suggestive of diffuse alveolar damage was absent. Endothelial
# The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: [email protected]
Downloaded from http://jjco.oxfordjournals.org/ at Simon Fraser University on June 5, 2015
*For reprints and all correspondence: Satoshi Ikeda, Department of Respiratory Medicine, Kanagawa Cardiovascular and Respiratory Center, Tomioka-Higashi 6-16-1, Kanazawa-ku, Yokohama, Japan. E-mail: [email protected]
498
Diffuse alveolar hemorrhage by bevacizumab
cells of the small – medium-sized muscular arteries and capillaries were often swollen and occasionally desquamated (Fig. 3B and C). The sub-endothelial space was occasionally enlarged due to fibroedematous changes (Fig. 3C and D; autopsied lung from another unrelated disease served as a negative control). The similar pathological changes in blood vessels were also observed in the kidney and the digestive tract (Fig. 4).
DISCUSSION
Figure 1. Chest computed tomography (CT) scans before treatment. A tumor can be observed in the left upper lobe, and mediastinal and hilar lymph nodes were enlarged.
Figure 2. Macroscopic examination. Diffuse pulmonary hemorrhage was predominantly observed in both lower lobes. A cavity was found in the tumor lesion. However, no definitive bleeding source was identified in the central airways, major blood vessels and tumor lesion.
Downloaded from http://jjco.oxfordjournals.org/ at Simon Fraser University on June 5, 2015
Bevacizumab is a humanized monoclonal antibody that inhibits vascular endothelial growth factor (VEGF) (1). Bevacizumab is rarely associated with severe pulmonary hemorrhage, which could potentially be life threatening. The risk
factors previously reported are major blood vessel and bronchial vessel infiltration, encasement and abutting (2). However, these findings and the definite source of bleeding could not be detected on autopsy, although the cavitary lesion of the tumor was at first considered to be related to the bleeding. Considering the fact that DAH caused by cisplatin and docetaxel has never been reported apart from interstitial pneumonitis, bevacizumab is the most suspicious drug for DAH in our case. To the best of our knowledge, there has been only one report presenting a case affected by DAH after an injection of only 1.25 mg/body bevacizumab into the eyeball (3). In this report, DAH was diagnosed solely through the examination of bronchial lavage fluid; the potential cause of DAH was not investigated. In the present case, autopsy revealed DAH as well as small artery and capillary injuries, although major vessels were intact. Moreover, the similar pathological changes in blood vessels were observed in the kidney and the digestive tract. Thus, DAH in the present case could be considered as a specific adverse effect primarily caused by inhibition of VEGF. VEGF not only stimulates endothelial cell proliferation but also promotes endothelial survival and helps maintain vascular integrity (4). Therefore, the inhibition of VEGF with bevacizumab may make alveolar capillaries fragile. Moreover, autopsy findings in the present case would support this hypothesis. In clinical practice, situations in which bevacizumab is used are increasing. The retrospective analysis by Nadler et al. (5) reported that the maintenance therapy using bevacizumab was effective to treat lung cancer. On the other hand, the meta-analysis by Ranpura et al. (6) reported the association of increased treatment-related mortality with bevacizumab. The important thing in our case is that DAH developed after the
Jpn J Clin Oncol 2014;44(5)
499
Figure 4. Microscopic appearance of the kidney autopsied is shown. A marked hyalinization in a sub-endothelial space of a small artery is found (arrows). Left panel, HE stain; right panel, Periodic Acid-Methenamine-silver stain. Magnification is 400 each.
fourth course of chemotherapy with bevacizumab, indicating that accumulation of capillary injuries is necessary for developing DAH. Therefore, chest physicians and oncologists should be aware that DAH could develop during any course of chemotherapy with bevacizumab.
Acknowledgements This patient was included in the clinical trial conducted by Thoracic Oncology Research Group (TORG). The trial number is TORG 1016 (UMIN 000004368).
Downloaded from http://jjco.oxfordjournals.org/ at Simon Fraser University on June 5, 2015
Figure 3. Microscopic examination. Representative photographs from microscopic examination are presented. Fresh red blood cells were filled in the alveolar spaces (A, Hematoxylin and eosin (HE) stain, 40). Endothelial cells of the capillaries (B, arrows, HE stain, 400) and small – medium-sized muscular arteries (C, HE stain, 400) were swollen and occasionally desquamated. The sub-endothelial space of muscular arteries was occasionally enlarged due to fibroedematous changes (C, arrow heads, HE stain, 400). Autopsied lung from another unrelated disease served as a negative control (D, HE stain, 400).
500
Diffuse alveolar hemorrhage by bevacizumab
Conflict of interest statement None declared.
References 1. Grothey A, Galanis E. Targeting angiogenesis: progress with anti-VEGF treatment with large molecules. Nat Rev Clin Oncol 2009;6:507 –18. 2. Reck M, Barlesi F, Crino L, et al. Predicting and managing the risk of pulmonary haemorrhage in patients with NSCLC treated with bevacizumab: a consensus report from a panel of experts. Ann Oncol 2012;23:1111–20.
3. Seto R, Yamada H, Wada H, Osawa M, Nagao T, Nakano Y. Diffuse alveolar haemorrhage may be associated with intravitreal injection of bevacizumab in a patient with systemic risk factors. BMJ Case Rep 2011; doi:10.1136/bcr.08.2010.3224. 4. Kilickap S, Abali H, Celik I. Bevacizumab, bleeding, thrombosis, and warfarin. J Clin Oncol 2003;21:35 –42. 5. Nadler E, Yu E, Ravelo A, Sing A, Forsyth M, Gruschkus S. Bevacizumab treatment to progression after chemotherapy: outcomes from a U.S. community practice network. Oncologist 2011;16:486– 96. 6. Ranpura V, Hapani S, Wu S. Treatment-related mortality with bevacizumab in cancer patients: a meta-analysis. JAMA 2011;305: 487 –94.
Downloaded from http://jjco.oxfordjournals.org/ at Simon Fraser University on June 5, 2015
