- Email: [email protected]
How Should We Use Bevacizumab in Patients with Non-small Cell Lung Cancer?
Journal of Thoracic Oncology • Volume 6, Number 12, December 2011
David Gandara, MD University of California at Davis Sacramento, California
TABLE 1. Randomized Studies of First-Line Bevacizumab in Combination with Chemotherapy in NSCLC E4599
Edith M. Marom, MD The University of Texas M. D. Anderson Cancer Center Houston, Texas
REFERENCES 1. Byrne MJ, Nowak AK. Modified RECIST criteria for assessment of response in malignant pleural mesothelioma. Ann Oncol 2004; 15:257–260. 2. Tsao AS, Garland L, Redman M, et al. A practical guide of the Southwest Oncology Group to measure malignant pleural mesothelioma tumors by RECIST and modified RECIST criteria. J Thorac Oncol 6:598 – 601. 3. Nowak AK, Armato SG III, Ceresoli GL, et al. Imaging in pleural mesothelioma: a review of imaging research presented at the 9th International Meeting of the International Mesothelioma Interest Group. Lung Cancer 2010;70:1– 6. 4. Ceresoli GL, Chiti A, Zucali PA, et al. Early response evaluation in malignant pleural mesothelioma by positron emission tomography with [18F]fluorodeoxyglucose. J Clin Oncol 2006;24:4587– 4593. 5. Yildirim H, Metintas M, Entok E, et al. Clinical value of fluorodeoxyglucose-positron emission tomography/computed tomography in differentiation of malignant mesothelioma from asbestos-related benign pleural disease: an observational pilot study. J Thorac Oncol 2009;4:1480 –1484. 6. Francis RJ, Byrne MJ, van der Schaaf AA, et al. Early prediction of response to chemotherapy and survival in malignant pleural mesothelioma using a novel semiautomated 3-dimensional volume-based analysis of serial 18F-FDG PET scans. J Nucl Med 2007;48: 1449 –1458. 7. Schaefer NG, Veit-Haibach P, Soyka JD, et al. Continued pemetrexed and platin-based chemotherapy in patients with malignant pleural mesothelioma (MPM): Value of 18F-FDGPET/CT. Eur J Radiol In press. 8. Veit-Haibach P, Schaefer NG, Steinert HC, et al. Combined FDG-PET/CT in response evaluation of malignant pleural mesothelioma. Lung Cancer 2010;67:311–317.
How Should We Use Bevacizumab in Patients with Non-small Cell Lung Cancer? To the Editor: The first phase III study of bevacizumab in combination with chemotherapy in patients with nonsquamous non-small cell lung cancer (E4599) was conducted in
Letters to the Editor
Bev N RR (%) PFS (mo)
— 444 15 4.5
15 mg 434 35 6.2
OS (mo)
10.3
12.3
AVAiL
HR 0.66
— 347 20 6.1
7.5 mg 345 34 6.7
15 mg 351 30 6.5
13.7
14.1
14.5
HR 0.79
JO19907
HR 0.75 (7.5 mg) 0.82 (15 mg) HR 0.94 (7.5 mg) 0.97 (15 mg)
— 59 31 5.9
15 mg 121 61 6.3
23.4
22.8
HR 0.61 HR 0.99
NSCLC, non-small cell lung cancer; RR, response rate; PFS, progression-free survival; OS, overall survival; HR, hazard ratio.
the United States, and both progressionfree survival (PFS) and overall survival (OS) were significantly improved in the bevacizumab arm1: however, in the second phase III study (AVAiL) conducted in the European Union, there was no significant difference in OS.2 When clinicians make a treatment decision, there are three important points to be considered: whether it prolongs OS, whether it improves patients’ quality of life, and how much it costs. Regarding bevacizumab, the cost is high, and its toxicity could compromise quality of life and sometimes lead to serious conditions, such as pulmonary hemorrhage and thromboembolism. Therefore, OS improvement is necessary by using bevacizumab; however, only one phase III study has shown a survival advantage of bevacizumab as mentioned above. Consequently, skeptical oncologists do not use bevacizumab for non-small cell lung cancer patients even if they are free from contraindications. Table 1 summarizes the results of three randomized studies of bevacizumab, E4599,1 AVAiL,2 and a Japanese phase II study (JO19907).3 As shown from the improved response rate and PFS, bevacizumab has reproducibly demonstrated a strong antitumor effect throughout the Disclosure: The authors declare no conflicts of interest. Address for correspondence: Young Hak Kim, MD, Department of Respiratory Medicine, Graduate School of Medicine, Kyoto University, 54 Shogoin-Kawaharacho, Sakyo-ku, Kyoto 606-8507, Japan. E-mail: [email protected] Copyright © 2011 by the International Association for the Study of Lung Cancer ISSN: 1556-0864/11/0612-2145
Copyright © 2011 by the International Association for the Study of Lung Cancer
studies; however, only the E4599 study demonstrated improved OS. How could we use this potent drug appropriately? Broglio and Berry4 addressed the importance of survival postprogression (SPP) and pointed out that lack of statistical significance in OS does not necessarily imply lack of improvement in OS, especially when SPP is longer than 12 months. Despite the recent development of efficient second- or third-line chemotherapy, SPP longer than 12 months is not so common, except in patients with activating epidermal growth factor receptor (EGFR) mutations. It seems quite reasonable to assume that more than 30% of included patients (East-Asian, nonsquamous) had EGFR mutations and would have received EGFR-tyrosine kinase inhibitor when disease progressed in each arm, and the marked improvement of OS in those patients might have negated the significant difference in PFS in the JO19907 study. Collectively, bevacizumab in combination with chemotherapy may be more recommendable for patients with wildtype EGFR than patients with EGFR mutations in the current situation. As for patients with EGFR mutants, the recently published BeTa study,5 a randomized phase III study comparing second-line erlotinib with or without bevacizumab, may be useful. In this study, PFS doubled (3.4 versus 1.7 months, hazard ratio [HR]: 0.62), but OS was almost identical (9.3 versus 9.2 months, HR: 0.97). Interestingly, the improvement of OS was more prominent in EGFR mutants (HR: 0.44) than EGFR wild-type (HR: 1.11) in subgroup analysis. As the authors mentioned,
2145
Letters to the Editor
this result should be interpreted with caution because only 30 patients in the study had EGFR-mutated tumors and the 95% confidence intervals for the HRs were wide (upper limit ⬎1) and overlapping; however taking account of this promising data, bevacizumab combined with EGFRtyrosine kinase inhibitor is attractive for patients with EGFR mutations and randomized studies are warranted. Young Hak Kim, MD, PhD Michiaki Mishima, MD, PhD Department of Respiratory Medicine Graduate School of Medicine Kyoto University Sakyo-ku, Kyoto, Japan
REFERENCES 1. Sandler A, Gray R, Perry MC, et al. Paclitaxelcarboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med 2006;355:2542–2550. 2. Reck M, von Pawel J, Zatloukal P, et al. Overall survival with cisplatin-gemcitabine and bevacizumab or placebo as first-line therapy for nonsquamous non-small-cell lung cancer: results from a randomised phase III trial (AVAiL). Ann Oncol 2010;21:1804 –1809. 3. Murakami H, Yamamoto N, Kunitoh H, et al. Randomized phase II study of bevacizumab combined with CBDCA-PTA in Japanese patients with advanced non-squamous NSCLC. Japanese Society of Medical Oncology (JSMO) Meeting Abstracts, 2010. 4. Broglio KR, Berry DA. Detecting an overall survival benefit that is derived from progression-free survival. J Natl Cancer Inst 2009; 101:1642–1649. 5. Herbst RS, Ansari R, Bustin F, et al. Efficacy of bevacizumab plus erlotinib versus erlotinib alone in advanced non-small-cell lung cancer after failure of standard first-line chemotherapy (BeTa): a double-blind, placebo-controlled, phase 3 trial. Lancet 2011;377:1846 –1854.
Techniques of Surgery and Radiotherapy for Multimodal Treatment of Pleural Mesothelioma To the Editor: The place of extra pleural pneumonectomy (EPP) in the treatment of
2146
Journal of Thoracic Oncology • Volume 6, Number 12, December 2011
N0-1 epithelioïd mesothelioma with curative intent is still debatable. Postoperative hemithoracic radiotherapy has been recommended, since the publication of Rusch in 2001. Nevertheless, peritoneal or contralateral pleural recurrences are frequent in the literature. We read with interest the article by Rice et al.1 in the August issue of the journal that the recommendations of the International Association for the Study of Lung Cancer and the International Mesothelioma Interest Group concerning EPP state that “in cases where the pericardium and/or diaphragm are not involved by tumor, these structures may be left intact.” In our consecutive series of 15 patients, we preserved the pericardium and the diaphragm to avoid peritoneal or pericardial seeding of the tumor.2 Polyglactin woven mesh was used to reinforce the denervated diaphragm to lower it, open the pleural sac, and facilitate radiotherapy. There were no postoperative deaths. Preservation of the diaphragm and pericardium seems to facilitate the postoperative course without increase of recurrences in these areas. For the last 4 years, we have routinely performed a laparoscopy, a contralateral thoracoscopy, and a mediastinoscopy during the same anesthesia, 1 week before EPP. During this period, 10 laparoscopies were carried out and 3 peritoneal invasions were detected which excluded resection for those patients. As stated by Chi et al.3 in the June issue of the journal, local control remains poor despite conventional adju-
Disclosure: The author declares no conflicts of interest. Address for correspondence: Pierre Bonnette, MD, Department of Thoracic Surgery, Hoˆpital Foch, 40, rue Worth, 925151 Suresnes, France. E-mail: [email protected] Copyright © 2011 by the International Association for the Study of Lung Cancer ISSN: 1556-0864/11/0612-2146
vant hemithoracic radiotherapy. This can be improved by the delivery of adjuvant intensity-modulated radiotherapy and especially helical tomotherapy which we adopted for the last five patients in our series.4 In our opinion, this current strategy should minimize postoperative mortality, local recurrences, and peritoneal and contralateral pleural seeding. We noted the disappointing results following EPP in the small MARS feasibility study,5 but in the EPP arm, 5 patients had no surgery, it was completed satisfactorily in only 16 of 24 patients, 4 patients died perioperatively, and only 8 received conventional radiotherapy, and it is too early to draw conclusions from this study. Pierre Bonnette, MD Department of Thoracic Surgery Hoˆpital Foch Suresnes, France
REFERENCES 1. Rice D, Rusch V, Pass H, et al. Recommendations for uniform definitions of surgical techniques for malignant pleural mesothelioma: a consensus report of the International Association for the Study of Lung Cancer International Staging Committee and the International Mesothelioma Interest Group. J Thorac Oncol 2011;6:1304 –1312. 2. Bonnette P. Me´sothe´liome pleural: ou` en sont la chirurgie radicale et le traitement multimodal? Rev Pneumol Clin 2011;67:184 –190. 3. Chi A, Liao Z, Nguyen NP, et al. Intensitymodulated radiotherapy after extrapleural pneumonectomy in the combined-modality treatment of malignant pleural mesothelioma. J Thorac Oncol 2011;6:1132–1141. 4. Sylvestre A, Mahe´ MA, Lisbona A, et al. Mesothelioma at era of helical tomotherapy: results of two institutions in combining chemotherapy, surgery and radiotherapy. Lung Cancer In press. 5. Treasure T, Lang-Lazdunski L, Waller D, et al. Extra-pleural pneumonectomy versus no extra-pleural pneumonectomy for patients with malignant pleural mesothelioma: clinical outcomes of the Mesothelioma and Radical Surgery (MARS) randomised feasibility study. Lancet Oncol 2011;12:763–772.
Copyright © 2011 by the International Association for the Study of Lung Cancer
David Gandara, MD University of California at Davis Sacramento, California
TABLE 1. Randomized Studies of First-Line Bevacizumab in Combination with Chemotherapy in NSCLC E4599
Edith M. Marom, MD The University of Texas M. D. Anderson Cancer Center Houston, Texas
REFERENCES 1. Byrne MJ, Nowak AK. Modified RECIST criteria for assessment of response in malignant pleural mesothelioma. Ann Oncol 2004; 15:257–260. 2. Tsao AS, Garland L, Redman M, et al. A practical guide of the Southwest Oncology Group to measure malignant pleural mesothelioma tumors by RECIST and modified RECIST criteria. J Thorac Oncol 6:598 – 601. 3. Nowak AK, Armato SG III, Ceresoli GL, et al. Imaging in pleural mesothelioma: a review of imaging research presented at the 9th International Meeting of the International Mesothelioma Interest Group. Lung Cancer 2010;70:1– 6. 4. Ceresoli GL, Chiti A, Zucali PA, et al. Early response evaluation in malignant pleural mesothelioma by positron emission tomography with [18F]fluorodeoxyglucose. J Clin Oncol 2006;24:4587– 4593. 5. Yildirim H, Metintas M, Entok E, et al. Clinical value of fluorodeoxyglucose-positron emission tomography/computed tomography in differentiation of malignant mesothelioma from asbestos-related benign pleural disease: an observational pilot study. J Thorac Oncol 2009;4:1480 –1484. 6. Francis RJ, Byrne MJ, van der Schaaf AA, et al. Early prediction of response to chemotherapy and survival in malignant pleural mesothelioma using a novel semiautomated 3-dimensional volume-based analysis of serial 18F-FDG PET scans. J Nucl Med 2007;48: 1449 –1458. 7. Schaefer NG, Veit-Haibach P, Soyka JD, et al. Continued pemetrexed and platin-based chemotherapy in patients with malignant pleural mesothelioma (MPM): Value of 18F-FDGPET/CT. Eur J Radiol In press. 8. Veit-Haibach P, Schaefer NG, Steinert HC, et al. Combined FDG-PET/CT in response evaluation of malignant pleural mesothelioma. Lung Cancer 2010;67:311–317.
How Should We Use Bevacizumab in Patients with Non-small Cell Lung Cancer? To the Editor: The first phase III study of bevacizumab in combination with chemotherapy in patients with nonsquamous non-small cell lung cancer (E4599) was conducted in
Letters to the Editor
Bev N RR (%) PFS (mo)
— 444 15 4.5
15 mg 434 35 6.2
OS (mo)
10.3
12.3
AVAiL
HR 0.66
— 347 20 6.1
7.5 mg 345 34 6.7
15 mg 351 30 6.5
13.7
14.1
14.5
HR 0.79
JO19907
HR 0.75 (7.5 mg) 0.82 (15 mg) HR 0.94 (7.5 mg) 0.97 (15 mg)
— 59 31 5.9
15 mg 121 61 6.3
23.4
22.8
HR 0.61 HR 0.99
NSCLC, non-small cell lung cancer; RR, response rate; PFS, progression-free survival; OS, overall survival; HR, hazard ratio.
the United States, and both progressionfree survival (PFS) and overall survival (OS) were significantly improved in the bevacizumab arm1: however, in the second phase III study (AVAiL) conducted in the European Union, there was no significant difference in OS.2 When clinicians make a treatment decision, there are three important points to be considered: whether it prolongs OS, whether it improves patients’ quality of life, and how much it costs. Regarding bevacizumab, the cost is high, and its toxicity could compromise quality of life and sometimes lead to serious conditions, such as pulmonary hemorrhage and thromboembolism. Therefore, OS improvement is necessary by using bevacizumab; however, only one phase III study has shown a survival advantage of bevacizumab as mentioned above. Consequently, skeptical oncologists do not use bevacizumab for non-small cell lung cancer patients even if they are free from contraindications. Table 1 summarizes the results of three randomized studies of bevacizumab, E4599,1 AVAiL,2 and a Japanese phase II study (JO19907).3 As shown from the improved response rate and PFS, bevacizumab has reproducibly demonstrated a strong antitumor effect throughout the Disclosure: The authors declare no conflicts of interest. Address for correspondence: Young Hak Kim, MD, Department of Respiratory Medicine, Graduate School of Medicine, Kyoto University, 54 Shogoin-Kawaharacho, Sakyo-ku, Kyoto 606-8507, Japan. E-mail: [email protected] Copyright © 2011 by the International Association for the Study of Lung Cancer ISSN: 1556-0864/11/0612-2145
Copyright © 2011 by the International Association for the Study of Lung Cancer
studies; however, only the E4599 study demonstrated improved OS. How could we use this potent drug appropriately? Broglio and Berry4 addressed the importance of survival postprogression (SPP) and pointed out that lack of statistical significance in OS does not necessarily imply lack of improvement in OS, especially when SPP is longer than 12 months. Despite the recent development of efficient second- or third-line chemotherapy, SPP longer than 12 months is not so common, except in patients with activating epidermal growth factor receptor (EGFR) mutations. It seems quite reasonable to assume that more than 30% of included patients (East-Asian, nonsquamous) had EGFR mutations and would have received EGFR-tyrosine kinase inhibitor when disease progressed in each arm, and the marked improvement of OS in those patients might have negated the significant difference in PFS in the JO19907 study. Collectively, bevacizumab in combination with chemotherapy may be more recommendable for patients with wildtype EGFR than patients with EGFR mutations in the current situation. As for patients with EGFR mutants, the recently published BeTa study,5 a randomized phase III study comparing second-line erlotinib with or without bevacizumab, may be useful. In this study, PFS doubled (3.4 versus 1.7 months, hazard ratio [HR]: 0.62), but OS was almost identical (9.3 versus 9.2 months, HR: 0.97). Interestingly, the improvement of OS was more prominent in EGFR mutants (HR: 0.44) than EGFR wild-type (HR: 1.11) in subgroup analysis. As the authors mentioned,
2145
Letters to the Editor
this result should be interpreted with caution because only 30 patients in the study had EGFR-mutated tumors and the 95% confidence intervals for the HRs were wide (upper limit ⬎1) and overlapping; however taking account of this promising data, bevacizumab combined with EGFRtyrosine kinase inhibitor is attractive for patients with EGFR mutations and randomized studies are warranted. Young Hak Kim, MD, PhD Michiaki Mishima, MD, PhD Department of Respiratory Medicine Graduate School of Medicine Kyoto University Sakyo-ku, Kyoto, Japan
REFERENCES 1. Sandler A, Gray R, Perry MC, et al. Paclitaxelcarboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med 2006;355:2542–2550. 2. Reck M, von Pawel J, Zatloukal P, et al. Overall survival with cisplatin-gemcitabine and bevacizumab or placebo as first-line therapy for nonsquamous non-small-cell lung cancer: results from a randomised phase III trial (AVAiL). Ann Oncol 2010;21:1804 –1809. 3. Murakami H, Yamamoto N, Kunitoh H, et al. Randomized phase II study of bevacizumab combined with CBDCA-PTA in Japanese patients with advanced non-squamous NSCLC. Japanese Society of Medical Oncology (JSMO) Meeting Abstracts, 2010. 4. Broglio KR, Berry DA. Detecting an overall survival benefit that is derived from progression-free survival. J Natl Cancer Inst 2009; 101:1642–1649. 5. Herbst RS, Ansari R, Bustin F, et al. Efficacy of bevacizumab plus erlotinib versus erlotinib alone in advanced non-small-cell lung cancer after failure of standard first-line chemotherapy (BeTa): a double-blind, placebo-controlled, phase 3 trial. Lancet 2011;377:1846 –1854.
Techniques of Surgery and Radiotherapy for Multimodal Treatment of Pleural Mesothelioma To the Editor: The place of extra pleural pneumonectomy (EPP) in the treatment of
2146
Journal of Thoracic Oncology • Volume 6, Number 12, December 2011
N0-1 epithelioïd mesothelioma with curative intent is still debatable. Postoperative hemithoracic radiotherapy has been recommended, since the publication of Rusch in 2001. Nevertheless, peritoneal or contralateral pleural recurrences are frequent in the literature. We read with interest the article by Rice et al.1 in the August issue of the journal that the recommendations of the International Association for the Study of Lung Cancer and the International Mesothelioma Interest Group concerning EPP state that “in cases where the pericardium and/or diaphragm are not involved by tumor, these structures may be left intact.” In our consecutive series of 15 patients, we preserved the pericardium and the diaphragm to avoid peritoneal or pericardial seeding of the tumor.2 Polyglactin woven mesh was used to reinforce the denervated diaphragm to lower it, open the pleural sac, and facilitate radiotherapy. There were no postoperative deaths. Preservation of the diaphragm and pericardium seems to facilitate the postoperative course without increase of recurrences in these areas. For the last 4 years, we have routinely performed a laparoscopy, a contralateral thoracoscopy, and a mediastinoscopy during the same anesthesia, 1 week before EPP. During this period, 10 laparoscopies were carried out and 3 peritoneal invasions were detected which excluded resection for those patients. As stated by Chi et al.3 in the June issue of the journal, local control remains poor despite conventional adju-
Disclosure: The author declares no conflicts of interest. Address for correspondence: Pierre Bonnette, MD, Department of Thoracic Surgery, Hoˆpital Foch, 40, rue Worth, 925151 Suresnes, France. E-mail: [email protected] Copyright © 2011 by the International Association for the Study of Lung Cancer ISSN: 1556-0864/11/0612-2146
vant hemithoracic radiotherapy. This can be improved by the delivery of adjuvant intensity-modulated radiotherapy and especially helical tomotherapy which we adopted for the last five patients in our series.4 In our opinion, this current strategy should minimize postoperative mortality, local recurrences, and peritoneal and contralateral pleural seeding. We noted the disappointing results following EPP in the small MARS feasibility study,5 but in the EPP arm, 5 patients had no surgery, it was completed satisfactorily in only 16 of 24 patients, 4 patients died perioperatively, and only 8 received conventional radiotherapy, and it is too early to draw conclusions from this study. Pierre Bonnette, MD Department of Thoracic Surgery Hoˆpital Foch Suresnes, France
REFERENCES 1. Rice D, Rusch V, Pass H, et al. Recommendations for uniform definitions of surgical techniques for malignant pleural mesothelioma: a consensus report of the International Association for the Study of Lung Cancer International Staging Committee and the International Mesothelioma Interest Group. J Thorac Oncol 2011;6:1304 –1312. 2. Bonnette P. Me´sothe´liome pleural: ou` en sont la chirurgie radicale et le traitement multimodal? Rev Pneumol Clin 2011;67:184 –190. 3. Chi A, Liao Z, Nguyen NP, et al. Intensitymodulated radiotherapy after extrapleural pneumonectomy in the combined-modality treatment of malignant pleural mesothelioma. J Thorac Oncol 2011;6:1132–1141. 4. Sylvestre A, Mahe´ MA, Lisbona A, et al. Mesothelioma at era of helical tomotherapy: results of two institutions in combining chemotherapy, surgery and radiotherapy. Lung Cancer In press. 5. Treasure T, Lang-Lazdunski L, Waller D, et al. Extra-pleural pneumonectomy versus no extra-pleural pneumonectomy for patients with malignant pleural mesothelioma: clinical outcomes of the Mesothelioma and Radical Surgery (MARS) randomised feasibility study. Lancet Oncol 2011;12:763–772.
Copyright © 2011 by the International Association for the Study of Lung Cancer