In response to Drs. Mehrkens, Stummer, and Kreth
1
RESPONSE TO DRS. BAUMAN ET AL.: PRETREATMENT FACTORS PREDICT OVERALL SURVIVAL FOR PATIENTS WITH LOW-GRADE GLIOMA: A RECURSIVE PARTITIONING ANALYSIS (IJROBP 1997;45[4]:923-929, 1999) To the Editor: The efficacy of external beam radiation for treating patients with WHO Grade II gliomas remains uncertain despite the results of the European prospective randomized studies. Neither higher tumor doses nor the immediate initiation of radiation therapy after surgery were associated with a significant survival advantage (1,2). These somewhat disappointing results might be explained by the pro- nounced clinical (biological) heterogeneity of WHO Grade II gliomas, which has eventually rendered favorable effects of radiation therapy on selected patient subgroups undetectable in the EORTC studies. There- fore, identification of risk cohorts, as performed by Bauman et al., appears essential in order to overcome the effects of tumor heteroge- neity and to improve the design of subsequent clinical trials. Using recursive partitioning analysis of three institutional databases (which were merged), Bauman et al. quantified the effects of pretreatment factors such as age (. 40 vs. # 40 yrs.), Karnofsky score (, 70 vs. $ 70), and focal enhancement on CT/MRI (yes vs. no). Partitioning analysis yielded subgroups of patients with median survivals ranging from as low as 12 months (KPS , 70, age . 40 yrs.) to as high as 128 months (KPS $ 70, age 18-40 yrs.). These highly divergent survival times underscore the necessity to tailor the design of modern clinical trials to more homogeneous patient subgroups. One might wonder, for a number of reasons, if the prognostic model created by Bauman et al. should be considered representative for this heterogeneous disease. It was remarkable that the factor “treating institution” was not considered in the recursive partitioning analysis, despite its enormous prognostic influence on multivariate analysis (sur- vival was longest in the University of California, San Francisco (UCSF) and shortest in the Norwegian Radium Hospital (NRH)). This institu- tion-dependent prognostic factor could not be translated in terms of patient- and/or treatment related factors. Even though the authors have stated that differences in referral patterns, surgical radicality and as- signment of tumor pathology of the three institutions would explain treatment results in favor of the UCSF, this speculation was not sup- ported by the presented data set. Treatment-related factors (e.g. extent of resection) and histology-related factors did not yield any prognostic influence in the final prognostic model. Thus, the prognostic importance of the institutional-related factor was not explained in the paper of Bauman et al. and excluding treating institution from recursive parti- tioning analysis would consequently appear inappropriate. In 1997 Kreth et al. (3) have similarly quantified the impact of pretreat- ment factors for 197 adult patients with WHO Grade II astrocytomas and oligo-astrocytomas, treated with interstitial radiosurgery. In accordance with the paper of Bauman et al. highly divergent survival groups were identified. In contrast, the study of Kreth et al. focuses on several tumor- related factors in greater detail. Most importantly, patients with large pre-treatment tumor volumes ( 20 ml) fared significantly worse. The powerful influence of pre-treatment tumor volume has also been recog- nized by others (1,4), and it seems surprising that this factor was neither investigated nor discussed in the Bauman paper. Possibly, one part of the unexplained institution-dependent differences in survival may be due to imbalances regarding tumor-related prognostic factors in the individual centers. We agree with Bauman et al. that modern treatment strategies (such as stereotactic radiotherapy and interstitial radiosurgery) would probably in- fluence survival only if appropriate patient subgroups could be identified. Therefore, any decision model should consider the complex network of patient- tumor- and treatment-related factors. JAN H. MEHRKENS, M.D. WALTER STUMMER, M.D. FRIEDRICH W. KRETH, M.D. Department of Neurosurgery Klinikum Grosshadern Ludwig- Maximilians-University Klinikum Grobhadern Marchioninistr. 15 81377 Munich, Germany PII S0360-3016(00)00651-9 1. Karim ABMF, Maat B, Haltevoll R, Menten J, Rutten EHJM, Thomas DGT, Mascarenhas F, Horiot JC, Parvinen LM, van Reijn M, Jager JJ, Fabrini MG, van Alphen AM, Hamers HP, Gaspar L, Noordman E, Pierat M, van Glabbeke M. A randomized trial on dose-response in radiation therapy of low-grade cerebral glioma: European Organiza- tion for Research and Treatment of Cancer (EORTC) Study 22844. Int J Radiat Oncol Biol Phys 1996; 36: 549-556. 2. Karim ABMF, Cornu P, Bleehen N, et al. Immediate postoperative radiotherapy in low grade glioma improves progression free survival but not overall survival: preliminary results of an EORTC/MRC ran- domized Phase III study. Abstr. 1544, Proc Am Soc Clin Oncol 17:400a, 1998 3. Kreth FW, Faist M, Rossner R, Volk B, Ostertag CB. Supratentorial World Health Organization Grade 2 Astrocytomas and Oligoastrocy- tomas. A new pattern of prognostic factors. Cancer 1997;79: 370-379. 4. Berger MS, Deliganis AV, Dobbins J, Keles GE. The effect of extent of resection on recurrence in patients with low grade cerebral hemi- sphere gliomas. Cancer 1994; 74: 1784-1791. IN RESPONSE TO DRS. MEHRKENS, STUMMER, AND KRETH To the Editor: We want to thank Drs. Mehrkens, Stummer, and Kreth for their considered comments on our paper, “Pretreatment factors predict overall survival for patients with low grade glioma,” IJROBP 1999;45(4): 923–929. Certainly, the prognostic factor of tumor volume may be an important one, either measured directly (1) or indirectly through the T staging system (2). Unfortunately, for our analysis, we were limited to variables common to three retrospective databases and tumor volume was not one of those variables. The decision not to include treating institution as a prognostic variable is explained in the paper and was motivated primarily by our desire to generate a model that might be used by other institutions for comparison purposes. The institutional differences noted in this retrospective analysis highlight the importance of prospective multi-institutional trials in the treatment of low-grade glioma (3) and suggest that referral patterns to specific institutions may select patients destined to have especially good outcomes. We would certainly not want to imply that the recursive partitioning model defined by our analysis will be the definitive one. Indeed, recursive partitioning analysis of prospective databases such as the EORTC/MRC low-grade glioma trials and North American Intergroup trial would be highly desirable and may yield a different or more robust model. GLENN BAUMAN, M.D., F.R.C.P.C. GREGORY CAIRNCROSS, M.D. DAVID MACDONALD, M.D., F.R.C.P.C. London Regional Cancer Centre London, Ontario N6A 4L6 Canada PII S0360-3016(00)00652-0 1. Kreth FW, Faist M, Rossner R, Volk B, Ostertag CB. Supratentorial World Health Organization grade 2 astrocytomas and oligoastrocyto- mas: A new pattern of prognostic factors. Cancer 1997;79:730 –739. 2. Karim ABMF, Maat B, Haltevol R, Menten J, Rutten EHJM, Thomas DGT, Mascarenhas F, Horiot JC, Parvinen LM, van Reijn M, Jagger JJ, Fabrini MG, van Alphen AM, Hamers HP, Gaspar L, Noordman E, Periat M, van glabbeke M. A randomized trial of dose-response in radiation therapy of low-grade cerebral glioma: European Organization for Research and Treatment of Cancer (EORTC) Study 22844. Int J Radiat Oncol Biol Phys 1996;36:549 –556. 3. Shaw EG. Looking through the retrospectoscope in the era of evidence- based medicine. J Clin Oncol 1997;15:1289 –1290. SHOULD THE DELTA-TCP CONCEPT BE REPLACED BY “LOCAL CONTROL PROBABILITY RATIOS”? To the Editor: In a recent paper a tool was proposed to evaluate and quantitate “the influence of the different dose regions in a nonuniformly irradiated tumor upon the probability of controlling that tumor” (1). Given 614 I. J. Radiation Oncology ● Biology ● Physics Volume 48, Number 2, 2000
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Transcript of In response to Drs. Mehrkens, Stummer, and Kreth
RESPONSE TO DRS. BAUMAN ET AL.: PRETREATMENTFACTORS PREDICT OVERALL SURVIVAL FOR PATIENTS
WITH LOW-GRADE GLIOMA: A RECURSIVEPARTITIONING ANALYSIS
(IJROBP 1997;45[4]:923-929, 1999)
To the Editor: The efficacy of external beam radiation for treatingpatients with WHO Grade II gliomas remains uncertain despite theresults of the European prospective randomized studies. Neither highertumor doses nor the immediate initiation of radiation therapy aftersurgery were associated with a significant survival advantage (1,2).These somewhat disappointing results might be explained by the pro-nounced clinical (biological) heterogeneity of WHO Grade II gliomas,which has eventually rendered favorable effects of radiation therapy onselected patient subgroups undetectable in the EORTC studies. There-fore, identification of risk cohorts, as performed by Bauman et al.,appears essential in order to overcome the effects of tumor heteroge-neity and to improve the design of subsequent clinical trials. Usingrecursive partitioning analysis of three institutional databases (whichwere merged), Bauman et al. quantified the effects of pretreatmentfactors such as age (. 40 vs.# 40 yrs.), Karnofsky score (, 70 vs.$70), and focal enhancement on CT/MRI (yes vs. no). Partitioninganalysis yielded subgroups of patients with median survivals rangingfrom as low as 12 months (KPS, 70, age. 40 yrs.) to as high as 128months (KPS$ 70, age 18-40 yrs.). These highly divergent survivaltimes underscore the necessity to tailor the design of modern clinicaltrials to more homogeneous patient subgroups.
One might wonder, for a number of reasons, if the prognostic modelcreated by Bauman et al. should be considered representative for thisheterogeneous disease. It was remarkable that the factor “treatinginstitution” was not considered in the recursive partitioning analysis,despite its enormous prognostic influence on multivariate analysis (sur-vival was longest in the University of California, San Francisco (UCSF)and shortest in the Norwegian Radium Hospital (NRH)). This institu-tion-dependent prognostic factor could not be translated in terms ofpatient- and/or treatment related factors. Even though the authors havestated that differences in referral patterns, surgical radicality and as-signment of tumor pathology of the three institutions would explaintreatment results in favor of the UCSF, this speculation was not sup-ported by the presented data set. Treatment-related factors (e.g. extentof resection) and histology-related factors did not yield any prognosticinfluence in the final prognostic model. Thus, the prognostic importanceof the institutional-related factor was not explained in the paper ofBauman et al. and excluding treating institution from recursive parti-tioning analysis would consequently appear inappropriate.
In 1997 Kreth et al. (3) have similarly quantified the impact of pretreat-ment factors for 197 adult patients with WHO Grade II astrocytomas andoligo-astrocytomas, treated with interstitial radiosurgery. In accordancewith the paper of Bauman et al. highly divergent survival groups wereidentified. In contrast, the study of Kreth et al. focuses on several tumor-related factors in greater detail. Most importantly, patients with largepre-treatment tumor volumes ( 20 ml) fared significantly worse. Thepowerful influence of pre-treatment tumor volume has also been recog-nized by others (1,4), and it seems surprising that this factor was neitherinvestigated nor discussed in the Bauman paper. Possibly, one part of theunexplained institution-dependent differences in survival may be due toimbalances regarding tumor-related prognostic factors in the individualcenters.
We agree with Bauman et al. that modern treatment strategies (such asstereotactic radiotherapy and interstitial radiosurgery) would probably in-fluence survival only if appropriate patient subgroups could be identified.Therefore, any decision model should consider the complex network ofpatient- tumor- and treatment-related factors.
JAN H. MEHRKENS, M.D.WALTER STUMMER, M.D.FRIEDRICH W. KRETH, M.D.Department of NeurosurgeryKlinikum Grosshadern Ludwig-Maximilians-UniversityKlinikum GrobhadernMarchioninistr. 1581377 Munich, Germany
PII S0360-3016(00)00651-9
1. Karim ABMF, Maat B, Haltevoll R, Menten J, Rutten EHJM, ThomasDGT, Mascarenhas F, Horiot JC, Parvinen LM, van Reijn M, Jager JJ,Fabrini MG, van Alphen AM, Hamers HP, Gaspar L, Noordman E,Pierat M, van Glabbeke M. A randomized trial on dose-response inradiation therapy of low-grade cerebral glioma: European Organiza-tion for Research and Treatment of Cancer (EORTC) Study 22844.IntJ Radiat Oncol Biol Phys1996; 36: 549-556.
2. Karim ABMF, Cornu P, Bleehen N, et al. Immediate postoperativeradiotherapy in low grade glioma improves progression free survivalbut not overall survival: preliminary results of an EORTC/MRC ran-domized Phase III study. Abstr. 1544, Proc Am Soc Clin Oncol17:400a, 1998
3. Kreth FW, Faist M, Rossner R, Volk B, Ostertag CB. SupratentorialWorld Health Organization Grade 2 Astrocytomas and Oligoastrocy-tomas.A new pattern of prognostic factors. Cancer1997;79: 370-379.
4. Berger MS, Deliganis AV, Dobbins J, Keles GE. The effect of extentof resection on recurrence in patients with low grade cerebral hemi-sphere gliomas.Cancer1994; 74: 1784-1791.
IN RESPONSE TO DRS. MEHRKENS, STUMMER, ANDKRETH
To the Editor:We want to thank Drs. Mehrkens, Stummer, and Kreth fortheir considered comments on our paper, “Pretreatment factors predictoverall survival for patients with low grade glioma,”IJROBP1999;45(4):923–929.
Certainly, the prognostic factor of tumor volume may be an importantone, either measured directly (1) or indirectly through the T staging system(2). Unfortunately, for our analysis, we were limited to variables commonto three retrospective databases and tumor volume was not one of thosevariables.
The decision not to include treating institution as a prognostic variableis explained in the paper and was motivated primarily by our desire togenerate a model that might be used by other institutions for comparisonpurposes. The institutional differences noted in this retrospective analysishighlight the importance of prospective multi-institutional trials in thetreatment of low-grade glioma (3) and suggest that referral patterns tospecific institutions may select patients destined to have especially goodoutcomes.
We would certainly not want to imply that the recursive partitioningmodel defined by our analysis will be the definitive one. Indeed, recursivepartitioning analysis of prospective databases such as the EORTC/MRClow-grade glioma trials and North American Intergroup trial would behighly desirable and may yield a different or more robust model.
GLENN BAUMAN , M.D., F.R.C.P.C.GREGORY CAIRNCROSS, M.D.DAVID MACDONALD, M.D., F.R.C.P.C.London Regional Cancer CentreLondon, Ontario N6A 4L6Canada
PII S0360-3016(00)00652-0
1. Kreth FW, Faist M, Rossner R, Volk B, Ostertag CB. SupratentorialWorld Health Organization grade 2 astrocytomas and oligoastrocyto-mas: A new pattern of prognostic factors.Cancer1997;79:730–739.
2. Karim ABMF, Maat B, Haltevol R, Menten J, Rutten EHJM, ThomasDGT, Mascarenhas F, Horiot JC, Parvinen LM, van Reijn M, Jagger JJ,Fabrini MG, van Alphen AM, Hamers HP, Gaspar L, Noordman E,Periat M, van glabbeke M. A randomized trial of dose-response inradiation therapy of low-grade cerebral glioma: European Organizationfor Research and Treatment of Cancer (EORTC) Study 22844.Int JRadiat Oncol Biol Phys1996;36:549–556.
3. Shaw EG. Looking through the retrospectoscope in the era of evidence-based medicine.J Clin Oncol1997;15:1289–1290.
SHOULD THE DELTA-TCP CONCEPT BE REPLACED BY“LOCAL CONTROL PROBABILITY RATIOS”?
To the Editor: In a recent paper a tool was proposed to evaluate andquantitate “the influence of the different dose regions in a nonuniformlyirradiated tumor upon the probability of controlling that tumor” (1). Given
614 I. J. Radiation Oncology● Biology ● Physics Volume 48, Number 2, 2000
