Correspondence
between patients with two to four metastases and those with five to ten metastases (3·07 mL vs 3·54 mL).1 Additionally, the minimum volume of 0·02 mL at the bottom of the range for both groups raises questions about whether the 1 T MRI used by the investigators is sufficiently sensitive to measure tumours of this size. Fourth, stereotactic radiosurgery was not shown to be better than whole-brain radiotherapy in patients with five to ten metastases. Wholebrain radiotherapy is the standard treatment for non-oligometastatic patients. A Cochrane review3 showed that stereotactic radiosurgery plus whole-brain radiotherapy does not increase survival in patients with two to four brain metastases compared with whole-brain radiotherapy alone, but this combination did increase the frequency of local control, particularly in patients with only one brain metastasis. Use of whole-brain radiotherapy has been questioned because it is associated with late effect on neurocognitive function,4 but brain tumour progression seems to adversely affect neurocognitive function more than whole-brain radiotherapy does.1,5 Neurological function needs more detailed assessment than the MiniMental State Examination used by Yamomoto and colleagues, and in view of the scarce data for wholebrain radiotherapy in their study, the conclusions about neurological function should be interpreted with caution. In conclusion, despite the relevance of Yamamoto and colleagues’ study, its messages need to be interpreted carefully. Oversimplification of oncological treatment should be avoided. The feasibility of stereotactic radiosurgery in patients with up to ten brain metastases seems to be undiscussed in the context of modern radiation technology such as radiosurgery with CyberKnife or Linacbased. Therefore the use of stereotactic radiosurgery in non-oligometastatic www.thelancet.com/oncology Vol 15 June 2014
patients—who died mainly from primary disease in Yamomoto and colleagues’ study—does not seem to be beneficial. We declare no competing interests.
Filippo Alongi, *Alba Fiorentino, Pierina Navarria, Lorenzo Bello, Marta Scorsetti albafi[email protected] Department of Radiation Oncology, Sacro Cuore Hospital, Negrar-Verona 37134, Italy (FA, AF); Department of Radiotherapy and Radiosurgery, Istituto Clinico Humanitas Cancer Center, Milano, Italy (PN, MS); Department of Neurosurgery, Istituto Clinico Humanitas Cancer Center, Milano, Italy (LB) 1
2
3
4
5
Yamamoto M, Serizawa T, Shuto T, et al. Stereotactic radiosurgery for patients with multiple brain metastases (JLGK0901): a multi-institutional prospective observational study. Lancet Oncol 2014; 15: 387–95. Aoyama H, Shirato H, Tago M, et al. Stereotactic radiosurgery plus whole-brain radiation therapy vs stereotactic radiosurgery alone for treatment of brain metastases: a randomized controlled trial. JAMA 2006; 295: 2483–91. Patil CG, Pricola K, Sarmiento JM, Garg SK, Bryant A, Black KL. Whole brain radiation therapy (WBRT) alone versus WBRT and radiosurgery for the treatment of brain metastases. Cochrane Database Syst Rev 2012; 9: CD006121. Soffietti R, Kocher M, Abacioglu UM, et al. A European Organisation for Research and Treatment of Cancer phase III trial of adjuvant whole-brain radiotherapy versus observation in patients with one to three brain metastases from solid tumors after surgical resection or radiosurgery: quality-of-life results. J Clin Oncol 2013; 31: 65–72. Li J, Bentzen SM, Renschler M, Mehta MP. Regression after whole-brain radiation therapy for brain metastases correlates with survival and improved neurocognitive function. J Clin Oncol 2007; 25: 1260–66.
We congratulate Masaaki Yamamoto and colleagues1 for their important contribution to the management of patients with brain metastases, which showed that overall survival in patients with five to ten brain lesions was not inferior to those with two to four lesions when treated with stereotactic radiotherapy. We believe, however, that caution is needed when interpreting these results and we have several concerns. First, although the non-inferior design might be technically feasible for non-randomised studies, it is usually only applied to randomised
phase 3 studies.2-4 Second, the nonrandomised nature of the study introduced selection bias for the three groups, which was substantially varied. In addition to brain metastasis, the conditions of the primary site and other metastatic sites obviously affect survival, yet this study limitation was not mentioned in the article. The fact that deaths unrelated to brain disease accounted for 92% of all deaths suggests that lesions other than brain metastases affected the survival in this study population. In Japan where the study was conducted, clinical guidelines recommend stereotactic radiosurgery as an option for patients with up to four brain metastases only, as the authors mentioned. Oncologists refer patients for stereotactic radiosurgery using different criteria for patients with brain metastases up to four lesions than for patients with more than four lesions. Consequently, in Yamamoto and colleagues’ study, they treated twice as many patients with two to four brain lesions than patients with more than four lesions, in contrast to their preplanned ratio of 1:1. This result might have been a consequence of selection bias between the groups. Additionally, the proportions of patients with pretreatment neurological symptoms were similar between the group with two to four brain lesions (33%) and the group with five to ten lesions (31%). These results suggest that the oncologists applied stricter criteria when selecting patients with multiple brain-metastases for stereotactic radiosurgery referral than for the selection of patients with fewer brainmetastases. Additional data about the characteristics of patients who had brain metastases but were not referred for stereotactic radiosurgery would clarify this issue. Needless to say, the work by Yamamoto and colleagues is invaluable for the indication that stereotactic radiosurgery is a promising option for management e247
Correspondence
For the Research Registry System of the National Institute of Health see http://www.clinicaltrials.gov/ ct2/results?term=Noninferiority &recr=&rslt=&ty
of brain metastases, even in patients with multiple metastases, if patients are carefully selected. Well designed, randomised studies are now needed to further generalise these results. We declare no competing interests.
*Yuichi Takiguchi, Ikuo Sekine, Shunichiro Iwasawa, Ryota Kurimoto, Takashi Uehara [email protected] Department of Medical Oncology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan (YT, IS, SI, RK); Department of Reproductive Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan (TU) 1
2
3
4
Yamamoto M, Serizawa T, Shuto T, et al. Stereotactic radiosurgery for patients with multiple brain metastases (JLGK0901): a multi-institutional prospective observational study. Lancet Oncol 2014; 15: 387–95. Weintraub WS. Cutting through the statistical fog: understanding and evaluating noninferiority trials. Int J Clin Pract 2010; 64: 1359–66. Riechelmann RP, Alex A, Cruz L, Bariani GM, Hoff PM. Non-inferiority cancer clinical trials: scope and purposes underlying their design. Ann Oncol 2013; 24: 1942–47. Schiller P, Burchardi N, Niestroj M, Kieser M. Quality of reporting of clinical non-inferiority and equivalence randomised trials–update and extension. Trials 2012; 13: 214.
Authors’ reply We thank Filippo Alongi and colleagues for their interest in our work.1 We are aware that there has been a debate for more than 20 years as to whether it is meaningful to calculate survival after stereotactic radiosurgery in a cohort, because about 90% of patients died in our study due to extracerebral disease progression after stereotactic radiosurgery for brain metastases. However, overall survival is still the most certain endpoint, as reported by Korn and colleagues,2 and the majority of previous studies have used overall survival to assess results after stereotactic radiosurgery. Nevertheless, as Alongi and colleagues point out, overall survival alone cannot be regarded as sufficient. Thus, we analysed several secondary endpoints in our study to compensate for this weakness. With regard to the distribution of original tumours, the proportion of e248
patients with primary lung cancer (76%; 8% small-cell lung cancer and 68% non-small-cell lung cancer) in our study did not differ markedly from those seen in previously reported randomised trials.3,4 Another possible weakness of our study might be that clinical factors are obviously heterogeneous. However, we feel that these heterogeneous patient groups reflect actual clinical practice. Although the study protocol stated that 1·0 T or higher MRI units should be used for dose planning, 1·0 T was actually used in only 14 (1·2%) patients treated at one facility. As Hayashi and colleagues report,5 the smallest tumours detected on MRI images were extremely small—0·003 mL in the 1·0 T group and 0·002 mL in the 1·5 T group.2 Therefore, the minimum cumulative tumour volume of 0·02 mL in the five to ten tumour group was considered to be reasonable. Also, no investigator used a 3·0 T MRI unit for dose planning. We intended to assess long-term changes in neurocognitive function in two patient groups only, those with one to four tumours and those with five to ten tumours; we did not intend to meticulously test change in neurocognitive function. We briefly discussed the validity of the Mini Mental State Examination (MMSE) for evaluating neurocognitive function in the Methods section of our Article.1 Of note, the MMSE can easily be done within 10 min, which is crucial for busy physicians. We also appreciate the interest that Yuichi Takiguchi and colleagues have taken in our recent publication. Many of the potential limitations—eg, limitations of the non-randomised, observational study; patient selection bias; tumour volume-relating factors; patient number proportions in the three groups, etc—were discussed in our original Article1 and above. With regard to whether a non-inferiority test can be applied for a non-randomised, observational study, we respectfully disagree with Takiguchi and colleagues’ opinion. 21 observational studies
using a non-inferiority test can now be found in the Research Registry System of the National Institute of Health. Furthermore, a search of PubMed identified eight citations for observational studies that used a noninferiority test. In conclusion, scarce evidence exists that shows a superiority of wholebrain radiotherapy over stereotactic radiosurgery alone for patients with five to ten tumours, and we believe that our results constitute the highest level of evidence in support of using stereotactic radiosurgery alone for such patients. We declare no competing interests.
*Masaaki Yamamoto, Toru Serizawa, Takashi Shuto, Atsuya Akabane, Yoshinori Higuchi, Jun Kawagishi, Kazuhiro Yamanaka, Yasunori Sato, Hidefumi Jokura [email protected] Katsuta Hospital Mito Gamma House, 5125-2 Nakane, Hitachi-naka, Ibaraki 312–0011, Japan (MY); Tokyo Gamma Unit Center, Tsukiji Neurological Clinic, Tokyo, Japan (TS); Department of Neurosurgery, Yokohama Rosai Hospital, Yokohama, Japan (TS); Gamma Knife Center, NTT Medical Center Tokyo, Tokyo Japan (AA); Department of Neurological Surgery, Chiba University Graduate School of Medicine, Chiba, Japan (YH); Jiro Suzuki Memorial Gamma House, Furukawa Seiryo Hospital, Osaki, Japan (JK, HJ); Department of Neurosurgery, Osaka City University Graduate School of Medicine, Osaka, Japan (KY); Clinical Research Center, Chiba University Graduate School of Medicine, Chiba, Japan (YS) 1
2
3
4
5
Yamamoto M, Serizawa T, Shuto T, et al. Stereotactic radiosurgery for patients with multiple brain metastases (JLGK0901): a multi-institutional prospective observational study. Lancet Oncol 2014; 15: 387–95. Korn EL, Freidlin B, Abrams JS. Overall survival as the outcome for randomized clinical trials with effective subsequent therapies. J Clin Oncol 2011; 29: 2439–42. Aoyama H, Shirato H, Tago M, et al. Stereotactic radiosurgery plus whole-brain radiation therapy vs stereotactic radiosurgery alone for treatment of brain metastases: a randomized controlled trial. JAMA 2006; 295: 2483–91. Murray KJ, Scott C, Greenberg HM, et al. A randomized phase II study of accelerated hyperfractionation versus standard in patients with unresected brain metastases: A report of the Radiation Therapy Oncology Group (RTOG) 9104. Int J Radiation Oncology Biol Phys 1997; 39: 571–74. Hayashi M, Yamamoto M, Nishimura C, et al. Do recent advances in MR technologies contribute to better gamma knife radiosurgery treatment results for brain metastases? Neuroradiol J 2007; 20: 481–90.
www.thelancet.com/oncology Vol 15 June 2014
between patients with two to four metastases and those with five to ten metastases (3·07 mL vs 3·54 mL).1 Additionally, the minimum volume of 0·02 mL at the bottom of the range for both groups raises questions about whether the 1 T MRI used by the investigators is sufficiently sensitive to measure tumours of this size. Fourth, stereotactic radiosurgery was not shown to be better than whole-brain radiotherapy in patients with five to ten metastases. Wholebrain radiotherapy is the standard treatment for non-oligometastatic patients. A Cochrane review3 showed that stereotactic radiosurgery plus whole-brain radiotherapy does not increase survival in patients with two to four brain metastases compared with whole-brain radiotherapy alone, but this combination did increase the frequency of local control, particularly in patients with only one brain metastasis. Use of whole-brain radiotherapy has been questioned because it is associated with late effect on neurocognitive function,4 but brain tumour progression seems to adversely affect neurocognitive function more than whole-brain radiotherapy does.1,5 Neurological function needs more detailed assessment than the MiniMental State Examination used by Yamomoto and colleagues, and in view of the scarce data for wholebrain radiotherapy in their study, the conclusions about neurological function should be interpreted with caution. In conclusion, despite the relevance of Yamamoto and colleagues’ study, its messages need to be interpreted carefully. Oversimplification of oncological treatment should be avoided. The feasibility of stereotactic radiosurgery in patients with up to ten brain metastases seems to be undiscussed in the context of modern radiation technology such as radiosurgery with CyberKnife or Linacbased. Therefore the use of stereotactic radiosurgery in non-oligometastatic www.thelancet.com/oncology Vol 15 June 2014
patients—who died mainly from primary disease in Yamomoto and colleagues’ study—does not seem to be beneficial. We declare no competing interests.
Filippo Alongi, *Alba Fiorentino, Pierina Navarria, Lorenzo Bello, Marta Scorsetti albafi[email protected] Department of Radiation Oncology, Sacro Cuore Hospital, Negrar-Verona 37134, Italy (FA, AF); Department of Radiotherapy and Radiosurgery, Istituto Clinico Humanitas Cancer Center, Milano, Italy (PN, MS); Department of Neurosurgery, Istituto Clinico Humanitas Cancer Center, Milano, Italy (LB) 1
2
3
4
5
Yamamoto M, Serizawa T, Shuto T, et al. Stereotactic radiosurgery for patients with multiple brain metastases (JLGK0901): a multi-institutional prospective observational study. Lancet Oncol 2014; 15: 387–95. Aoyama H, Shirato H, Tago M, et al. Stereotactic radiosurgery plus whole-brain radiation therapy vs stereotactic radiosurgery alone for treatment of brain metastases: a randomized controlled trial. JAMA 2006; 295: 2483–91. Patil CG, Pricola K, Sarmiento JM, Garg SK, Bryant A, Black KL. Whole brain radiation therapy (WBRT) alone versus WBRT and radiosurgery for the treatment of brain metastases. Cochrane Database Syst Rev 2012; 9: CD006121. Soffietti R, Kocher M, Abacioglu UM, et al. A European Organisation for Research and Treatment of Cancer phase III trial of adjuvant whole-brain radiotherapy versus observation in patients with one to three brain metastases from solid tumors after surgical resection or radiosurgery: quality-of-life results. J Clin Oncol 2013; 31: 65–72. Li J, Bentzen SM, Renschler M, Mehta MP. Regression after whole-brain radiation therapy for brain metastases correlates with survival and improved neurocognitive function. J Clin Oncol 2007; 25: 1260–66.
We congratulate Masaaki Yamamoto and colleagues1 for their important contribution to the management of patients with brain metastases, which showed that overall survival in patients with five to ten brain lesions was not inferior to those with two to four lesions when treated with stereotactic radiotherapy. We believe, however, that caution is needed when interpreting these results and we have several concerns. First, although the non-inferior design might be technically feasible for non-randomised studies, it is usually only applied to randomised
phase 3 studies.2-4 Second, the nonrandomised nature of the study introduced selection bias for the three groups, which was substantially varied. In addition to brain metastasis, the conditions of the primary site and other metastatic sites obviously affect survival, yet this study limitation was not mentioned in the article. The fact that deaths unrelated to brain disease accounted for 92% of all deaths suggests that lesions other than brain metastases affected the survival in this study population. In Japan where the study was conducted, clinical guidelines recommend stereotactic radiosurgery as an option for patients with up to four brain metastases only, as the authors mentioned. Oncologists refer patients for stereotactic radiosurgery using different criteria for patients with brain metastases up to four lesions than for patients with more than four lesions. Consequently, in Yamamoto and colleagues’ study, they treated twice as many patients with two to four brain lesions than patients with more than four lesions, in contrast to their preplanned ratio of 1:1. This result might have been a consequence of selection bias between the groups. Additionally, the proportions of patients with pretreatment neurological symptoms were similar between the group with two to four brain lesions (33%) and the group with five to ten lesions (31%). These results suggest that the oncologists applied stricter criteria when selecting patients with multiple brain-metastases for stereotactic radiosurgery referral than for the selection of patients with fewer brainmetastases. Additional data about the characteristics of patients who had brain metastases but were not referred for stereotactic radiosurgery would clarify this issue. Needless to say, the work by Yamamoto and colleagues is invaluable for the indication that stereotactic radiosurgery is a promising option for management e247
Correspondence
For the Research Registry System of the National Institute of Health see http://www.clinicaltrials.gov/ ct2/results?term=Noninferiority &recr=&rslt=&ty
of brain metastases, even in patients with multiple metastases, if patients are carefully selected. Well designed, randomised studies are now needed to further generalise these results. We declare no competing interests.
*Yuichi Takiguchi, Ikuo Sekine, Shunichiro Iwasawa, Ryota Kurimoto, Takashi Uehara [email protected] Department of Medical Oncology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan (YT, IS, SI, RK); Department of Reproductive Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan (TU) 1
2
3
4
Yamamoto M, Serizawa T, Shuto T, et al. Stereotactic radiosurgery for patients with multiple brain metastases (JLGK0901): a multi-institutional prospective observational study. Lancet Oncol 2014; 15: 387–95. Weintraub WS. Cutting through the statistical fog: understanding and evaluating noninferiority trials. Int J Clin Pract 2010; 64: 1359–66. Riechelmann RP, Alex A, Cruz L, Bariani GM, Hoff PM. Non-inferiority cancer clinical trials: scope and purposes underlying their design. Ann Oncol 2013; 24: 1942–47. Schiller P, Burchardi N, Niestroj M, Kieser M. Quality of reporting of clinical non-inferiority and equivalence randomised trials–update and extension. Trials 2012; 13: 214.
Authors’ reply We thank Filippo Alongi and colleagues for their interest in our work.1 We are aware that there has been a debate for more than 20 years as to whether it is meaningful to calculate survival after stereotactic radiosurgery in a cohort, because about 90% of patients died in our study due to extracerebral disease progression after stereotactic radiosurgery for brain metastases. However, overall survival is still the most certain endpoint, as reported by Korn and colleagues,2 and the majority of previous studies have used overall survival to assess results after stereotactic radiosurgery. Nevertheless, as Alongi and colleagues point out, overall survival alone cannot be regarded as sufficient. Thus, we analysed several secondary endpoints in our study to compensate for this weakness. With regard to the distribution of original tumours, the proportion of e248
patients with primary lung cancer (76%; 8% small-cell lung cancer and 68% non-small-cell lung cancer) in our study did not differ markedly from those seen in previously reported randomised trials.3,4 Another possible weakness of our study might be that clinical factors are obviously heterogeneous. However, we feel that these heterogeneous patient groups reflect actual clinical practice. Although the study protocol stated that 1·0 T or higher MRI units should be used for dose planning, 1·0 T was actually used in only 14 (1·2%) patients treated at one facility. As Hayashi and colleagues report,5 the smallest tumours detected on MRI images were extremely small—0·003 mL in the 1·0 T group and 0·002 mL in the 1·5 T group.2 Therefore, the minimum cumulative tumour volume of 0·02 mL in the five to ten tumour group was considered to be reasonable. Also, no investigator used a 3·0 T MRI unit for dose planning. We intended to assess long-term changes in neurocognitive function in two patient groups only, those with one to four tumours and those with five to ten tumours; we did not intend to meticulously test change in neurocognitive function. We briefly discussed the validity of the Mini Mental State Examination (MMSE) for evaluating neurocognitive function in the Methods section of our Article.1 Of note, the MMSE can easily be done within 10 min, which is crucial for busy physicians. We also appreciate the interest that Yuichi Takiguchi and colleagues have taken in our recent publication. Many of the potential limitations—eg, limitations of the non-randomised, observational study; patient selection bias; tumour volume-relating factors; patient number proportions in the three groups, etc—were discussed in our original Article1 and above. With regard to whether a non-inferiority test can be applied for a non-randomised, observational study, we respectfully disagree with Takiguchi and colleagues’ opinion. 21 observational studies
using a non-inferiority test can now be found in the Research Registry System of the National Institute of Health. Furthermore, a search of PubMed identified eight citations for observational studies that used a noninferiority test. In conclusion, scarce evidence exists that shows a superiority of wholebrain radiotherapy over stereotactic radiosurgery alone for patients with five to ten tumours, and we believe that our results constitute the highest level of evidence in support of using stereotactic radiosurgery alone for such patients. We declare no competing interests.
*Masaaki Yamamoto, Toru Serizawa, Takashi Shuto, Atsuya Akabane, Yoshinori Higuchi, Jun Kawagishi, Kazuhiro Yamanaka, Yasunori Sato, Hidefumi Jokura [email protected] Katsuta Hospital Mito Gamma House, 5125-2 Nakane, Hitachi-naka, Ibaraki 312–0011, Japan (MY); Tokyo Gamma Unit Center, Tsukiji Neurological Clinic, Tokyo, Japan (TS); Department of Neurosurgery, Yokohama Rosai Hospital, Yokohama, Japan (TS); Gamma Knife Center, NTT Medical Center Tokyo, Tokyo Japan (AA); Department of Neurological Surgery, Chiba University Graduate School of Medicine, Chiba, Japan (YH); Jiro Suzuki Memorial Gamma House, Furukawa Seiryo Hospital, Osaki, Japan (JK, HJ); Department of Neurosurgery, Osaka City University Graduate School of Medicine, Osaka, Japan (KY); Clinical Research Center, Chiba University Graduate School of Medicine, Chiba, Japan (YS) 1
2
3
4
5
Yamamoto M, Serizawa T, Shuto T, et al. Stereotactic radiosurgery for patients with multiple brain metastases (JLGK0901): a multi-institutional prospective observational study. Lancet Oncol 2014; 15: 387–95. Korn EL, Freidlin B, Abrams JS. Overall survival as the outcome for randomized clinical trials with effective subsequent therapies. J Clin Oncol 2011; 29: 2439–42. Aoyama H, Shirato H, Tago M, et al. Stereotactic radiosurgery plus whole-brain radiation therapy vs stereotactic radiosurgery alone for treatment of brain metastases: a randomized controlled trial. JAMA 2006; 295: 2483–91. Murray KJ, Scott C, Greenberg HM, et al. A randomized phase II study of accelerated hyperfractionation versus standard in patients with unresected brain metastases: A report of the Radiation Therapy Oncology Group (RTOG) 9104. Int J Radiation Oncology Biol Phys 1997; 39: 571–74. Hayashi M, Yamamoto M, Nishimura C, et al. Do recent advances in MR technologies contribute to better gamma knife radiosurgery treatment results for brain metastases? Neuroradiol J 2007; 20: 481–90.
www.thelancet.com/oncology Vol 15 June 2014
