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Journal of Clinical Oncology, Vol 24, No 16 (June 1), 2006: pp. 2563-2569 © 2006 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.04.5963 Radiotherapy and Temozolomide for Newly Diagnosed Glioblastoma: Recursive Partitioning Analysis of the EORTC 26981/22981-NCIC CE3 Phase III Randomized Trial
From the University Hospital Lausanne, Lausanne, Switzerland; European Organisation for Research and Treatment of Cancer Data Center, Brussels, Belgium; Princess Margaret Hospital, Toronto, Ontario; University of Western Ontario, London, Ontario; and University of Calgary, Calgary, Alberta, Canada; Erasmus Medical Center, University of Rotterdam, the Netherlands; Universitätsklinikum Tübingen, University of Tübingen, Tübingen, Germany; San Raffaele Scientific Institute, Milan, and Medical Oncology Department-Azienda Ospedale-Università, Padova, Italy; Inselspital, Bern, Switzerland; and University Hospital Bellvitge, Barcelona, Spain Address reprint requests to René-Olivier Mirimanoff, MD, Department of Radiation Oncology, University Hospital Lausanne, Rue du Bugnon, CH-1011 Lausanne, Switzerland; e-mail: rene-olivier.mirimanoff{at}chuv.ch
PURPOSE: The European Organisation for Research and Treatment of Cancer and National Cancer Institute of Canada trial on temozolomide (TMZ) and radiotherapy (RT) in glioblastoma (GBM) has demonstrated that the combination of TMZ and RT conferred a significant and meaningful survival advantage compared with RT alone. We evaluated in this trial whether the recursive partitioning analysis (RPA) retains its overall prognostic value and what the benefit of the combined modality is in each RPA class. PATIENTS AND METHODS: Five hundred seventy-three patients with newly diagnosed GBM were randomly assigned to standard postoperative RT or to the same RT with concomitant TMZ followed by adjuvant TMZ. The primary end point was overall survival. The European Organisation for Research and Treatment of Cancer RPA used accounts for age, WHO performance status, extent of surgery, and the Mini-Mental Status Examination. RESULTS: Overall survival was statistically different among RPA classes III, IV, and V, with median survival times of 17, 15, and 10 months, respectively, and 2-year survival rates of 32%, 19%, and 11%, respectively (P < .0001). Survival with combined TMZ/RT was higher in RPA class III, with 21 months median survival time and a 43% 2-year survival rate, versus 15 months and 20% for RT alone (P = .006). In RPA class IV, the survival advantage remained significant, with median survival times of 16 v 13 months, respectively, and 2-year survival rates of 28% v 11%, respectively (P = .0001). In RPA class V, however, the survival advantage of RT/TMZ was of borderline significance (P = .054). CONCLUSION: RPA retains its prognostic significance overall as well as in patients receiving RT with or without TMZ for newly diagnosed GBM, particularly in classes III and IV.
Until recently, the outcome of glioblastoma (GBM), the most common and most malignant brain tumor in adults, has not improved greatly. Postoperative radiotherapy (RT) is recognized as standard therapy based on six randomized studies published between 1976 and 1991,1 whereas the addition of chemotherapy to radiotherapy has been a more controversial issue—a meta-analysis based on 12 randomized trials suggests only a small benefit.2 Indeed, many studies in the past decade have demonstrated that pretreatment prognostic factors have more impact on outcome than any new and potentially active therapy or treatment strategy.3-6 The development of a set of classes on high-grade glioma from a recursive partitioning model of treatment- and pretreatment-related prognostic variables by Curran et al4 proved useful and was tested and validated in a number of subsequent trials.5,7-17 The recursive partitioning analysis (RPA) classification was developed to compare survival categories and to obtain homogenous subsets of patients.4 It can be useful in refining stratification and the design of phase III randomized studies, and its judicious use and interpretation in phase II studies could avoid the undertaking of phase III studies based on false expectations.5 In large randomized trials, RPA also has the potential to determine if a particular category of patients will benefit most from newer approaches and if some may be spared unnecessary treatment. The recent trial by the European Organisation for Research and Treatment of Cancer (EORTC) and National Cancer Institute of Canada (NCIC) Clinical Trials Group (EORTC 26981/22981-NCIC CE3) was the first study to demonstrate unequivocally that the addition of temozolomide (TMZ) to RT early in the course of GBM provides a statistically significant and clinically meaningful survival benefit.18 We present RPA of the EORTC/NCIC trial to determine if RPA classes III through V retained their prognostic value in the overall population and if the advantage of the combined treatment of RT/TMZ remains beneficial in all RPA classes.
Trial Summary EORTC 26981/22981-NCIC CE3 enrolled 573 patients from 85 institutions between August 2000 and March 2002. Details of the trial methods and the main results were published elsewhere.18 Patients from 18 to 70 years of age with newly diagnosed and histologically confirmed GBM; a WHO performance status of 0 to 2; and adequate hematologic, renal, and hepatic function were eligible. Patients were randomly assigned to standard focal RT alone or to the same RT plus concomitant daily TMZ followed by adjuvant TMZ. Conformal RT with three-dimensional planning was administered for a total daily dose of 60 Gy at 2 Gy/fraction on 5 days a week for 6 weeks, with a linear accelerator. Concomitant chemotherapy consisted of TMZ at a daily dose of 75 mg/m2 on 7 days a week from the first until the last day of RT, up to 49 days. After a 4-week break, patients received up to six cycles of adjuvant TMZ for 5 days every 28 days. The dose was 150 mg/m2 for the first adjuvant cycle and was increased to 200 mg/m2 beginning with the second cycle, provided there were no hematologic toxicities. Prophylaxis against Pneumocystis carinii with either pentamidine or trimethoprim-sulfamethoxazole was mandatory during concomitant RT/TMZ.15 The primary end point was overall survival; secondary end points were progression-free survival, safety, and quality of life.
Recursive Partitioning Analysis
Statistical Analysis The prognostic value for survival, independent of treatment received, according to the RPA classification was estimated using the Kaplan-Meier method.21 This technique was also used to assess the efficacy of RT with or without TMZ in the three classes. The trend test was used to assess the ordering of the classes. The log-rank test was used for each treatment comparison. The interaction tests (heterogeneity and trend tests) were also computed.
Patient Demographics Patient characteristics are presented in Table 2. RT and RT/TMZ treatment arms were well balanced for the repartition of RPA classes, with 14% and 15% of patients in class III, 52% and 53% in class IV, and 34% and 32% in class V, respectively. The percentage of patients receiving corticosteroids at the time of random assignment was slightly higher in the RT group than in the RT/TMZ group.
Overall Study Results The median follow-up for all patients was 28 months. Among patients still alive after 28 months, the median follow-up was 27 months (minimum 13, maximum 39 months). Two hundred nineteen patients in the RT/TMZ arm and 261 in the RT-only arm died, with a median survival time of 15 v 12 months, respectively, and a 2-year survival rate of 27% v 10%, respectively (P < .001).18
Validation of RPA Classes
Overall Survival by Treatment Arm in RPA Classes III Through V The survival benefit of combined treatment was highest in RPA class III, with a median survival time of 21 v 15 months and a 2-year survival rate of 43% v 20%, respectively (hazard ratio [HR], 0.48; P = .006; Fig 2). In RPA class IV, the advantage remained highly significant, with a median survival time of 16 v 13 months and a 2-year survival rate of 28% v 11%, respectively (HR, 0.61; P = .0001; Fig 3). For patients in RPA class V, however, the difference between the two treatment arms was small and of borderline significance, with a median survival time of 10 v 9 months and a 2-year survival rate of 17% v 6%, respectively (HR, 0.74; P = .054; Fig 4). This trial did not have enough power to definitively identify a difference in treatment efficacy among the three classes based on interaction tests (heterogeneity, P = .28; trend, P = .12).
The recently published results of our EORTC/NCIC randomized study have shown unequivocally that the addition of TMZ to RT confers a meaningful survival advantage compared with postoperative RT alone in GBM.18 However, for decades, pretherapeutic prognostic factors—in particular their regrouping in RPA classes—had a much more powerful impact on survival than any adjuvant treatment.3-6,13 For this reason, RPA analysis within the framework of our positive EORTC/NCIC trial is particularly important. RPA analysis can be used as a tool to identify patients from a phase II trial who could benefit from a particular and novel treatment. This technique was tested in numerous phase II trials in GBM.7-12,14-17,22 However, when compared with patients from the RTOG database using RPA analysis, none of the new treatments appeared superior to previously tested therapies. At EORTC, we have used RPA analysis in strategic decisions on whether to embark on phase III randomized trials in GBM. The first example is the Accelerated Radiotherapy with Carbogen and Nicotinamide (ARCON) protocol, based on promising preclinical data.23,24 In our phase I/II EORTC Radiotherapy Group ARCON trial for GBM, 115 patients were treated with carbogen, nicotinamide, and accelerated RT in three steps.16 The overall median survival time was 11 months. However, survival times by RPA class were quite comparable with those of the RTOG database, and we concluded that the results do not support the development of a randomized trial.16 Therefore, no further study on ARCON in GBM was undertaken by the EORTC. In contrast, the second example was our phase II study on concomitant RT/TMZ followed by adjuvant TMZ.15 The median survival time for the 64 enrolled patients was 16 months. Median survival time was 24+ months for Class III, 14 months for Class IV, and 9 months for Class V, which compared quite favorably with the RTOG database results.15 These promising results represented a strong incentive at EORTC to undertake the EORTC/NCIC randomized phase III trial.18 Table 4 shows median and 2-year survival values in the phase II RT/TMZ trial,15 the TMZ arm of the phase III trial,18 and the RTOG database4,5 by RPA class. Results of the phase II and phase III trials appear fairly similar and consistently superior to those of the RTOG database across all RPA classes.
One objective of the present analysis was to verify whether the EORTC RPA classification retained its overall value within the phase III randomized EORTC/NCIC trial, in which a fairly large difference was observed between the two treatment arms. Our results with the 573 patients show that the overall median and 2-year survival values differed among RPA classes III, IV, and V and this was highly statistically different (P < .001), confirming the distinction among these three prognostic classes. We also used RPA methodology to evaluate the effect of combined therapy in each of the three RPA classes of the EORTC/NCIC randomized study. The highest treatment effect on survival was observed in RPA class III, with a gain in the median survival time of 7 months and in the 2-year survival rate of 24% with RT/TMZ (P = .006). For this category of patients, the addition of TMZ to RT provided a 43% probability of survival at 2 years. The EORTC/NCIC RPA system excludes the more favorable grade 3 gliomas, so these results appear promising for such a devastating disease. The combination of TMZ/RT in RPA class IV still offers a significant and useful advantage, more than doubling the 2-year survival rate compared with RT alone(P = .0001). In the worst prognostic category, RPA V, the gain appeared smaller (P = .054). Within the framework of the EORTC/NCIC trial, 06-methylguanine-DNA methyltransferase (MGMT) methylation in GBM was an independent favorable prognostic factor. Among patients with methylated MGMT, a large survival benefit was observed when TMZ was added to RT.25 We analyzed the impact of MGMT status in each RPA class. However, the subsets were too small to draw any meaningful conclusions. It appears from our trial that simple clinical (RPA) or sophisticated laboratory (MGMT) tools can be used to predict individual patient outcome and should also be considered for stratification procedures in future protocols, in which novel therapies will be added to RT and TMZ.
Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. 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.
Dollar Amount Codes (A) < $10,000 (B) $10,000-99,999 (C) > $100,000 (N/R) Not Required
We thank Frances Godson for her excellent assistance in the preparation of the manuscript.
Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. Laperriere N, Zuraw L, Cairncross G, et al: Radiotherapy for newly diagnosed malignant glioma in adults: A systematic review. Radiother Oncol 64:259-273, 2002[CrossRef][Medline] 2. Glioma Meta-analysis Trialists (GMT) Group: Chemotherapy in adult high-grade glioma: A systematic review and meta-analysis of individual patient data from 12 randomised trials. Lancet 359:1011-1018, 2002[CrossRef][Medline] 3. Latif AZB, Signorini D, Gregor A, et al: Application of the MRC brain tumour prognostic index to patients with malignant glioma not managed in randomized control trial. J Neurol Neurosurg Psychiatry 64:747-750, 1998 4. Curran WJ Jr, Scott JB, Horton J, et al: Recursive partitioning analysis of prognostic factors in three Radiation Therapy Oncology Group malignant glioma trials. J Natl Cancer Inst 85:690-691, 1993 5. Scott CB, Scarantino C, Urtasun R, et al: Validation and predictive power of Radiation Therapy Oncology Group (RTOG) recursive partitioning analysis classes for malignant glioma patients: A report using RTOG 90-60. Int J Radiat Oncol Biol Phys 40:51-55, 1998[CrossRef][Medline] 6. Behin A, Hoang-Zuan K, Carpentier AF, et al: Primary brain tumours in adults. Lancet 361:323-331, 2003[CrossRef][Medline] 7. Videtic GMM, Gaspar LE, Zamorano L, et al: Use of the RTOG recursive partitioning analysis to validate the benefit of iodine-125 implants in the primary treatment of malignant gliomas. Int J Radiat Oncol Biol Phys 45:687-692, 1999[CrossRef][Medline] 8. Videtic GMM, Gaspar LE, Zamorano L, et al: Implant volume as a prognostic variable in brachytherapy decision-making for malignant gliomas stratified by the RTOG recursive partitioning analysis. Int J Radiat Oncol Biol Phys 51:963-968, 2001[CrossRef][Medline] 9. Fisher B, Won M, Macdonald D, et al: Phase II study of topotecan plus cranial radiation for glioblastoma multiforme: Results of Radiation Therapy Oncology Group 9513. Int J Radiat Oncol Biol Phys 53:980-986, 2002[CrossRef][Medline] 10. Coughlin C, Scott C, Langer C, et al: Phase III two-arm RTOG trial (94-11) of bischloroethyl-nitrosourea plus accelerated hyperfractionated radiotherapy (64.0 or 70.4 Gy) based on tumor volume (> 20 or < or = 20 cm(2), respectively) in the treatment of newly-diagnosed radiosurgery-ineligible glioblastoma multiforme patients. Int J Radiat Oncol Biol Phys 48:1351-1358, 2000[CrossRef][Medline] 11. Langer CJ, Ruffer J, Rhodes H, et al: Phase II Radiation Therapy Oncology Group trial of weekly paclitaxel and conventional external beam radiation therapy for supratentorial glioblastoma multiforme. Int J Radiat Oncol Biol Phys 51:113-119, 2001[Medline] 12. Sultanem K, Patrocinio H, Lambert C, et al: The use of hypofractionated intensity-modulated irradiation in the treatment of glioblastoma multiforme: Preliminary results of a prospective trial. Int J Radiat Oncol Biol Phys 58:247-252, 2004[CrossRef][Medline] 13. Lamborn KR, Chang SM, Prados MD: Prognostic factors for survival of patients with glioblastoma: Recursive partitioning analysis. Neuro-oncol 6:227-235, 2004[Abstract] 14. Del Rowe J, Scott C, Werner-Wasik M, et al: Single-arm open-label phase II study of intravenously administered tirapazamine and radiation therapy for glioblastoma multiforme. J Clin Oncol 18:1254-1259, 2000 15. Stupp R, Dietrich P-Y, Ostermann Kraljevic S, et al: Promising survival for patients with newly diagnosed glioblastoma multiforme treated with concomitant radiation plus temozolomide followed by adjuvant temozolomide. J Clin Oncol 20:1375-1382, 2002 16. Miralbell R, Mornex F, Greiner R, et al: Accelerated radiotherapy, carbogen and nicotinamide in glioblastoma multiforme: Report of European Organization for Research and Treatment of Cancer Trial 22933. J Clin Oncol 17:3143-3149, 1999 17. Sarkaria JH, Mehta MP, Loeffler JS, et al: Radiosurgery in the initial management of malignant gliomas: Survival comparison with the RTOG recursive partitioning analysis. Int J Radiat Oncol Biol Phys 32:931-941, 1995[CrossRef][Medline] 18. 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 19. Folstein MF, Folstein SE, McHugh PR: "Mini-mental state." A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 12:189-198, 1975[CrossRef][Medline] 20. Buckner JC: Factors influencing survival in high-grade gliomas. Semin Oncol 30(suppl 19):10-14, 2003[Medline] 21. Kaplan ES, Meier P: Non-parametric estimation from incomplete observations. J Am Stat Assoc 53:457-481, 1958[CrossRef] 22. Lustig RA, Scott CB, Curran WJ: Does stereotactic eligibility for the treatment of glioblastoma cause selection bias in randomized studies? Am J Clin Oncol 27:516-521, 2004[CrossRef][Medline] 23. Kjellen E, Joiner M. Collier JM, et al: A therapeutic benefit from combining normobaric carbogen or oxygen with nicotinamide in fractionated X-ray treatments. Radiother Oncol 22:81-89, 1991[CrossRef][Medline] 24. Sun LQ, Coucke PH, Mirimanoff RO, et al: Fractionated irradiation combined with carbogen breathing and nicotinamide in two human glioblastoma grafted in nude mice. Radiat Res 155:26-31, 2001[CrossRef][Medline] 25. Hegi ME, Diserens A-C, Gorlia T, et al: MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med 352:997-1003, 2005 Submitted October 20, 2005; accepted March 13, 2006.
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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
26, and these patients had a significantly worse prognosis.
