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Journal of Clinical Oncology, Vol 24, No 27 (September 20), 2006: pp. 4412-4417 © 2006 American Society of Clinical Oncology. DOI: 10.1200/JCO.2006.06.9104 Phase II Trial of Lomustine Plus Temozolomide Chemotherapy in Addition to Radiotherapy in Newly Diagnosed Glioblastoma: UKT-03
From the Department of General Neurology, Hertie Institute for Clinical Brain Research; Departments of Radiation Oncology and Neuropathology, University of Tübingen, Tübingen; Departments of Neurosurgery and Neurology, University of Mainz, Mainz; Department of Neuropathology, University of Duesseldorf, Düsseldorf, Germany Address reprint requests to Ulrich Herrlinger, MD, Clinical Neurooncology Unit, Department of Neurology, University of Bonn, Sigmund-Freud-Str 25, D-53105 Bonn, Germany; e-mail: Ulrich.Herrlinger{at}ukb.uni-bonn.de
PURPOSE: To evaluate toxicity and efficacy of the combination of lomustine, temozolomide (TMZ) and involved-field radiotherapy in patients with newly diagnosed glioblastoma (GBM). PATIENTS AND METHODS: Thirty-one adult patients (median Karnofsky performance score 90; median age, 51 years) accrued in two centers received involved-field radiotherapy (60 Gy in 2-Gy fractions) and chemotherapy with lomustine 100 mg/m2 (day 1) and TMZ 100 mg/m2/d (days 2 to 6) with individual dose adjustments according to hematologic toxicity. RESULTS: A median of five courses (range, one to six courses) were delivered. WHO grade 4 hematotoxicity was observed in five patients (16%) and one of these patients died as a result of septicemia. Nonhematologic toxicity included one patient with WHO grade 4 drug-induced hepatitis (leading to discontinuation of lomustine and TMZ) and one patient with WHO grade 2 lung fibrosis (leading to discontinuation of lomustine). The progression-free survival (PFS) rate at 6 months was 61.3%. The median PFS was 9 months (95% CI, 5.3 to 11.7 months), the median overall survival time (MST) was 22.6 months (95% CI, 12.5 to not assessable), the 2-year survival rate was 44.7%. O6-Methylguanine–DNA methyltransferase (MGMT) gene-promoter methylation in the tumor tissue was associated with longer PFS (P = .014, log-rank test) and MST (P = .037). CONCLUSION: The combination of lomustine, TMZ, and radiotherapy had acceptable toxicity and yielded promising survival data in patients with newly diagnosed GBM. MGMT gene-promoter methylation was a strong predictor of survival.
Glioblastoma (GBM) has a dismal prognosis. For decades, surgery followed by radiotherapy alone was the standard of care. In meta-analyses,1,2 adjuvant chemotherapy with nitrosoureas (carmustine, lomustine) seemed to be associated with some survival benefit. Only recently have the first randomized trials documented a significant improvement in survival by adjuvant chemotherapy.3,4 These trials implemented temozolomide (TMZ) as part of the standard of care for newly diagnosed GBM. However, even with TMZ, median overall survival time (MST) remains relatively low at 14.6 months. Thus, improved chemotherapy protocols that further extend survival are urgently needed. Part of the DNA damage induced by nitrosoureas and TMZ is repaired by the suicide enzyme, O6-methylguanine–DNA methyltransferase (MGMT). Thus, their combination might overcome MGMT-mediated resistance via MGMT depletion, yielding superior treatment results than either treatment alone. The University of Tuebingen Medical Center (UKT) -03 phase II trial therefore combined oral TMZ with oral lomustine. To avoid excess toxicity as well as undertreatment, TMZ and lomustine doses were adjusted individually depending on the hematologic toxicity observed during the previous course. Given that the methylation status of the MGMT promoter is predictive for survival of GBM patients treated with alkylating agents,5,6 we also investigated the predictive value of MGMT promoter methylation in the trial population.
Patients UKT-03 accrued patients at the University of Tuebingen (Tuebingen, Germany) and Mainz (Mainz, Germany) Medical Centers. The trial was approved by the local Ethics Committees. All patients gave written informed consent. The main inclusion criteria were histologic diagnosis of GBM, surgery no longer than 21 days before, no prior radiotherapy or chemotherapy, age older than 18 years, Karnofsky performance score of 70 or higher, and no alterations in bone marrow reserve, liver function, or renal function.
Treatment and Surveillance In each course, toxicity was monitored and graded according to the WHO recommendations for grading of acute and subacute toxicity. Hematologic toxicity was evaluated by weekly blood tests for leukocytes, platelets, and hemoglobin. Blood chemistry (Na, K, creatinine, AST, ALT, coagulation studies) and urinalysis were performed at the start of each course. Every second course and after the last course, pulmonary function was assessed by spirometry. Response assessment was based on contrast-enhanced magnetic resonance imaging (MRI) after courses 2, 4, and 6.8 After chemotherapy, patients were observed at 3-month intervals by clinical examination and MRI. Lomustine/TMZ therapy was to be discontinued if MRI-documented progression occurred, on patient's request, if the patient became pregnant, or if unacceptable toxicity occurred, defined as any WHO grade 4 nonhematologic toxicity or delay of the next course of chemotherapy for more than 6 weeks due to hematologic toxicity.
End Points and Statistical Analysis The calculation of the sample size in a one-step design was based on the assumption that the study treatment was superior to standard first-line therapy if the lower 95% CI of the PFS rate at 6 months (PFS-6) in UKT-03 was higher than 35%. This was the PFS-6 in a large previous GBM trial with radiotherapy alone, which was the standard of care for GBM when the trial was opened.9 This criteria was met if 16 of 30 patients (53.3%) or more were progression free at 6 months. For acceptable toxicity, no more than 10% of patients should have experienced WHO grade 4 nonhematologic toxicity. To avoid excess toxicity, early stopping rules were implemented and toxicity data were screened constantly. If after inclusion of seven, 14, 21, and 28 patients, more than 50% of patients experienced WHO grade 4 toxicity, including hematologic toxicity, or more than two patients had died as a result of therapy-related causes, the trial would have been closed prematurely.
MGMT Analysis
Patient Characteristics Thirty-one patients were accrued between November 2002 and December 2003 (Table 1). With 31 patients, one patient more than originally planned was accrued because at the end of the accrual period, two eligible patients consented at the same time. Twenty patients were treated at the University of Tuebingen and 11 patients were treated at the University of Mainz. All patients screened were accrued and all patients were assessable for toxicity.
Treatment A total of 131 courses of lomustine/TMZ were delivered. The median number of courses delivered was five (range, one to six courses). All patients received course 1, 28 of 31 patients (90.3%) received two courses, 23 of 31 patients (74.2%) received three courses, 22 of 31 patients (71%) received four courses; 16 of 31 patients (51.6%) received five courses, and 11 of 31 patients (35.5%) received all six courses. The dose of lomustine was modified or lomustine was discontinued prematurely in seven patients (22.1%). The lomustine dose was adjusted for hematologic toxicity in four of these patients (12.9%). In two of these patients TMZ also was adjusted, whereas the other two patients did not have a WBC or platelet nadir before day 25 so that a TMZ dose adjustment was not necessary. Lomustine was discontinued due to nonhematologic toxicity in three patients (9.7%), including one patient with a nonlethal accidental fourfold lomustine overdose (who later on developed progressive disease), one patient with WHO grade 4 toxic hepatitis, and one patient with lomustine-induced WHO grade 2 lung fibrosis. In the first two patients, TMZ therapy was stopped too, whereas in the latter patient, only lomustine was stopped and TMZ (19 courses with 200 mg/m2/d) was continued. The TMZ dose was adjusted in 15 patients (48.3%). Two patients (6.5%) had a stepwise increase by three dose levels up to 200 mg/m2/d, six patients (19.4%) had an increase by two dose levels, and five patients (16.1%) had an increase by one dose level. In two patients (6.5%) TMZ was reduced by one dose level because of hematologic toxicity.
Toxicity
Therapeutic Efficacy A total of 30 of 31 patients were assessable for outcome assessment. 20 patients with measurable residual tumor after resection were assessable for response: one patient had complete response; no partial response was seen. The median PFS was 9 months (range, 1.9 to 29.3+ months; 95% CI, 5.3 to 11.7 months; Fig 1A). More than 24 months after primary therapy, two patients are still stable despite discontinuation of therapy. PFS-6 was 61.3% and PFS-12 was 29%. PFS-6 was thus higher than 53.3% (16 to 30 patients), which was needed to meet the predefined efficacy criteria. Twenty-eight of 31 patients (90.3%) had tumor progression. One patient died as a result of complications during course 1; two patients are stable after more than 24 months. All 28 patients with progression were assessable for second-line therapy, including a second resection in 10 patients. Nine patients (32.1%) had dose-dense second-line TMZ (100 mg/m2/d for 7 of 14 days),13 eight patients (28.6%) had second-line nimustine/teniposide,14 five patients (17.9%) received a second course of radiotherapy, two patients had second-line surgery without additional therapy, and four patients did not have any additional therapy. MST after second-line therapy was 9.7 months (range, 1.1 to 26+ months). The efficacy of different second-line chemotherapies cannot be compared because the population of patients receiving dose-dense TMZ was different from the population receiving nimustine/teniposide: patients with a long first PFS (median, 16.5 months) received TMZ, whereas patients with a short PFS (median, 4.3 months) had mainly nimustine/teniposide. MST from the diagnosis of GBM is presented in Figure 1B. Thirteen patients are alive at the end of the study assessment (January 2006). The MST was 22.6 months (range, 1.9 to 34.2 months; 95% CI, 12.5 to not assessable months). The percentage of patients surviving was 71% at 1 year and 44.7% at 2 years.
MGMT Methylation Status and Survival Tumor specimens of 23 patients were available for MGMT analysis. Eight patients had undergone surgery elsewhere and histologic samples were not available when we decided to determine MGMT promoter methylation retrospectively. Four of 23 samples did not yield sufficient tumor DNA. Thus, 19 tumors were assessable for MGMT promoter methylation. Eight patients had a methylated MGMT promoter and 11 patients did not. The log-rank test indicated that both PFS and MST were significantly longer in patients with a methylated MGMT promoter (Fig 2). The median PFS was 6 months with a nonmethylated and 19 months with a methylated MGMT promoter (P = .014). MST was 12.5 months with a nonmethylated promoter and was not reached in patients with a methylated MGMT promoter (2-year survival rate 75%). In the group of eight patients with methylated MGMT promoter, only two patients have died 2 years after closure of the trial. Only one of the patients died as a result of progressive tumor, whereas the other died from complications of therapy.
The combination of lomustine, TMZ, and radiotherapy showed promising activity and acceptable toxicity. Furthermore, it confirmed previous reports5,6 that the methylation status of the MGMT gene promoter region is highly predictive for survival in GBM patients receiving alkylating chemotherapy. The 2-year survival rate of 44.7% in UKT-03 is biologically meaningful in that patients who respond to chemotherapy seem to have an extended benefit and a potential for long-term survival. To exclude that the UKT-03 patient population is highly selected for favorable prognostic factors, the UKT-03 population was assigned to one of the prognostic groups developed by recursive partitioning analysis15 and validated in a large number of glioma patients enrolled in Radiation Therapy Oncology Group trials.16 In the prognostic group including the majority of UKT-03 patients, groups III and IV, the 2-year survival rates were markedly higher in UKT-03 (46.9% and 42.1%) than in the Radiation Therapy Oncology Group database (35% and 15%; data not shown). The UKT-03 schedule with lomustine on day 1 and TMZ (100 mg/m2/d) on 5 consecutive days seems to be more effective than the combinations of carmustine and a single application of TMZ (550 mg/m2). This combination was not substantially more active than TMZ alone in patients with recurrent GBM17,18 and had only modest activity in newly diagnosed anaplastic glioma.19 In contrast, Barrié et al7 reported high objective response rates and a comparably long MST (12.7 months) with a schedule (carmustine 150 mg/m2 day 1 + TMZ 110 mg/m2/d days 1 through 5) similar to UKT-03 in inoperable, newly diagnosed GBM. Although the combination of lomustine and TMZ yielded promising results in UKT-03, it did not overcome MGMT-mediated resistance because the MGMT promoter methylation status remained a potent predictor of survival (Fig 2). In fact, the apparent prolongation of survival was achieved only in patients with a methylated MGMT promoter, whereas patients with a nonmethylated promoter seemed to have no benefit. The MST in the latter group was 12.5 months, which is identical to that in patients with a nonmethylated MGMT promoter receiving TMZ alone (12.7 months) in the European Organisation for Research and Treatment of Cancer/National Cancer Institute of Canada trial6 (12.2 months; Table 3).
The acute toxicity of the lomustine/TMZ regimen was acceptable. The rate of high-grade acute hematologic toxicity was higher than with TMZ monotherapy (7% during concomitant and 14% during adjuvant TMZ therapy).3 With the individual dose adjustment in UKT-03, toxicity was well controlled and TMZ dose reductions were necessary in less than 10% of patients. Considering that half of the UKT-03 patients had subsequent escalations of their TMZ dose, it can be debated whether the doses of lomustine and TMZ could be increased further. Other trials have used higher doses for the nitrosourea part (eg, carmustine 150 mg/m2)7,17,19,20 or for TMZ (110 mg/m2/d over 5 days).7 One recent phase I trial even suggests the combination of carmustine 120 mg/m2 (day 1) with TMZ at 200 mg/m2/d (days 2 to 6).21 In contrast to the dosing of lomustine and TMZ, the sequence of nitrosourea and TMZ application used in UKT-03 (TMZ after nitrosourea) may not be altered because the reversal of this sequence is associated with higher toxicity rates.22 Not only primary therapy with lomustine/TMZ, but also second-line therapy may have contributed to the promising outcome in UKT-03. With a second MST of 9.7 months and a 1-year survival rate after treatment for recurrent disease of 43.9%, the results of second-line therapy are much better than previous results (eg, 21% 1-year survival reported by Wong et al23). The efficacy of second-line therapy was particularly high with dose-dense TMZ.13 Most importantly, our data support the notion that patients who were stable for a longer time after primary TMZ therapy may have another prolonged stabilization on second-line therapy with TMZ.24 Thus, patients who benefit from primary TMZ chemotherapy can or even should have TMZ at recurrence. In conclusion, the UKT-03 data presented here should prompt additional evaluation in a phase III trail and should induce efforts to analyze the predictive value of MGMT promoter methylation prospectively.
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)
U.H. and J.R. contributed equally to this work. Presented in part at the 41st Annual Meeting of the American Society of Clinical Oncology, May 13-17, 2005, Orlando, FL, and at the Annual Meeting of the German Society of Hematology and Oncology, October 1-5, 2005, Hannover, Germany. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Hegi ME, Diserens AC, Gorlia T, et al: MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med 352:997-1003, 2005 7. Barrié M, Couprie C, Dufour H, et al: Temozolomide in combination with BCNU before and after radiotherapy in patients with inoperable newly diagnosed glioblastoma multiforme. Ann Oncol 16:1177-1184, 2005 8. Macdonald DR, Cascino TL, Schold SC, et al: Response criteria for phase II studies of supratentorial malignant glioma. J Clin Oncol 8:1277-1280, 1990[Abstract] 9. Prados MD, Wara WM, Sneed PK, et al: Phase III trial of accelerated hyperfractionation with or without difluoromethylornithine (DFMO) versus standard fractionated radiotherapy with or without DFMO for newly diagnosed patients with glioblastoma multiforme. Int J Radiat Oncol Biol Phys 49:71-77, 2001[CrossRef][Medline] 10. Reifenberger J, Ring GU, Gies U, et al: Analysis of p53 mutation and epidermal growth factor receptor amplification in recurrent gliomas with malignant progression. J Neuropathol Exp Neurol 55:822-831, 1996[Medline] 11. Herman JG, Graff JR, Myohanen S, et al: Methylation-specific PCR: A novel PCR assay for methylation status of CpG islands. Proc Natl Acad Sci U S A 93:9821-9826, 1996 12. Möllemann M, Wolter M, Felsberg J, et al: Frequent promoter hypermethylation and low expression of the MGMT gene in oligodendroglial tumors. Int J Cancer 113:379-385, 2005[CrossRef][Medline] 13. Wick W, Steinbach JP, Küker WM, et al: One week on/one week off: A novel active regimen of temozolomide for recurrent glioblastoma. Neurology 62:2113-2115, 2004 14. Weller N, Muller B, Koch R, et al: Neuro-Oncology Working Group 01 trial of nimustine plus teniposide versus nimustine plus cytarabine chemotherapy in addition to involved-field radiotherapy in the first-line treatment of malignant glioma. J Clin Oncol 21:3276-3284, 2003 15. Curran WJ, Scott CB, Horton J, et al: Recursive partitioning analysis of prognostic factors in three Radiation Therapy Oncology Group malignant glioma trials. J Natl Cancer Inst 85:704-710, 1993 16. 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 90-06. Int J Radiat Oncol Biol Phys 40:51-55, 1998[CrossRef][Medline] 17. Schold SC Jr, Kuhn JG, Chang SM, et al: A phase I trial of 1,3-bis(2-chloroethyl)-1-nitrosourea plus temozolomide: A North American Brain Tumor Consortium study. Neuro-oncol 2:34-39, 2000[Abstract] 18. Prados MD, Yung WK, Fine HA, et al: Phase 2 study of BCNU and temozolomide for recurrent glioblastoma multiforme: North American Brain Tumor Consortium study. Neuro-oncol 6:33-37, 2004[CrossRef][Medline] 19. Chang SM, Prados MD, Yung WK, et al: Phase II study of neoadjuvant 1, 3-bis (2-chloroethyl)-1-nitrosourea and temozolomide for newly diagnosed anaplastic glioma: A North American Brain Tumor Consortium Trial. Cancer 100:1712-1716, 2004[CrossRef][Medline] 20. Raizer JJ, Malkin MG, Kleber M, et al: Phase 1 study of 28-day, low-dose temozolomide and BCNU in the treatment of malignant gliomas after radiation therapy. Neuro-oncol 6:247-252, 2004[Abstract] 21. Fabbro M, Bauchet L, Kerr C, et al: A dose finding phase I study of temozolomide (TMZ) and BCNU combined regimen (TEMOBIC) as a treatment of high-grade glioma (HGG) in adult chemo-naive patients. J Clin Oncol 23:126s,2005 (suppl; abstr 1550) 22. Hammond LA, Eckardt JR, Kuhn JG, et al: A randomized phase I and pharmacological trial of sequences of 1,3-bis(2-chloroethyl)-1-nitrosourea and temozolomide in patients with advanced solid neoplasms. Clin Cancer Res 10:1645-1656, 2004 23. Wong ET, Hess KR, Gleason MJ, et al: Outcomes and prognostic factors in recurrent glioma patients enrolled onto phase II clinical trials. J Clin Oncol 17:2572-2578, 1999 24. Franceschi E, Omuro AM, Lassman AB, et al: Salvage temozolomide for prior temozolomide responders. Cancer 104:2473-2476, 2005[CrossRef][Medline] Submitted April 5, 2006; accepted July 19, 2006. This article has been cited by other articles:
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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
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