- Email: [email protected]
Induction Chemotherapy Inevitably Leads to Inferior Outcome in Combined Modality Treatment for Unresectable Stage III Non-small Cell Lung Cancer
Letters to the Editor
operated tumor, node, metastasis Stage II NSCLC patients. Therefore, an effective secondary prevention is imperative in these patients to ensure the best outcomes. Notwithstanding, it has been shown that lung cancer patients often receive a higher dose of radiation with conventional-dose CT than that considered safe, which could increase significantly their already increased lifetime cancer risk.4 As a result, strategies are stringently needed to decrease radiation doses during the postoperative follow-up in these patients, the majority of whom will never relapse. Given the results of NLST, it seems that utility of low-dose CT should also be tested in these patients who have completed curative treatment, but who remain at increased risk for recurrent disease. Further studies of the underlying economic, psychosocial, and physical barriers of low-dose CT in this population are probably warranted. Constantin A. Dasanu, MD, PhD Department of Hematology-Oncology St. Francis Hospital and Medical Center Hartford, CT
Ion Codreanu, MD, PhD
Department of Radiology The University of Arizona Medical Center Tucson, AZ
REFERENCES 1. Field JK, Smith RA, Aberle DR, et al.; IASLC CT Screening Workshop 2011 Participants. International Association for the Study of Lung Cancer Computed Tomography Screening Workshop 2011 report. J Thorac Oncol 2012;7:10–19. 2. Aberle DR, Adams AM, Berg CD, et al.; National Lung Screening Trial Research Team. Reduced lung-cancer mortality with low-dose computed tomographic screening. N Engl J Med 2011;365:395–409. 3. Gauger J, Patz EF Jr, Coleman RE, Herndon JE 2nd. Clinical stage I non-small cell lung cancer including FDG-PET Imaging: sites and time to recurrence. J Thorac Oncol 2007;2:499–505. 4. Stiles BM, Mirza F, Towe CW, et al. Cumulative radiation dose from medical imaging procedures in patients undergoing resection for lung cancer. Ann Thorac Surg 2011;92:1170–1178; discussion 1178.
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Journal of Thoracic Oncology • Volume 7, Number 5, May 2012
Induction Chemotherapy Inevitably Leads to Inferior Outcome in Combined Modality Treatment for Unresectable Stage III Non-small Cell Lung Cancer
To the Editor: We read with interest the recent retrospective report of Chen et al.1 on the deleterious effects of delayed initiation of radiotherapy (RT) after induction chemotherapy (CHT) in stage III non-small cell lung cancer (NSCLC) due to tumor regrowth occurring within a few weeks. They have concluded that RT treatment planning should begin as soon as possible after the administration of induction CHT to maximize its benefits and provided a volumetric analysis of tumors to support their conclusion of accelerated repopulation as the mechanism for regrowth during delays. Their results in fact reconfirm the study of El-Sharouni et al.2 which compared computed tomography (CT) scans-based assessment of tumor changes before and after induction CHT, with an emphasis on the time interval from the last induction CHT cycle to the timing of the RT treatment planning CT scan. They showed that during the waiting period (for the planning CT scan and start of RT), a total of 41% of all tumors became incurable. Bozcuk et al.3 recently looked at the benefits of induction CHT before RT in NSCLC using a meta-analytical approach with metaregression analysis. Using 13 completed randomized clinical trials involving a total of 2776 patients, they found that the time to RT initiation was inversely associated with the benefit from induction CHT at 2 ( p = 0.050) and 3 years ( p = 0.093). Disclosure: The authors declare no conflicts of interest. Address for correspondence: Branislav Jeremic, MD, PhD, Institute of Lung Diseases, Institutski put 4, 21204 Sremska kamenica, Serbia. E-mail: [email protected] Copyright © 2012 by the International Association for the Study of Lung Cancer ISSN: 1556-0864/12/944-945
As noted by the authors, a range of prospective randomized clinical trials followed by recent meta-analyses4 have confirmed that in unresectable stage III NSCLC patients meeting the selection criteria for such trials, the standard of care is concurrent RT-CHT, with CHT initiated on day 1 of RT, as compared with sequential CHT followed by RT. Furthermore, the recently published randomized trial (CALGB 39801)5 of concurrent RT-CHT with or without the addition of induction CHT showed that the experimental arm generated excess toxicity and provided no survival benefit over concurrent RT-CHT alone.5 With this evidence in mind, the present report by Chen et al. fails to adequately justify their conclusion about future clinical research in this setting without clear upfront patient and/or tumor selection criteria which may prompt an indication for the use of induction CHT. In addition, they identify “logistical/scheduling constraints in 14 of 21 cases” which are otherwise not characterized as the basis for delays in RT initiation after induction. This suggests a number of variables in their study population which would not conventionally make these patients trial eligible. Without better characterization of their population, it then becomes difficult to understand why one should optimize what is already an inferior (i.e., induction CHT) approach to managing stage III NSCLC but not further optimize the better (RT-CHT) approach associated with the optimal survival. We share the authors’ goals in providing the best care possible for patients confronting locally advanced lung cancer and agree that optimizing the delivery of RT is a priority. The old notion of “doing something while the patient waits for the radiotherapy planning scan” is clearly not tenable. A more detailed analysis of the clinical circumstances in the present series would have further served to justify that proposition. Branislav Jeremic, MD, PhD Institute of Lung Diseases Sremska Kamenica, Serbia Gregory M.M. Videtic, MD The Cleveland Clinic Cleveland, Ohio
Copyright © 2012 by the International Association for the Study of Lung Cancer
Journal of Thoracic Oncology • Volume 7, Number 5, May 2012
REFERENCES 1. Chen CP, Weinberg VK, Jahan TM, et al. Implications of delayed initiation of radio therapy accelerated repopulation after induction chemotherapy for stage III nonsmall cell lung cancer. J Thorac Oncol 2011;6:1857–1864. 2. El Sharouni SY, Kal HB, Battermann JJ. Accelerated regrowth of non-small-cell lung tumors after induction chemotherapy. Br J Cancer 2003;89:2184–2189. 3. Bozcuk H, Artac M, Ozdogan M. Correlates of benefit from neoadjuvant chemotherapy before radiotherapy in non-small cell lung cancer: a meta-analytical approach with metaregression analysis. J BUON 2010;15:43–50. 4. Aupérin A, Le Péchoux C, Rolland E, et al. Meta-analysis of concomitant versus sequential radiochemotherapy in locally advanced non-small-cell lung cancer. J Clin Oncol 2010; 28:2181–2190. 5. Vokes EE, Herndon JE II, Kelley MJ, et al; Cancer and Leukemia Group B. Induction chemotherapy followed by chemoradiotherapy compared with chemoradiotherapy alone for regionally advanced unresectable stage III Non-smallcell lung cancer: Cancer and Leukemia Group B. J Clin Oncol 2007; 25:1698–1704.
One Size Does Not Fit All Lung Cancer Patients In Response: We thank Drs. Jeremic and Videtic for highlighting points related to our article.1 We concur that the standard of care for eligible patients with unresectable stage III non–small-cell lung cancer is concurrent chemoradiation, as proven in phase III randomized trials. In our introduction, we described our study rationale. For patients who have poor performance David M. Jablons, MD, has served as a consultant for Genentech, BI, and Lilly, has received payment for lectures, and has received grants. Thierry M. Jahan, MD, has also received grants. Sue S. Yom, MD, PhD, has served as a consultant for Genentech, has provided expert testimony for Norman A. Moses, Elk and Elk, Co., and has received a grant from the AMA Women Physicians Congress, UCSF Research Allocation Program, and the UCSF Office for Medical Education. The other authors declare no conflicts of interest. Address for correspondence: Sue S. Yom, MD, PhD, UCSF Radiation Oncology, 1600 Divisadero St., Suite H-1031, San Francisco CA, 94143. Copyright © 2012 by the International Association for the Study of Lung Cancer ISSN: 1556-0864/12/945
status, unduly large radiotherapy fields, or medical comorbidities that make upfront chemoradiation unrealistic or even risky, sequential chemoradiotherapy is an alternative that is preferable to radiotherapy alone.2 It is understood that these patients represent a different population than that represented in concurrent chemoradiation trials. There is a request for justification for future clinical research. However, we are not proposing more prospective studies of induction-chemotherapy strategies. This was neither the goal nor the main point of our study. Nonetheless, as the issue has now been raised, it is worth mentioning that the question of induction chemotherapy has not been entirely settled for poor-prognosis patients. A randomized phase II study, Locally Advanced Multi-Modality Protocol, included an arm of induction carboplatin/paclitaxel followed by concurrent chemoradiation. The induction arm produced lower median survival, but more patients with low Karnofsky performance status, male sex, and weight loss received induction; in addition, the trial accrued slowly and closed early.3 The cancer and leukemia group B 39801 phase III study randomized patients to either two cycles of carboplatin/paclitaxel followed by concurrent chemoradiation versus concurrent chemoradiation alone. The median overall survival was longer in the induction arm (14 months versus 12 months), but this difference was not statistically significant, and both arms underperformed relative to historical controls. With more than 5% weight loss, survival was longer with induction, a finding that was not significant on detailed reanalysis. However, it was noted that prognostic factors were highly determinant of outcome, raising questions about the benefit of chemoradiation in these patients.4 None of these studies addressed the issue of which approach was to be adopted for patients unable to have upfront concurrent chemoradiation or whose overall prognosis was so poor as to put the benefit of concurrent chemoradiation in doubt. Regardless of what we all may consider optimal, many patients have received induction chemotherapy before subsequent definitive or palliative treatment. We intended to present our experiences with these patients who were
Copyright © 2012 by the International Association for the Study of Lung Cancer
Letters to the Editor
treated off clinical trials. We included available prognostic factors and other variables in our study, such as patient demographics, performance status, and type of induction chemotherapy used. Nonetheless, we acknowledge that this retrospectively selected population sample is small and heterogeneous. It has been estimated that as many as 59% of patients with locally advanced lung cancer are ineligible for concurrent chemoradiation at presentation.5 We believe there will be continued use of induction regimens off protocol for certain classes of high-risk or poorprognosis patients. Information from studies such as ours can help manage expectations and optimize outcomes in these difficult situations. We thank our colleagues for their interest in our work. Sue S. Yom, MD, PhD Chien P. Chen, MD, PhD Thierry M. Jahan, MD David M. Jablons, MD Departments of Radiation Oncology, Medical Oncology, and Thoracic Surgery University of California San Francisco, CA references 1. Chen CP, Weinberg VK, Jahan TM, Jablons DM, Yom SS. Implications of delayed initiation of radiotherapy: accelerated repopulation after induction chemotherapy for stage III non-small cell lung cancer. J Thorac Oncol 2011;6:1857–1864. 2. Dillman RO, Herndon J, Seagren SL, Eaton WL Jr, Green MR. Improved survival in stage III non-small-cell lung cancer: sevenyear follow-up of cancer and leukemia group B (CALGB) 8433 trial. J Natl Cancer Inst 1996;88:1210–1215. 3. Belani CP, Choy H, Bonomi P, et al. Combined chemoradiotherapy regimens of paclitaxel and carboplatin for locally advanced nonsmall-cell lung cancer: a randomized phase II locally advanced multi-modality protocol. J Clin Oncol 2005;23:5883–5891. 4. Stinchcombe TE, Hodgson L, Herndon JE 2nd, et al.; Cancer and Leukemia Group B. Treatment outcomes of different prognostic groups of patients on cancer and leukemia group B trial 39801: induction chemotherapy followed by chemoradiotherapy compared with chemoradiotherapy alone for unresectable stage III non-small cell lung cancer. J Thorac Oncol 2009;4:1117–1125. 5. De Ruysscher D, Botterweck A, Dirx M, et al. Eligibility for concurrent chemotherapy and radiotherapy of locally advanced lung cancer patients: a prospective, population-based study. Ann Oncol 2009;20:98–102.
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operated tumor, node, metastasis Stage II NSCLC patients. Therefore, an effective secondary prevention is imperative in these patients to ensure the best outcomes. Notwithstanding, it has been shown that lung cancer patients often receive a higher dose of radiation with conventional-dose CT than that considered safe, which could increase significantly their already increased lifetime cancer risk.4 As a result, strategies are stringently needed to decrease radiation doses during the postoperative follow-up in these patients, the majority of whom will never relapse. Given the results of NLST, it seems that utility of low-dose CT should also be tested in these patients who have completed curative treatment, but who remain at increased risk for recurrent disease. Further studies of the underlying economic, psychosocial, and physical barriers of low-dose CT in this population are probably warranted. Constantin A. Dasanu, MD, PhD Department of Hematology-Oncology St. Francis Hospital and Medical Center Hartford, CT
Ion Codreanu, MD, PhD
Department of Radiology The University of Arizona Medical Center Tucson, AZ
REFERENCES 1. Field JK, Smith RA, Aberle DR, et al.; IASLC CT Screening Workshop 2011 Participants. International Association for the Study of Lung Cancer Computed Tomography Screening Workshop 2011 report. J Thorac Oncol 2012;7:10–19. 2. Aberle DR, Adams AM, Berg CD, et al.; National Lung Screening Trial Research Team. Reduced lung-cancer mortality with low-dose computed tomographic screening. N Engl J Med 2011;365:395–409. 3. Gauger J, Patz EF Jr, Coleman RE, Herndon JE 2nd. Clinical stage I non-small cell lung cancer including FDG-PET Imaging: sites and time to recurrence. J Thorac Oncol 2007;2:499–505. 4. Stiles BM, Mirza F, Towe CW, et al. Cumulative radiation dose from medical imaging procedures in patients undergoing resection for lung cancer. Ann Thorac Surg 2011;92:1170–1178; discussion 1178.
944
Journal of Thoracic Oncology • Volume 7, Number 5, May 2012
Induction Chemotherapy Inevitably Leads to Inferior Outcome in Combined Modality Treatment for Unresectable Stage III Non-small Cell Lung Cancer
To the Editor: We read with interest the recent retrospective report of Chen et al.1 on the deleterious effects of delayed initiation of radiotherapy (RT) after induction chemotherapy (CHT) in stage III non-small cell lung cancer (NSCLC) due to tumor regrowth occurring within a few weeks. They have concluded that RT treatment planning should begin as soon as possible after the administration of induction CHT to maximize its benefits and provided a volumetric analysis of tumors to support their conclusion of accelerated repopulation as the mechanism for regrowth during delays. Their results in fact reconfirm the study of El-Sharouni et al.2 which compared computed tomography (CT) scans-based assessment of tumor changes before and after induction CHT, with an emphasis on the time interval from the last induction CHT cycle to the timing of the RT treatment planning CT scan. They showed that during the waiting period (for the planning CT scan and start of RT), a total of 41% of all tumors became incurable. Bozcuk et al.3 recently looked at the benefits of induction CHT before RT in NSCLC using a meta-analytical approach with metaregression analysis. Using 13 completed randomized clinical trials involving a total of 2776 patients, they found that the time to RT initiation was inversely associated with the benefit from induction CHT at 2 ( p = 0.050) and 3 years ( p = 0.093). Disclosure: The authors declare no conflicts of interest. Address for correspondence: Branislav Jeremic, MD, PhD, Institute of Lung Diseases, Institutski put 4, 21204 Sremska kamenica, Serbia. E-mail: [email protected] Copyright © 2012 by the International Association for the Study of Lung Cancer ISSN: 1556-0864/12/944-945
As noted by the authors, a range of prospective randomized clinical trials followed by recent meta-analyses4 have confirmed that in unresectable stage III NSCLC patients meeting the selection criteria for such trials, the standard of care is concurrent RT-CHT, with CHT initiated on day 1 of RT, as compared with sequential CHT followed by RT. Furthermore, the recently published randomized trial (CALGB 39801)5 of concurrent RT-CHT with or without the addition of induction CHT showed that the experimental arm generated excess toxicity and provided no survival benefit over concurrent RT-CHT alone.5 With this evidence in mind, the present report by Chen et al. fails to adequately justify their conclusion about future clinical research in this setting without clear upfront patient and/or tumor selection criteria which may prompt an indication for the use of induction CHT. In addition, they identify “logistical/scheduling constraints in 14 of 21 cases” which are otherwise not characterized as the basis for delays in RT initiation after induction. This suggests a number of variables in their study population which would not conventionally make these patients trial eligible. Without better characterization of their population, it then becomes difficult to understand why one should optimize what is already an inferior (i.e., induction CHT) approach to managing stage III NSCLC but not further optimize the better (RT-CHT) approach associated with the optimal survival. We share the authors’ goals in providing the best care possible for patients confronting locally advanced lung cancer and agree that optimizing the delivery of RT is a priority. The old notion of “doing something while the patient waits for the radiotherapy planning scan” is clearly not tenable. A more detailed analysis of the clinical circumstances in the present series would have further served to justify that proposition. Branislav Jeremic, MD, PhD Institute of Lung Diseases Sremska Kamenica, Serbia Gregory M.M. Videtic, MD The Cleveland Clinic Cleveland, Ohio
Copyright © 2012 by the International Association for the Study of Lung Cancer
Journal of Thoracic Oncology • Volume 7, Number 5, May 2012
REFERENCES 1. Chen CP, Weinberg VK, Jahan TM, et al. Implications of delayed initiation of radio therapy accelerated repopulation after induction chemotherapy for stage III nonsmall cell lung cancer. J Thorac Oncol 2011;6:1857–1864. 2. El Sharouni SY, Kal HB, Battermann JJ. Accelerated regrowth of non-small-cell lung tumors after induction chemotherapy. Br J Cancer 2003;89:2184–2189. 3. Bozcuk H, Artac M, Ozdogan M. Correlates of benefit from neoadjuvant chemotherapy before radiotherapy in non-small cell lung cancer: a meta-analytical approach with metaregression analysis. J BUON 2010;15:43–50. 4. Aupérin A, Le Péchoux C, Rolland E, et al. Meta-analysis of concomitant versus sequential radiochemotherapy in locally advanced non-small-cell lung cancer. J Clin Oncol 2010; 28:2181–2190. 5. Vokes EE, Herndon JE II, Kelley MJ, et al; Cancer and Leukemia Group B. Induction chemotherapy followed by chemoradiotherapy compared with chemoradiotherapy alone for regionally advanced unresectable stage III Non-smallcell lung cancer: Cancer and Leukemia Group B. J Clin Oncol 2007; 25:1698–1704.
One Size Does Not Fit All Lung Cancer Patients In Response: We thank Drs. Jeremic and Videtic for highlighting points related to our article.1 We concur that the standard of care for eligible patients with unresectable stage III non–small-cell lung cancer is concurrent chemoradiation, as proven in phase III randomized trials. In our introduction, we described our study rationale. For patients who have poor performance David M. Jablons, MD, has served as a consultant for Genentech, BI, and Lilly, has received payment for lectures, and has received grants. Thierry M. Jahan, MD, has also received grants. Sue S. Yom, MD, PhD, has served as a consultant for Genentech, has provided expert testimony for Norman A. Moses, Elk and Elk, Co., and has received a grant from the AMA Women Physicians Congress, UCSF Research Allocation Program, and the UCSF Office for Medical Education. The other authors declare no conflicts of interest. Address for correspondence: Sue S. Yom, MD, PhD, UCSF Radiation Oncology, 1600 Divisadero St., Suite H-1031, San Francisco CA, 94143. Copyright © 2012 by the International Association for the Study of Lung Cancer ISSN: 1556-0864/12/945
status, unduly large radiotherapy fields, or medical comorbidities that make upfront chemoradiation unrealistic or even risky, sequential chemoradiotherapy is an alternative that is preferable to radiotherapy alone.2 It is understood that these patients represent a different population than that represented in concurrent chemoradiation trials. There is a request for justification for future clinical research. However, we are not proposing more prospective studies of induction-chemotherapy strategies. This was neither the goal nor the main point of our study. Nonetheless, as the issue has now been raised, it is worth mentioning that the question of induction chemotherapy has not been entirely settled for poor-prognosis patients. A randomized phase II study, Locally Advanced Multi-Modality Protocol, included an arm of induction carboplatin/paclitaxel followed by concurrent chemoradiation. The induction arm produced lower median survival, but more patients with low Karnofsky performance status, male sex, and weight loss received induction; in addition, the trial accrued slowly and closed early.3 The cancer and leukemia group B 39801 phase III study randomized patients to either two cycles of carboplatin/paclitaxel followed by concurrent chemoradiation versus concurrent chemoradiation alone. The median overall survival was longer in the induction arm (14 months versus 12 months), but this difference was not statistically significant, and both arms underperformed relative to historical controls. With more than 5% weight loss, survival was longer with induction, a finding that was not significant on detailed reanalysis. However, it was noted that prognostic factors were highly determinant of outcome, raising questions about the benefit of chemoradiation in these patients.4 None of these studies addressed the issue of which approach was to be adopted for patients unable to have upfront concurrent chemoradiation or whose overall prognosis was so poor as to put the benefit of concurrent chemoradiation in doubt. Regardless of what we all may consider optimal, many patients have received induction chemotherapy before subsequent definitive or palliative treatment. We intended to present our experiences with these patients who were
Copyright © 2012 by the International Association for the Study of Lung Cancer
Letters to the Editor
treated off clinical trials. We included available prognostic factors and other variables in our study, such as patient demographics, performance status, and type of induction chemotherapy used. Nonetheless, we acknowledge that this retrospectively selected population sample is small and heterogeneous. It has been estimated that as many as 59% of patients with locally advanced lung cancer are ineligible for concurrent chemoradiation at presentation.5 We believe there will be continued use of induction regimens off protocol for certain classes of high-risk or poorprognosis patients. Information from studies such as ours can help manage expectations and optimize outcomes in these difficult situations. We thank our colleagues for their interest in our work. Sue S. Yom, MD, PhD Chien P. Chen, MD, PhD Thierry M. Jahan, MD David M. Jablons, MD Departments of Radiation Oncology, Medical Oncology, and Thoracic Surgery University of California San Francisco, CA references 1. Chen CP, Weinberg VK, Jahan TM, Jablons DM, Yom SS. Implications of delayed initiation of radiotherapy: accelerated repopulation after induction chemotherapy for stage III non-small cell lung cancer. J Thorac Oncol 2011;6:1857–1864. 2. Dillman RO, Herndon J, Seagren SL, Eaton WL Jr, Green MR. Improved survival in stage III non-small-cell lung cancer: sevenyear follow-up of cancer and leukemia group B (CALGB) 8433 trial. J Natl Cancer Inst 1996;88:1210–1215. 3. Belani CP, Choy H, Bonomi P, et al. Combined chemoradiotherapy regimens of paclitaxel and carboplatin for locally advanced nonsmall-cell lung cancer: a randomized phase II locally advanced multi-modality protocol. J Clin Oncol 2005;23:5883–5891. 4. Stinchcombe TE, Hodgson L, Herndon JE 2nd, et al.; Cancer and Leukemia Group B. Treatment outcomes of different prognostic groups of patients on cancer and leukemia group B trial 39801: induction chemotherapy followed by chemoradiotherapy compared with chemoradiotherapy alone for unresectable stage III non-small cell lung cancer. J Thorac Oncol 2009;4:1117–1125. 5. De Ruysscher D, Botterweck A, Dirx M, et al. Eligibility for concurrent chemotherapy and radiotherapy of locally advanced lung cancer patients: a prospective, population-based study. Ann Oncol 2009;20:98–102.
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