University of Zurich Zurich Open Repository and Archive Winterthurerstr. 19 CH-857 Zurich http://www.zora.uzh.ch Year: 29 Long-term survival of glioblastoma patients treated with radiotherapy and lomustine plus temozolomide Glas, M; Happold, C; Rieger, J; Wiewrodt, D; Bähr, O; Steinbach, J P; Wick, W; Kortmann, R; Reifenberger, G; Weller, M; Herrlinger, U Glas, M; Happold, C; Rieger, J; Wiewrodt, D; Bähr, O; Steinbach, J P; Wick, W; Kortmann, R; Reifenberger, G; Weller, M; Herrlinger, U (29). Long-term survival of glioblastoma patients treated with radiotherapy and lomustine plus temozolomide. Journal of Clinical Oncology, 27(8):1257-1261. Postprint available at: http://www.zora.uzh.ch Posted at the Zurich Open Repository and Archive, University of Zurich. http://www.zora.uzh.ch Originally published at: Journal of Clinical Oncology 29, 27(8):1257-1261.
VOLUME 27 NUMBER 8 MARCH 1 29 JOURNAL OF CLINICAL ONCOLOGY O R I G I N A L R E P O R T Long-Term Survival of Patients With Glioblastoma Treated With Radiotherapy and Lomustine Plus Temozolomide Martin Glas, Caroline Happold, Johannes Rieger, Dorothee Wiewrodt, Oliver Bähr, Joachim P. Steinbach, Wolfgang Wick, Rolf-Dieter Kortmann, Guido Reifenberger, Michael Weller, and Ulrich Herrlinger From the Division of Clinical Neurooncology, Department of Neurology, University of Bonn; Department of General Neurology, Hertie Institute for Clinical Brain Research, University of Tübingen; Dr. Senckenbergisches Institut of Neurooncology, University of Frankfurt, Frankfurt am Main; Department of Neurosurgery, University of Mainz; Department of Neurooncology, University of Heidelberg; Department of Radiation Oncology, University of Leipzig; and Department of Neuropathology, Heinrich-Heine-University of Duesseldorf, Germany; and Department of Neurology, University Hospital Zürich, Zürich, Switzerland. Submitted July 19, 28; accepted October 28, 28; published online ahead of print at www.jco.org on February 2, 29. Authors disclosures of potential conflicts of interest and author contributions are found at the end of this article. Corresponding author: Ulrich Herrlinger, MD, Division of Clinical Neurooncology, Department of Neurology, University of Bonn, Sigmund-Freud-Str 25, D-5315 Bonn, Germany; e-mail: Ulrich.Herrlinger@ ukb.uni-bonn.de. The Appendix is included in the full-text version of this article, available online at www.jco.org. It is not included in the PDF version (via Adobe Reader ). 29 by American Society of Clinical Oncology 732-183X/9/278-1257/$2. DOI: 1.12/JCO.28.19.2195 A B S T R A C T Purpose To evaluate long-term survival in a prospective series of patients newly diagnosed with glioblastoma and treated with a combination of lomustine (CCNU), temozolomide (TMZ), and radiotherapy. Patients and Methods Thirty-nine patients received radiotherapy of the tumor site only (6 Gy) and CCNU/TMZ chemotherapy (n 31 received standard-dose CCNU, 1 mg/m 2 on day 1 and TMZ 1 mg/m 2 /d ondays2to6;n 8 received intensified-dose CCNU 11 mg/m 2 on day 1 and TMZ 15 mg/m 2 on days 2 to 6) for up to six courses. Results In the whole cohort, the median overall survival (mos) was 23.1 months; 47.4% survived for 2 years, and 18.5% survived for 4 years. After a median follow-up of 41.5 months, mos had not been reached in the intensified group and was significantly higher than in the standard group (22.6 months; P.24). In the intensified group, four of eight patients survived for at least 56 months, two of them without recurrence. O 6 -methylguanine DNA methyltransferase (MGMT) gene promotor methylation in the tumor tissue was associated with significantly longer mos (methylated, 34.3 months v nonmethylated, 12.5 months). A multivariate Cox proportional hazard model revealed MGMT status (methylated v nonmethylated; relative risk [RR] of death,.43; P.3) and chemotherapy dose (intensified v standard; RR,.37; P.12) as independent prognostic factors. WHO grade 4 hematoxicity was observed more frequently in the intensified group (57% v 16%). Conclusion The combination of radiotherapy, CCNU, and TMZ yielded promising long-term survival data in patients with newly diagnosed glioblastoma. Intensification of CCNU/TMZ chemotherapy may add an additional survival benefit, albeit with greater acute toxicity. J Clin Oncol 27:1257-1261. 29 by American Society of Clinical Oncology INTRODUCTION Despite recent improvements in surgery and combined chemoradiotherapy, glioblastoma remains a devastating disease. Standard chemoradiotherapy includes concomitant and adjuvant temozolomide (TMZ) chemotherapy and leads to a median progression-free survival (mpfs) of 6.9 months and a median overall survival (mos) of 14.6 months. 1 When we used a combination of TMZ and lomustine (CCNU) in the UKT-3 trial, we previously reported promising survival data of an mpfs of 9 months and a high mos of 22.6 months. 2 Thirteen of 31 patients in the UKT-3 trial were alive at the end of the 24 months of follow-up period reported in the previous publication. 2 In this analysis, which was carried out 55 months after the accrual of the last patient to the UKT-3 trial, we report mature data on long-term survival in the UKT-3 cohort. In addition, we added the previously unpublished data set of a pilot group of eight patients treated with an intensified CCNU/TMZ regimen, which might confer even higher rates of long-term survival. Overall, we report on the long-term survival of 39 prospectively documented patients who received radiotherapy and combined CCNU/TMZ chemotherapy as first-line therapy for glioblastoma. PATIENTS AND METHODS This prospective series of patients treated with CCNU and TMZ included 31 patients treated in the UKT-3 trial 2 and eight patients treated in a prospective pilot group with increased CCNU and TMZ doses. All patients received treatment at the University of Tuebingen (Department of 29 by American Society of Clinical Oncology 1257 Information downloaded from jco.ascopubs.org and provided by Hauptbibliothek Universitaet Zuerich on June 22, 29 from
Glas et al Neurology, Tuebingen, Germany) and Mainz (Departments of Neurology and Neurosurgery, Mainz, Germany) Medical Centers. The main inclusion criteria for both groups were histologic diagnosis of glioblastoma; surgery no longer than 21 days before enrollment; no prior radiotherapy or chemotherapy; age older than 18 years; Karnofsky performance score (KPS) of 7 or higher; and no alterations in bone marrow reserve, liver function, or renal function. Both treatment regimens were approved by the local ethics committees. All patients gave written informed consent. In all patients, the therapyindependent prognostic factors of KPS at entry into the study and the extent of resection as determined by the neurosurgeon were defined. In addition, the study population was assigned to one of the prognostic groups developed by recursive partitioning analysis 3 and validated in a large number of glioma patients enrolled on Radiation Therapy Oncology Group trials. 4 The chemotherapy schedule included oral CCNU 1 mg/m 2 on day 1 followed by TMZ 1 mg/m 2 /d on days 2 through 6 of 6-week courses (standard group). The patients of the pilot cohort received a dose intensification of CCNU 11 mg/m 2 on day 1 followed by TMZ 15 mg/m 2 /d on days 2 through 6 (intensified group). A maximum of six courses were delivered, individual dose adjustments were made in subsequent courses, and discontinuation rules were as previously described. 2 Radiotherapy was delivered during courses 1 and 2 as involved-field radiotherapy, with a total dose of 6 Gy in single daily fractions of 2 Gy. Toxicity of the CCNU/TMZ treatment regimen was continously monitored throughout the treatment and follow-up phases in the whole cohort. O 6 -methylguanine DNA methyltransferase (MGMT) promoter methylation status was analyzed in all available samples by methylationspecific polymerase chain reaction (PCR), as previously described. 2,5 Response assessment was based on contrast-enhanced magnetic resonance imaging (MRI) after courses 2, 4, and 6. 6 After chemotherapy, patients were observed at 3-month intervals by clinical examination and contrastenhanced MRI. All patients were assessed for PFS on CCNU/TMZ and subsequent therapies, OS, and late toxicity. PFS and OS were calculated from the day of surgery that led to the histologic diagnosis of glioblastoma. Second PFS rates were calculated from the day of diagnosis of recurrence on MRI. Survival data were analyzed according to the Kaplan-Meier method by using the log-rank test for comparisons between different groups. Also, the influences of the MGMT promoter methylation status (methylated v nonmethylated), CCNU/TMZ dosing (intensified v standard), extent of resection (complete v incomplete resection or biopsy), and Radiation Therapy Oncology Group recursive partitioning analysis class (III v IV or V) were analyzed in univariate regression analyses by using a Cox proportional hazards model. Parameters with a significant influence on survival in the univariate analysis also were analyzed in a multivariate analysis. RESULTS Patient Characteristics and Therapy Applied Thirty-nine patients were accrued between March 22 and December 23. Thirty-one patients were treated in the UKT-3 trial (standard group), and eight patients were treated with higher doses of CCNU and TMZ in an additional pilot group (intensified group). Patient characteristics are listed in Table 1. The patients of the intensified group were older than the patients in the UKT-3 trial (median age, 59 v 51 years) but did not differ with respect to KPS. The patients in the intensified group received a median of 3.5 courses of CCNU/TMZ (range, one to six courses), and patients in the UKT-3 group received a median of 4.5 courses (range, one to six courses). Twenty-seven patients (69%) received second-line therapy (Appendix Table A1, online only) and had an mpfs of 6 months. Eleven of 27 patients had an additional tumor resection at recurrence. Repeat irradiation was applied in seven patients (mpfs, 4 months), and hyperthermia in one patient. Second-line chemotherapy consisted of intensified TMZ in 1 patients (mpfs, 7.5 months) and nimustine/teniposide in eight patients (mpfs, 3 Table 1. Demographic and Clinical Data of Patients Treated With CCNU and Temozolomide Characteristic Patients (N 39) No. % Age, years 5 11 28 5 28 72 Sex Male 31 79 Female 8 21 KPS 1 9 23 8-9 25 64 7 5 13 Extent of surgery Complete resection 14 36 Partial resection 19 49 Biopsy 4 1 NA 2 5 RTOG RPA class III 8 21 IV 24 62 V 7 18 Abbreviations: CCNU, lomustine; KPS, Karnofsky performance score; NA, not assessable; RTOG RPA, Radiation Therapy Oncology Group recursive partitioning analysis. months). Third-line (n 11; mpfs, 4 months) and fourth-line (n 3; mpfs, 2 months) therapies included repeat irradiation, intensified TMZ, nimustine, CCNU, pegylated liposomal doxorubicine, and imatinib/hydroxyurea. Toxicity Acute toxicity was higher in the intensified cohort than in the standard group, and grade 4 myelotoxicity occurred in four (57%) of seven assessable patients compared with 16% in the cohort of 31 patients treated with standard-dose CCNU/TMZ. As in the standarddose group, 2 one patient in the intensified cohort died as a result of septicemia during myelosuppression. No nonhematologic acute or delayed toxicity was observed. There were no signs of therapy-dependent late neurotoxicity in the patients who survived long term. In all three patients who have survived without recurrent disease, KPS at 54 to 69.5 months after inclusion into the trial has not decreased. Two of three patients who had one recurrence had a decrease of KPS from 1% to 7% and from 8% to 5% on progression, but they have remained on a stable KPS with successful treatment of recurrence. One additional patient has remained on a stable KPS of 1% despite recurrence. In summary, decreases in KPS in some long-term survivors were attributable to recurrent disease but not to CCNU/TMZ therapy. Long-Term Survival and Dependency on MGMT Promoter Methylation Status In the whole cohort of 39 patients, the mpfs was 1 months (range, 1 to 69 months). The mos was 23.1 months (Fig 1). OS was 47.4% at 2 years, 26.4% at 3 years, 18.5% at 4 years, and 15.8% at 5 years. Four (1.3%) of 39 patients have had no recurrence at last 1258 29 by American Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGY Information downloaded from jco.ascopubs.org and provided by Hauptbibliothek Universitaet Zuerich on June 22, 29 from
Long-Term Survival After CCNU TMZ for Glioblastoma A Cumulative Survival (proportion).4.3.2.1 Progression-Free Survival (proportion).4.3.2.1 methylated nonmethylated Fig 1. Overall survival in the cohort of 39 patients who received lomustine/ temozolomide combined with radiotherapy as first-line therapy for glioblastoma. B follow-up. Two (25%) of eight patients in the intensified group have remained recurrence free. Eight of 19 investigated patients in the standard group and three of four investigated patients of the intensified group had a methylated MGMT promotor. Survival strongly depended on the MGMT promoter methylation status. The mpfs (Fig 2A) was significantly higher in the methylated group (19 months; n 11) than in the nonmethylated group (7 months; n 12; P.64 for the comparison). This also translated into a substantial OS benefit (Fig 2B) for patients with a methylated MGMT promoter: mos was 12.5 months for nonmethylated-status patients but was 34.3 months for methylated-status patients (P.9). In the methylated group, 45% of patients survived for 3 years, and 36% of patients survived for 5 years. Overall Survival (proportion).4.3.2.1 Influence of Dose Escalation on Survival In the standard group, the mpfs was 9 months (range, 1.9 to 54 months; Fig 3A) and the mos was 22.6 months. 2 The long-term survival analysis now shows 41.9% of patients surviving 2 years, 16.9% of patients surviving 3 years, and 9.7% surviving 4 years (Fig 3B). In contrast, the eight patients in the intensified group had an mpfs of 26 months, and mos was not yet reached after a median follow-up time of 41.5 months (range, 1 to 69 months). Both PFS (P.14) and OS (P.24) were significantly higher in the intensified group than in the standard group. Four of eight patients in the intensified group have currently survived for at least 56 months, and two of them have survived without any recurrence or signs of late neurotoxicity. Of the four patients in the intensified group who could be assessed for MGMT promoter status, the three patients with a methylated promoter have all still survived after a follow-up time of 56 to 7 months, whereas the patient with a nonmethylated MGMT promoter died after 28 months. A univariate Cox proportional hazards analysis identified MGMT promoter methylation status and chemotherapy dose as factors that have an influence on survival (Table 2). In contrast, the extent of resection and the Radiation Therapy Oncology Group recursive partitioning analysis class have no such effect. A subsequent multivariate analysis confirmed that the presence of a methylated MGMT promoter and the application of intensified CCNU/TMZ were associated with a significantly reduced risk of death (Table 2). DISCUSSION methylated nonmethylated Fig 2. (A) Progression-free survival (PFS) and (B) overall survival (OS) according to the MGMT promoter methylation status in 23 assessable patients (unmethylated, n 12; methylated, n 11). Differences in survival between the two groups were statistically significant (log-rank test; P.64 for PFS and P.9 for OS). The data presented here suggest that the combination of CCNU, TMZ, and radiotherapy has encouraging activity in patients with www.jco.org 29 by American Society of Clinical Oncology 1259 Information downloaded from jco.ascopubs.org and provided by Hauptbibliothek Universitaet Zuerich on June 22, 29 from
Glas et al A Progression-Free Survival (proportion) B Overall Survival (proportion).4.3.2.1.4.3.2.1 intensified standard intensified standard Fig 3. (A) Progression-free survival (PFS) and (B) overall survival (OS) according to the chemotherapy dosing. Thirty-one patients received standard-dose chemotherapy (standard; lomustine [CCNU] 1 mg/m 2 on day 1, temozolomide [TMZ] 1 mg/m 2 on days 2 to 6), and eight patients received intensified-dose chemotherapy (intensified; CCNU 11 mg/m 2 on day 1, TMZ 15 mg/m 2 on days 2 to 6). Differences in survival between the two groups were statistically significant (log-rank test; P.14 for PFS and P.24 for OS). newly diagnosed glioblastoma and may lead to a substantial rate of patients with long-term survival. The rate of long-term survivors of greater than 24 months is stunning, at almost 5% in the whole cohort. To our knowledge, this might be the best rate ever observed in a prospective glioblastoma analysis, and it does not appear to be bias driven. 2 Patients with a nonmethylated MGMT promoter in our trial survived only 12.5 months, which is virtually identical to the median survival seen in previous trials, 7 and this suggests that the patients in our series have not been selected for good therapy-independent prognostic factors. The increased 2-year survival rate is biologically meaningful in that Table 2. Univariate and Multivariate Cox Regression Analysis for Factors That Potentially Influence Overall Survival in Patients Treated With CCNU and TMZ Factor by Analysis Type No. of Patients (N 39) Median Survival (months) Analysis HR 95% CI P Univariate RTOG RPA class 6 6 to 1.57.78 III 8 22.9 IV or V 31 24.8 Extent of resection 9 1 to 1.27.52 Complete 14 27.5 Partial or biopsy 23 22.6 MGMT promoter status.4.2 to.1 Methylated 11 34.3 Nonmethylated 12 12.5 CCNU/TMZ dosing 2.25 to 9.13 Intensified 8 41.5 Standard 31 22.6 Multivariate MGMT promoter status.43.22 to 6.3 Methylated 34.3 Nonmethylated 12.5 CCNU/TMZ dosing.37.9 to 3.12 Intensified 8 41.5 Standard 31 22.6 Abbreviations: CCNU, lomustine; TMZ, temozolomide; RTOG RPA, Radiation Therapy Oncology Group recursive partitioning analysis; MGMT, O6- methylguanine-dna methyltransferase. Comparison of condition 1 versus condition 2 for each factor. 2 test. RTOG RPA integrates data on performance score, age, and extent of resection. patients who benefit from chemotherapy seem to have a potential for long-term survival. Although historical comparisons may not be legitimate, CCNU/TMZ almost doubled the percentage of survivors at 24 months (47.5%) compared with the European Organisation for Research and Treatment of Cancer/National Cancer Institute of Canada trial that used TMZ monotherapy (26.5%). 1 The comparison with such historical data has to be taken with caution, because MGMT promoter methylation status is not known in many of our patients (41%) and because potential differences in the number of patients with methylated MGMT promoter may have a significant impact on survival data. With a survivor rate of 16% after 5 years, the rate of patients who are surviving long term and who are potentially cured is also increased, compared with the rate of 4% to 5% that is commonly reported for glioblastoma. 8 In contrast to other studies on long-term survivors, which have patients whose median ages are 4.2 years 8 or 51 years, 9 the long-term survivors in our study are not particularly young: the median age was 57 years (range, 29 to 67 years). Long-term survival was mainly induced by the efficient primary treatment that consisted of CCNU/TMZ. Four of seven patients who survived longer than 4 years have not relapsed at last follow-up, and mpfs was longer during CCNU/TMZ therapy (mpfs, 1 months) than during secondline therapy (mpfs, 6 months) or during additional salvage therapies. However, the high rate of patients who received a second resection (28%) or multiple salvage therapies or both might influence the OS to some extent. As in the UKT-3 cohort, the MGMT promoter status remains a strong factor to predict the benefit from therapy in the whole cohort of patients treated with standard or intensified 126 29 by American Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGY Information downloaded from jco.ascopubs.org and provided by Hauptbibliothek Universitaet Zuerich on June 22, 29 from
Long-Term Survival After CCNU TMZ for Glioblastoma CCNU/TMZ. The median survival time of patients with a nonmethylated MGMT promoter is 12.5 months, which is essentially the time that is achieved with radiotherapy alone as the first-line treatment. 1 In patients with a methylated MGMT promoter, the mos (34.5 months) is almost tripled that of patients with a nonmethylated MGMT promoter. Obviously, there is no evidence that CCNU/TMZinduced MGMT depletion breaks resistance to chemotherapy in MGMT-nonmethylated status patients. Thus, patients with a nonmethylated MGMT promoter in their tumor may not take benefit from CCNU/TMZ at any dose. Consequently, future trials that combine CCNU/TMZ chemotherapy or other alkylating combination chemotherapy may be restricted to patients with a methylated MGMT promoter or should be stratified according to MGMT promoter methylation status. A significant dose intensification of TMZ in the CCNU/TMZ combination therapy appears to add an additional, marked survival benefit in the presence of high but tolerable toxicity. Admittedly, the group of patients with intensified CCNU/TMZ is small, and conclusions are, therefore, limited, particularly because the MGMT promoter methylation status is not known in many of the patients. Nevertheless, PFS and OS in this group are substantially increased, and the mos in the mixed group of patients with MGMT-methylated and -nonmethylated status who were treated with intensified CCNU/ TMZ appears higher than the mos of the patients who received standard dose and who had a methylated MGMT promotor ( 41.5 v 27.9 months). Intriguingly, four of eight patients in the intensified group have currently survived for at least 56 months, two of them without recurrence. It is important to note that the excellent efficacy data in the intensified group may not be the result of a selection of patients with favorable prognostic factors. The inclusion criteria were identical to the inclusion criteria of a previous large, phase III trial. 1 More importantly, the median age (59.5 years) as a major prognostic factor was higher than in previous trials and was close to the average age of patients with newly diagnosed glioblastoma in the general population. In conclusion, the combination of CCNU and TMZ shows promising efficacy against newly diagnosed glioblastoma. The data presented here demonstrate an encouraging therapeutic potential but also demonstrate the toxic limitations of the dose-intensified regimen in this setting. Additional studies are warranted to optimize CCNU/ TMZ combination chemotherapy. AUTHORS DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under 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: Wolfgang Wick, Schering-Plough (C); Michael Weller, Schering-Plough (C); Ulrich Herrlinger, Schering-Plough (C) Stock Ownership: None Honoraria: Joachim P. Steinbach, Schering-Plough; Michael Weller, Schering-Plough; Ulrich Herrlinger, Schering-Plough Research Funding: None Expert Testimony: None Other Remuneration: None AUTHOR CONTRIBUTIONS Conception and design: Johannes Rieger, Rolf-Dieter Kortmann, Michael Weller, Ulrich Herrlinger Administrative support: Michael Weller Provision of study materials or patients: Dorothee Wiewrodt, Oliver Bähr, Joachim P. Steinbach, Wolfgang Wick, Rolf-Dieter Kortmann, Ulrich Herrlinger Collection and assembly of data: Martin Glas, Caroline Happold, Johannes Rieger, Dorothee Wiewrodt, Oliver Bähr, Joachim P. Steinbach, Wolfgang Wick, Guido Reifenberger, Ulrich Herrlinger Data analysis and interpretation: Martin Glas, Guido Reifenberger, Michael Weller, Ulrich Herrlinger Manuscript writing: Martin Glas, Michael Weller, Ulrich Herrlinger Final approval of manuscript: Martin Glas, Caroline Happold, Johannes Rieger, Dorothee Wiewrodt, Oliver Bähr, Joachim P. 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