Correspondence
consideration in this article. Certain relationships marked with a “U” are those for which no compensation was received; those relationships marked with a “C” were compensated. For a detailed description of the disclosure categories, or for more information about ASCO’s conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment or Leadership Position: None Consultant or Advisory Role: Barry A. Siegel, Siemens Healthcare (C), GE Healthcare (C); Fenghai Duan, WorldCare Clinical (C) Stock Ownership: Barry A. Siegel, Radiology Corporation of America Honoraria: Barry A. Siegel, Siemens Medical Solutions, GE Healthcare, Philips Healthcare Research Funding: None Expert Testimony: None Patents, Royalties, and Licenses: None Other Remuneration: None REFERENCES 1. Ryu J-S, Hyun IY: Prognostic impact of [18F]fluorodeoxyglucose positron emission tomography scanning in the era of molecular oncology. J Clin Oncol 32:1630, 2014 2. Berman AT, Ellenberg SS, Simone CB II: Predicting survival in non–small-cell lung cancer using positron emission tomography: Several conclusions from multiple comparisons. J Clin Oncol 32:1631-1632, 2014 3. Machtay M, Duan F, Siegel BA, et al: Prediction of survival by [18F]fluorodeoxyglucose positron emission tomography in patients with locally advanced
non–small-cell lung cancer undergoing definitive chemoradiation therapy: Results of the ACRIN 6668/RTOG 0235 trial. J Clin Oncol 31:3823-3830, 2013 4. Mauguen A, Pignon JP, Burdett S, et al: Surrogate endpoints for overall survival in chemotherapy and radiotherapy trials in operable and locally advanced lung cancer: A re-analysis of meta-analyses of individual patients’ data. Lancet Oncol 14:619-626, 2013 5. Machtay M, Paulus R, Moughan J, et al: Defining local-regional control and its importance in locally advanced non–small-cell lung carcinoma. J Thorac Oncol 7:716-722, 2012 6. Boellaard R, Krak NC, Hoekstra OS, et al: Effects of noise, image resolution, and ROI definition on the accuracy of standard uptake values: A simulation study. J Nucl Med 45:1519-1527, 2004 7. Wahl R, Jacene H, Kasamon Y, et al: From RECIST to PERCIST: Evolving considerations for PET response criteria in solid tumors. J Nucl Med 50:122S150S, 2009 (suppl 1) 8. Lodge MA, Chaudhry MA, Wahl RL: Noise considerations for PET quantification using maximum and peak standardized uptake value. J Nucl Med 53:1041-1047, 2012 9. Rosenzweig KE, Erdi Y, Schoder H, et al: Positron emission tomography after three-dimensional conformal radiation therapy for non-small cell lung carcinoma. 43rd Annual Meeting of the American Society for Therapeutic Radiation Oncology, San Francisco, CA, November 4-8, 2001 (abstr 159)
DOI: 10.1200/JCO.2013.54.6176; published online ahead of print at www.jco.org on April 21, 2014
■ ■ ■
Lessons Learned From Radiation Therapy Oncology Group 0525 Trial TO THE EDITOR: Gilbert et al1 are to be congratulated on the conception and execution of the large Radiation Therapy Oncology Group (RTOG) 0525 trial in patients with newly diagnosed glioblastoma (GBM) comparing standard dose (sd) postradiotherapy temozolomide (TMZ) with dose-dense TMZ.1 The hypothesis tested was whether dose-dense TMZ would improve overall survival on the basis of the premise of increased methylguanine methyltransferase (MGMT) enzyme depletion, the predominant enzymatic mechanism of DNA repair after alkylator-induced genotoxic injury. Several comments are warranted. In vitro experimental evidence suggests that glioma cell kill is a function of TMZ dose (ie, the maximum or peak concentration achieved rather than repeated exposure to TMZ as used in the RTOG 0525 study).2 Consequently, the negative results of RTOG 0525 are not altogether surprising. However, the clinical challenge with increasing TMZ dose is that of myelosuppression resulting in dose-limiting toxicity. Currently, there is no mechanism to abrogate TMZ-induced myelotoxicity, which in part reflects impoverished MGMT content in progenitor hematopoietic cells. As stated by the authors,1 the RTOG 0525 study confirmed results of the seminal European Organisation for Research and Treatment of Cancer (EORTC)/National Cancer Institute of Canada (NCIC) trial (radiation therapy [RT] v RT plus concurrent and post-RT sdTMZ) in patients with MGMT promoter methylated tumors, comprising one third of all newly diagnosed GBM tumors, that survival is improved with receipt of RT plus TMZ compared with unmethylated tumors.3 Importantly, as a result of the trial design that included RT plus TMZ in both treatment arms, RTOG 0525 neither confirmed or repudiated the results of EORTC/NCIC suggesting little to no benefit of RT plus TMZ in MGMT unmethwww.jco.org
ylated tumors. Currently, all patients with newly diagnosed GBM continue to be treated with RT plus TMZ regardless of MGMT methylation status and notwithstanding the limitations of this regimen in the majority of patients with GBM. Not addressed specifically in RTOG 0525 were age-specific survival data, in particular in the elderly cohort (defined by an age older than 70 years at time of diagnosis). There exists considerable controversy as to whether RT or TMZ alone is equivalent first-line treatment compared with RT plus TMZ in this population. This controversy persists despite recent randomized studies (the German NOA-084 and Nordic5 trials) that highlight the clinical use of either single modality of treatment (RT or sdTMZ). In large part, the disagreement regarding the best approach to physiologically fit elderly patients with GBM reflects a lack of evidence, given that there are no prospective trials comparing single-modality therapy (RT or TMZ) with combination therapy (RT plus TMZ). The EORTC/NCIC study3 showed little benefit to combination therapy in patients age 65 years and older; however the protocol excluded patients older than age 70 years. Additionally, the German4 and Nordic5 trials emphasized the clinical relevance of MGMT methylation status with respect to treatment allocation in elderly patients with GBM. Because elderly patients constitute nearly 25% of all patients with GBM, evidence-based treatment of this group is germane.6 A currently open trial by the NCIC/EORTC is addressing this controversy by comparing hypofractionated RT (40 Gy in 15 fractions) that is equivalent to standard fractionated RT (60 Gy in 30 fractions), with or without TMZ. Finally, the explanation for expansion of post-RT TMZ from six cycles as in the EORTC/NCIC study3 to 12 cycles in the RTOG 05251 study is never addressed. The hypothesis that prolonged maintenance TMZ improves survival is not apparent on the basis of the results of RTOG 0525. Only 40% of patients completed six cycles of TMZ, and only 15% completed the protocolmandated 12 cycles of TMZ. This patient group would seem to be self-selected by virtue of longer disease-free survival in those © 2014 by American Society of Clinical Oncology
Information downloaded from jco.ascopubs.org and provided by at University of Aberdeen on October 4, 2014 from Copyright © 2014 American Society of Clinical Oncology. All rights reserved. 139.133.11.2
1633
Correspondence
patients for whom the benefit of prolonged maintenance TMZ is unclear. Nonetheless, the use of 12 cycles of post-RT TMZ in patients with newly diagnosed GBM is a common practice, notwithstanding the lack of evidence to support prolonged maintenance TMZ. These comments are not meant to diminish the significant efforts by the RTOG study group but rather to ask whether this study is practice changing? No, although we should acknowledge the substudy of net clinical benefit contained within RTOG 0525 that highlights a hitherto neglected dimension of treatment effect and that will likely become a new standard assessment instrument in randomized trials of gliomas.7 Are the results sufficiently different than currently used therapies? No, RT plus TMZ remains the standard of care for protocol eligible young patients with newly diagnosed GBM. Might there be an opportunity to further refine the approach to GBM? Absolutely, but the challenge has been how and with what novel therapy.
Marc C. Chamberlain University of Washington, Seattle, WA
REFERENCES 1. Gilbert MR, Wang M, Aldape KD, et al: Dose-dense temozolomide for newly diagnosed glioblastoma: A randomized phase III clinical trial. J Clin Oncol 31:4085-4091, 2013 2. Bobola MS, Kolstoe DD, Blank A, et al: Minimally cytotoxic doses of temozolomide produce radiosensitization in human glioblastoma cells regardless of MGMT expression. Mol Cancer Ther 9:1208-1218, 2010 3. Stupp R, Mason WP, van den Bent MJ, et al: Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352:987-996, 2005 4. Malmstro¨m A, Grønberg BH, Marosi C, et al: Temozolomide versus standard 6-week radiotherapy versus hypofractionated radiotherapy in patients older than 60 years with glioblastoma: The Nordic randomised, phase 3 trial. Lancet Oncol 13:916-926, 2012 5. Wick W, Platten M, Meisner C, et al: Temozolomide chemotherapy alone versus radiotherapy alone for malignant astrocytoma in the elderly: The NOA-08 randomised, phase 3 trial. Lancet Oncol 13:707-715, 2012 6. Laperriere N, Weller M, Stupp R, et al: Optimal management of elderly patients with glioblastoma. Cancer Treat Rev 39:350-357, 2013 7. Armstrong TS, Wefel JS, Wang M, et al: Net clinical benefit analysis of Radiation Therapy Oncology Group 0525: A phase III trial comparing conventional adjuvant temozolomide with-dose intensive temozolomide in patients with newly diagnosed glioblastoma. J Clin Oncol 31:4076-4084, 2013
DOI: 10.1200/JCO.2013.54.6226; published online ahead of print at www.jco.org on April 21, 2014
AUTHOR’S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
The author(s) indicated no potential conflicts of interest.
■ ■ ■
Reply to M.C. Chamberlain We appreciate the laudatory comments in the letter by Chamberlain1 regarding our recent publication in Journal of Clinical Oncology2,3 and agree with many of his statements. However, we want to clarify several of his concerns. First, it is unclear whether in vitro experimental data regarding the efficacy of temozolomide truly mirrors in vivo and clinical experience. Beginning with the earliest clinical studies, the 5-day, lower dose schedule was felt to be superior to the single, large-dose administration of temozolomide, establishing the 5-day schedule as the standard single-agent dosing regimen.4 Additionally, a variety of dose-dense schedules of temozolomide have been tested in recurrent glioblastoma and support the hypothesis that more frequent and lower daily dosing (but an increase in total dose administered) may be superior to the standard 5-day dosing schedule. In single-arm phase II trials, a schedule of 7 days on/7 days off, 21 of 28 days, and daily low-dose temozolomide showed promising activity, providing the clinically based rationale for the RTOG 0525 study.5-7 Our results now allow us to reject this hypothesis with the confidence of a prospective randomized trial. We agree that the results from RTOG 0525 confirm the findings from the European Organisation for Research and Treatment of Cancer (EORTC)/National Cancer Institute of Canada (NCIC) study demonstrating the clinical usefulness of MGMT promoter methylation in tumors as a molecular marker for outcome.8,9 Whereas the EORTC/NCIC study was performed post hoc on a subset of tumor samples, our study provides the first, to our knowledge, prospective confirmation of the prognostic significance of MGMT methylation status. Chamberlain1 does raise an important question regarding patient age and optimal treatment. Unlike the EORTC/NCIC study in which patients up to the age of 70 years were included, the RTOG 0525 study did not have an upper age limit. The impact of age was not a 1634
© 2014 by American Society of Clinical Oncology
planned analysis, but given the increasing incidence of glioblastoma among the elderly, we recently examined the outcomes in these patients. This post hoc analysis revealed a median survival of 9.9 months with 30% 1-year survival for the standard-dose arm and a median survival of 9.6 months with 34% 1-year survival for patients on the dose-dense arm. These results compare favorably with other randomized clinical trials comparing radiation versus chemotherapy regimens in elderly patients with glioblastoma.10,11 We agree that the question of the duration of maintenance temozolomide after completion of concurrent radiation and temozolomide remains unanswered. In preparation for RTOG 0525, we conducted an informal survey and found that most physicians in the United States would recommend up to 12 cycles of maintenance chemotherapy; hence we allowed treatment continuation beyond six cycles if, in the opinion of the treating physician, the patient was benefitting from continued treatment. We did analyze the impact of voluntarily stopping at 6 cycles versus continuing. The number of patients voluntarily stopping at 6 cycles was too small to allow for a meaningful statistical comparison; this question therefore remains unanswered.2 Finally, we are pleased that Chamberlain shares our conviction that patient-centered outcomes measures such as neurocognitive function and patient reported outcomes (symptom burden and health-related quality of life) are important and should be integral components of these large potentially practice-changing studies.3 We would add to Chamberlain’s comments that these measures, referred to as net clinical benefits, provide information regarding the impact of disease in addition to treatment effects.
Mark R. Gilbert The University of Texas MD Anderson Cancer Center, Houston, TX
James Dignam and Stephanie Pugh Radiation Therapy Oncology Group Statistical Center, Philadelphia, PA JOURNAL OF CLINICAL ONCOLOGY
Information downloaded from jco.ascopubs.org and provided by at University of Aberdeen on October 4, 2014 from Copyright © 2014 American Society of Clinical Oncology. All rights reserved. 139.133.11.2
consideration in this article. Certain relationships marked with a “U” are those for which no compensation was received; those relationships marked with a “C” were compensated. For a detailed description of the disclosure categories, or for more information about ASCO’s conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment or Leadership Position: None Consultant or Advisory Role: Barry A. Siegel, Siemens Healthcare (C), GE Healthcare (C); Fenghai Duan, WorldCare Clinical (C) Stock Ownership: Barry A. Siegel, Radiology Corporation of America Honoraria: Barry A. Siegel, Siemens Medical Solutions, GE Healthcare, Philips Healthcare Research Funding: None Expert Testimony: None Patents, Royalties, and Licenses: None Other Remuneration: None REFERENCES 1. Ryu J-S, Hyun IY: Prognostic impact of [18F]fluorodeoxyglucose positron emission tomography scanning in the era of molecular oncology. J Clin Oncol 32:1630, 2014 2. Berman AT, Ellenberg SS, Simone CB II: Predicting survival in non–small-cell lung cancer using positron emission tomography: Several conclusions from multiple comparisons. J Clin Oncol 32:1631-1632, 2014 3. Machtay M, Duan F, Siegel BA, et al: Prediction of survival by [18F]fluorodeoxyglucose positron emission tomography in patients with locally advanced
non–small-cell lung cancer undergoing definitive chemoradiation therapy: Results of the ACRIN 6668/RTOG 0235 trial. J Clin Oncol 31:3823-3830, 2013 4. Mauguen A, Pignon JP, Burdett S, et al: Surrogate endpoints for overall survival in chemotherapy and radiotherapy trials in operable and locally advanced lung cancer: A re-analysis of meta-analyses of individual patients’ data. Lancet Oncol 14:619-626, 2013 5. Machtay M, Paulus R, Moughan J, et al: Defining local-regional control and its importance in locally advanced non–small-cell lung carcinoma. J Thorac Oncol 7:716-722, 2012 6. Boellaard R, Krak NC, Hoekstra OS, et al: Effects of noise, image resolution, and ROI definition on the accuracy of standard uptake values: A simulation study. J Nucl Med 45:1519-1527, 2004 7. Wahl R, Jacene H, Kasamon Y, et al: From RECIST to PERCIST: Evolving considerations for PET response criteria in solid tumors. J Nucl Med 50:122S150S, 2009 (suppl 1) 8. Lodge MA, Chaudhry MA, Wahl RL: Noise considerations for PET quantification using maximum and peak standardized uptake value. J Nucl Med 53:1041-1047, 2012 9. Rosenzweig KE, Erdi Y, Schoder H, et al: Positron emission tomography after three-dimensional conformal radiation therapy for non-small cell lung carcinoma. 43rd Annual Meeting of the American Society for Therapeutic Radiation Oncology, San Francisco, CA, November 4-8, 2001 (abstr 159)
DOI: 10.1200/JCO.2013.54.6176; published online ahead of print at www.jco.org on April 21, 2014
■ ■ ■
Lessons Learned From Radiation Therapy Oncology Group 0525 Trial TO THE EDITOR: Gilbert et al1 are to be congratulated on the conception and execution of the large Radiation Therapy Oncology Group (RTOG) 0525 trial in patients with newly diagnosed glioblastoma (GBM) comparing standard dose (sd) postradiotherapy temozolomide (TMZ) with dose-dense TMZ.1 The hypothesis tested was whether dose-dense TMZ would improve overall survival on the basis of the premise of increased methylguanine methyltransferase (MGMT) enzyme depletion, the predominant enzymatic mechanism of DNA repair after alkylator-induced genotoxic injury. Several comments are warranted. In vitro experimental evidence suggests that glioma cell kill is a function of TMZ dose (ie, the maximum or peak concentration achieved rather than repeated exposure to TMZ as used in the RTOG 0525 study).2 Consequently, the negative results of RTOG 0525 are not altogether surprising. However, the clinical challenge with increasing TMZ dose is that of myelosuppression resulting in dose-limiting toxicity. Currently, there is no mechanism to abrogate TMZ-induced myelotoxicity, which in part reflects impoverished MGMT content in progenitor hematopoietic cells. As stated by the authors,1 the RTOG 0525 study confirmed results of the seminal European Organisation for Research and Treatment of Cancer (EORTC)/National Cancer Institute of Canada (NCIC) trial (radiation therapy [RT] v RT plus concurrent and post-RT sdTMZ) in patients with MGMT promoter methylated tumors, comprising one third of all newly diagnosed GBM tumors, that survival is improved with receipt of RT plus TMZ compared with unmethylated tumors.3 Importantly, as a result of the trial design that included RT plus TMZ in both treatment arms, RTOG 0525 neither confirmed or repudiated the results of EORTC/NCIC suggesting little to no benefit of RT plus TMZ in MGMT unmethwww.jco.org
ylated tumors. Currently, all patients with newly diagnosed GBM continue to be treated with RT plus TMZ regardless of MGMT methylation status and notwithstanding the limitations of this regimen in the majority of patients with GBM. Not addressed specifically in RTOG 0525 were age-specific survival data, in particular in the elderly cohort (defined by an age older than 70 years at time of diagnosis). There exists considerable controversy as to whether RT or TMZ alone is equivalent first-line treatment compared with RT plus TMZ in this population. This controversy persists despite recent randomized studies (the German NOA-084 and Nordic5 trials) that highlight the clinical use of either single modality of treatment (RT or sdTMZ). In large part, the disagreement regarding the best approach to physiologically fit elderly patients with GBM reflects a lack of evidence, given that there are no prospective trials comparing single-modality therapy (RT or TMZ) with combination therapy (RT plus TMZ). The EORTC/NCIC study3 showed little benefit to combination therapy in patients age 65 years and older; however the protocol excluded patients older than age 70 years. Additionally, the German4 and Nordic5 trials emphasized the clinical relevance of MGMT methylation status with respect to treatment allocation in elderly patients with GBM. Because elderly patients constitute nearly 25% of all patients with GBM, evidence-based treatment of this group is germane.6 A currently open trial by the NCIC/EORTC is addressing this controversy by comparing hypofractionated RT (40 Gy in 15 fractions) that is equivalent to standard fractionated RT (60 Gy in 30 fractions), with or without TMZ. Finally, the explanation for expansion of post-RT TMZ from six cycles as in the EORTC/NCIC study3 to 12 cycles in the RTOG 05251 study is never addressed. The hypothesis that prolonged maintenance TMZ improves survival is not apparent on the basis of the results of RTOG 0525. Only 40% of patients completed six cycles of TMZ, and only 15% completed the protocolmandated 12 cycles of TMZ. This patient group would seem to be self-selected by virtue of longer disease-free survival in those © 2014 by American Society of Clinical Oncology
Information downloaded from jco.ascopubs.org and provided by at University of Aberdeen on October 4, 2014 from Copyright © 2014 American Society of Clinical Oncology. All rights reserved. 139.133.11.2
1633
Correspondence
patients for whom the benefit of prolonged maintenance TMZ is unclear. Nonetheless, the use of 12 cycles of post-RT TMZ in patients with newly diagnosed GBM is a common practice, notwithstanding the lack of evidence to support prolonged maintenance TMZ. These comments are not meant to diminish the significant efforts by the RTOG study group but rather to ask whether this study is practice changing? No, although we should acknowledge the substudy of net clinical benefit contained within RTOG 0525 that highlights a hitherto neglected dimension of treatment effect and that will likely become a new standard assessment instrument in randomized trials of gliomas.7 Are the results sufficiently different than currently used therapies? No, RT plus TMZ remains the standard of care for protocol eligible young patients with newly diagnosed GBM. Might there be an opportunity to further refine the approach to GBM? Absolutely, but the challenge has been how and with what novel therapy.
Marc C. Chamberlain University of Washington, Seattle, WA
REFERENCES 1. Gilbert MR, Wang M, Aldape KD, et al: Dose-dense temozolomide for newly diagnosed glioblastoma: A randomized phase III clinical trial. J Clin Oncol 31:4085-4091, 2013 2. Bobola MS, Kolstoe DD, Blank A, et al: Minimally cytotoxic doses of temozolomide produce radiosensitization in human glioblastoma cells regardless of MGMT expression. Mol Cancer Ther 9:1208-1218, 2010 3. Stupp R, Mason WP, van den Bent MJ, et al: Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352:987-996, 2005 4. Malmstro¨m A, Grønberg BH, Marosi C, et al: Temozolomide versus standard 6-week radiotherapy versus hypofractionated radiotherapy in patients older than 60 years with glioblastoma: The Nordic randomised, phase 3 trial. Lancet Oncol 13:916-926, 2012 5. Wick W, Platten M, Meisner C, et al: Temozolomide chemotherapy alone versus radiotherapy alone for malignant astrocytoma in the elderly: The NOA-08 randomised, phase 3 trial. Lancet Oncol 13:707-715, 2012 6. Laperriere N, Weller M, Stupp R, et al: Optimal management of elderly patients with glioblastoma. Cancer Treat Rev 39:350-357, 2013 7. Armstrong TS, Wefel JS, Wang M, et al: Net clinical benefit analysis of Radiation Therapy Oncology Group 0525: A phase III trial comparing conventional adjuvant temozolomide with-dose intensive temozolomide in patients with newly diagnosed glioblastoma. J Clin Oncol 31:4076-4084, 2013
DOI: 10.1200/JCO.2013.54.6226; published online ahead of print at www.jco.org on April 21, 2014
AUTHOR’S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
The author(s) indicated no potential conflicts of interest.
■ ■ ■
Reply to M.C. Chamberlain We appreciate the laudatory comments in the letter by Chamberlain1 regarding our recent publication in Journal of Clinical Oncology2,3 and agree with many of his statements. However, we want to clarify several of his concerns. First, it is unclear whether in vitro experimental data regarding the efficacy of temozolomide truly mirrors in vivo and clinical experience. Beginning with the earliest clinical studies, the 5-day, lower dose schedule was felt to be superior to the single, large-dose administration of temozolomide, establishing the 5-day schedule as the standard single-agent dosing regimen.4 Additionally, a variety of dose-dense schedules of temozolomide have been tested in recurrent glioblastoma and support the hypothesis that more frequent and lower daily dosing (but an increase in total dose administered) may be superior to the standard 5-day dosing schedule. In single-arm phase II trials, a schedule of 7 days on/7 days off, 21 of 28 days, and daily low-dose temozolomide showed promising activity, providing the clinically based rationale for the RTOG 0525 study.5-7 Our results now allow us to reject this hypothesis with the confidence of a prospective randomized trial. We agree that the results from RTOG 0525 confirm the findings from the European Organisation for Research and Treatment of Cancer (EORTC)/National Cancer Institute of Canada (NCIC) study demonstrating the clinical usefulness of MGMT promoter methylation in tumors as a molecular marker for outcome.8,9 Whereas the EORTC/NCIC study was performed post hoc on a subset of tumor samples, our study provides the first, to our knowledge, prospective confirmation of the prognostic significance of MGMT methylation status. Chamberlain1 does raise an important question regarding patient age and optimal treatment. Unlike the EORTC/NCIC study in which patients up to the age of 70 years were included, the RTOG 0525 study did not have an upper age limit. The impact of age was not a 1634
© 2014 by American Society of Clinical Oncology
planned analysis, but given the increasing incidence of glioblastoma among the elderly, we recently examined the outcomes in these patients. This post hoc analysis revealed a median survival of 9.9 months with 30% 1-year survival for the standard-dose arm and a median survival of 9.6 months with 34% 1-year survival for patients on the dose-dense arm. These results compare favorably with other randomized clinical trials comparing radiation versus chemotherapy regimens in elderly patients with glioblastoma.10,11 We agree that the question of the duration of maintenance temozolomide after completion of concurrent radiation and temozolomide remains unanswered. In preparation for RTOG 0525, we conducted an informal survey and found that most physicians in the United States would recommend up to 12 cycles of maintenance chemotherapy; hence we allowed treatment continuation beyond six cycles if, in the opinion of the treating physician, the patient was benefitting from continued treatment. We did analyze the impact of voluntarily stopping at 6 cycles versus continuing. The number of patients voluntarily stopping at 6 cycles was too small to allow for a meaningful statistical comparison; this question therefore remains unanswered.2 Finally, we are pleased that Chamberlain shares our conviction that patient-centered outcomes measures such as neurocognitive function and patient reported outcomes (symptom burden and health-related quality of life) are important and should be integral components of these large potentially practice-changing studies.3 We would add to Chamberlain’s comments that these measures, referred to as net clinical benefits, provide information regarding the impact of disease in addition to treatment effects.
Mark R. Gilbert The University of Texas MD Anderson Cancer Center, Houston, TX
James Dignam and Stephanie Pugh Radiation Therapy Oncology Group Statistical Center, Philadelphia, PA JOURNAL OF CLINICAL ONCOLOGY
Information downloaded from jco.ascopubs.org and provided by at University of Aberdeen on October 4, 2014 from Copyright © 2014 American Society of Clinical Oncology. All rights reserved. 139.133.11.2
