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Radiotherapy plus Concomitant and Adjuvant Temozolomide for=20 Glioblastoma
Roger Stupp, M.D., Warren P. Mason, M.D., = Martin J. van=20 den Bent, M.D., Michael Weller, M.D., Barbara Fisher, M.D., Martin J.B.=20 Taphoorn, M.D., Karl Belanger, M.D., Alba A. Brandes, M.D., Christine = Marosi,=20 M.D., Ulrich Bogdahn, M.D., J=FCrgen Curschmann, M.D., Robert C. Janzer, = M.D.,=20 Samuel K. Ludwin, M.D., Thierry Gorlia, M.Sc., Anouk Allgeier, Ph.D., = Denis=20 Lacombe, M.D., J. Gregory Cairncross, M.D., Elizabeth Eisenhauer, M.D., = Ren=E9 O.=20 Mirimanoff, M.D., for the European Organisation for Research and = Treatment of=20 Cancer Brain Tumor and Radiotherapy Groups and the National Cancer = Institute of=20 Canada Clinical Trials Group

 
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ABSTRACT

Background Glioblastoma, the = most common=20 primary brain tumor in adults, is usually rapidly fatal. The = current=20 standard of care for newly diagnosed glioblastoma is surgical = resection to the extent feasible, followed by adjuvant = radiotherapy.=20 In this trial we compared radiotherapy alone with = radiotherapy=20 plus temozolomide, given concomitantly with and after = radiotherapy,=20 in terms of efficacy and safety.

Methods Patients with newly diagnosed, histologically = confirmed=20 glioblastoma were randomly assigned to receive radiotherapy=20 alone (fractionated focal irradiation in daily fractions of = 2=20 Gy given 5 days per week for 6 weeks, for a total of 60 Gy) = or=20 radiotherapy plus continuous daily temozolomide (75 mg per = square=20 meter of body-surface area per day, 7 days per week from the = first to=20 the last day of radiotherapy), followed by six cycles of = adjuvant=20 temozolomide (150 to 200 mg per square meter for 5 days = during each=20 28-day cycle). The primary end point was overall = survival.=20

Results A total of 573 patients from 85 centers underwent=20 randomization. The median age was 56 years, and 84 percent of = patients had undergone debulking surgery. At a median = follow-up of 28=20 months, the median survival was 14.6 months with radiotherapy = plus=20 temozolomide and 12.1 months with radiotherapy alone. The = unadjusted=20 hazard ratio for death in the radiotherapy-plus-temozolomide=20 group was 0.63 (95 percent confidence interval, 0.52 to 0.75; = P<0.001 by the log-rank test). The two-year survival rate = was 26.5=20 percent with radiotherapy plus temozolomide and 10.4 percent = with=20 radiotherapy alone. Concomitant treatment with radiotherapy = plus=20 temozolomide resulted in grade 3 or 4 hematologic toxic = effects in 7=20 percent of patients.

Conclusions The addition of temozolomide to radiotherapy = for=20 newly diagnosed glioblastoma resulted in a clinically = meaningful=20 and statistically significant survival benefit with minimal=20 additional toxicity.

Glioblastoma is the most frequent primary malignant brain tumor = in=20 adults. Median survival is generally less than one year from = the time=20 of diagnosis, and even in the most favorable situations, most = patients die within two years.1,2,3=20 Standard therapy consists of surgical resection to the extent = that is=20 safely feasible, followed by radiotherapy; in the United = States,=20 adjuvant carmustine, a nitrosourea drug, is commonly = prescribed.4,5=20 Cooperative-group trials have investigated the addition of = various=20 chemotherapeutic regimens to radiotherapy,6,7,8,9=20 but no randomized phase 3 trial of nitrosourea-based adjuvant = chemotherapy has demonstrated a significant survival benefit = as=20 compared with radiotherapy alone, although there were more = long-term=20 survivors in the chemotherapy groups in some studies.10=20 A meta-analysis based on 12 randomized trials suggested a = small=20 survival benefit of chemotherapy, as compared with = radiotherapy alone=20 (a 5 percent increase in survival at two years, from 15 = percent to 20=20 percent).11=20 The meta-analysis included 37 percent of patients with = prognostically=20 more favorable, lower-grade gliomas.

Temozolomide, an oral alkylating agent, has demonstrated = antitumor=20 activity as a single agent in the treatment of recurrent glioma.12,13,14=20 The approved conventional schedule is a daily dose of 150 to=20 200 mg per square meter of body-surface area for 5 days of = every=20 28-day cycle. Daily therapy at a dose of 75 mg per square = meter=20 for up to seven weeks is safe; this level of exposure to = temozolomide15=20 depletes the DNA-repair enzyme O6-methylguanine-DNA=20 methyltransferase (MGMT).16=20 This effect may be important because low levels of MGMT in = tumor=20 tissue are associated with longer survival among patients = with=20 glioblastoma who are receiving nitrosourea-based adjuvant=20 chemotherapy.17,18=20

A pilot phase 2 trial demonstrated the feasibility of the = concomitant=20 administration of temozolomide with fractionated = radiotherapy,=20 followed by up to six cycles of adjuvant temozolomide, and = suggested=20 that this treatment had promising clinical activity (two-year = survival rate, 31 percent).19=20 The European Organisation for Research and Treatment of = Cancer=20 (EORTC) Brain Tumor and Radiotherapy Groups and the National = Cancer=20 Institute of Canada (NCIC) Clinical Trials Group therefore = initiated=20 a randomized, multicenter, phase 3 trial to compare this = regimen with=20 radiotherapy alone in patients with newly diagnosed=20 glioblastoma.

Methods

Patients

Patients 18 to 70 years of age with newly diagnosed and = histologically=20 confirmed glioblastoma (World Health Organization [WHO] grade = IV astrocytoma) were eligible for the study. Eligible = patients=20 had a WHO performance status of 2 or less and adequate = hematologic,=20 renal, and hepatic function (absolute neutrophil count, 3D≥=201500 = per cubic=20 millimeter; platelet count, 3D≥100,000 per cubic millimeter; serum creatinine = level, 1.5 = times the upper=20 limit of normal in the laboratory where it was measured; = total serum=20 bilirubin level, 3D≤1.5 times the upper limit of normal; and liver-function=20 values, <3 times the upper limit of normal for the = laboratory).=20 Patients who were receiving corticosteroids had to receive a=20 stable or decreasing dose for at least 14 days before = randomization.=20 All patients provided written informed consent, and the study = was approved by the ethics committees of the participating = centers.=20

Study Design and Treatment

Within six weeks after the histologic diagnosis of glioblastoma, = we randomly assigned eligible patients to receive standard = focal=20 radiotherapy alone (the control group) or standard = radiotherapy=20 plus concomitant daily temozolomide, followed by adjuvant=20 temozolomide. Randomization was performed at the EORTC Data = Center,=20 and patients were stratified according to WHO performance = status,=20 whether or not they had previously undergone debulking = surgery,=20 and the treatment center.20=20 The assigned treatment had to begin within one week after=20 randomization.

Radiotherapy consisted of fractionated focal irradiation at = a dose=20 of 2 Gy per fraction given once daily five days per week = (Monday=20 through Friday) over a period of six weeks, for a total dose = of 60=20 Gy. Radiotherapy was delivered to the gross tumor volume with = a=20 2-to-3-cm margin for the clinical target volume. Radiotherapy = was=20 planned with dedicated computed tomography (CT) and = three-dimensional=20 planning systems; conformal radiotherapy was delivered with = linear=20 accelerators with nominal energy of 6 MV or more, and quality = assurance was performed by means of individual case = reviews.21=20

Concomitant chemotherapy consisted of temozolomide (marketed = as=20 Temodal in Europe and Canada and Temodar in the United States;=20 Schering-Plough) at a dose of 75 mg per square meter per day, = given 7 days per week from the first day of radiotherapy = until=20 the last day of radiotherapy, but for no longer than 49 days. = After a 4-week break, patients were then to receive up to six = cycles of adjuvant temozolomide according to the standard = 5-day=20 schedule every 28 days. The dose was 150 mg per square meter=20 for the first cycle and was increased to 200 mg per square = meter=20 beginning with the second cycle, so long as there were no = hematologic=20 toxic effects. Because continuous daily temozolomide can = cause=20 lymphocytopenia, with a possible increased risk of = opportunistic=20 infections, patients in the radiotherapy-plus-temozolomide = group=20 were to receive prophylaxis against Pneumocystis carinii=20 pneumonia, consisting of either inhaled pentamidine or oral=20 trimethoprim=96sulfamethoxazole,22=20 during concomitant treatment with radiotherapy plus = temozolomide.=20 Antiemetic prophylaxis with metoclopramide or a=20 5-hydroxytryptamine3 antagonist was recommended = before the=20 initial doses of concomitant temozolomide and was required = during the=20 adjuvant five-day courses of temozolomide.

Surveillance and Follow-up

The baseline examination included CT or magnetic resonance = imaging=20 (MRI), full blood counts and blood chemistry tests, and a = physical=20 examination that included the Mini=96Mental State Examination = (MMSE) and a quality-of-life questionnaire. During = radiotherapy=20 (with or without temozolomide), patients were to be seen = every=20 week. Twenty-one to 28 days after the completion of = radiotherapy=20 and every 3 months thereafter, patients underwent a = comprehensive=20 evaluation, including administration of the MMSE and the=20 quality-of-life questionnaire and radiologic assessment of = the tumor.=20 During adjuvant temozolomide therapy, patients underwent a=20 monthly clinical evaluation and a comprehensive evaluation at = the=20 end of cycles 3 and 6. Tumor progression was defined = according=20 to the modified WHO criteria as an increase in tumor size by = 25=20 percent, the appearance of new lesions, or an increased need=20 for corticosteroids.23=20 When there was tumor progression or after two years of = follow-up,=20 patients were treated at the investigator's discretion, and = the type=20 of second-line therapy was recorded. Toxic effects were = graded=20 according to the National Cancer Institute Common Toxicity = Criteria,=20 version 2.0, with a score of 1 indicating mild adverse = effects, a=20 score of 2 moderate adverse effects, a score of 3 severe = adverse=20 effects, and a score of 4 life-threatening adverse = effects.=20

Statistical Analysis

The primary end point was overall survival; secondary end points = were progression-free survival, safety, and the quality of = life.=20 Overall survival and progression-free survival were analyzed = by=20 the Kaplan=96Meier method, with use of two-sided log-rank = statistics.=20 This study had 80 percent power at a significance level of = 0.05 to=20 detect a 33 percent increase in median survival (hazard ratio = for=20 death, 0.75), assuming that 382 deaths occurred. All analyses = were=20 conducted on an intention-to-treat basis. The Cox=20 proportional-hazards model was fitted to adjust for = stratification=20 factors and other confounding variables. Toxic effects are = reported=20 separately for the radiotherapy period, defined as extending = from day=20 1 of radiotherapy until 28 days after the last day of = radiotherapy,=20 or until the first day of adjuvant temozolomide therapy. The=20 adjuvant-therapy period was defined as extending from the = first day=20 of adjuvant temozolomide therapy until 35 days after day 1 of = the=20 last cycle of temozolomide. Findings with respect to the = quality of=20 life are not reported here.

Organization of the Trial

The concept of the trial was developed by Dr. Stupp in = collaboration=20 with the EORTC Data Center, the EORTC Brain Tumor and = Radiotherapy=20 Groups, and the NCIC Clinical Trials Group, represented by = Drs.=20 Cairncross and Eisenhauer. The radiotherapy design and = quality=20 assurance were supervised by Dr. Mirimanoff. The trial was = sponsored=20 by the EORTC Brain Tumor and Radiotherapy Groups (trial = 22981/26981)=20 in Europe and the NCIC Clinical Trials Group (trial CE.3) in=20 Canada. The trial was supported by an unrestricted = educational=20 grant from Schering-Plough, which also provided the study = drug;=20 however, Schering-Plough was not involved in trial design or=20 analysis. All data were collected by the EORTC and NCIC data=20 centers and reviewed by Drs. Stupp and Mirimanoff. The = analysis=20 was performed by the EORTC statistician, Mr. Gorlia. = Histologic=20 specimens were reviewed centrally (according to the revised = WHO=20 classification system24)=20 by a panel of three neuropathologists in Europe (Robert C. = Janzer in=20 Lausanne, Switzerland [chair]; Peter Wesseling in Nijmegen, = the=20 Netherlands; and Karima Mohktari in Paris) and a single=20 neuropathologist in Canada (Samuel Ludwin, Kingston, Ont.). = The=20 article was written by Dr. Stupp with support from a medical = writer=20 and coauthors; all authors reviewed the manuscript. =

Results

Patients

From August 2000 until March 2002, 573 patients from 85 = institutions=20 in 15 countries were randomly assigned to receive = radiotherapy=20 (286 patients) or radiotherapy plus temozolomide (287 = patients).=20 Nearly 50 percent of the patients were enrolled at 17 = institutions.=20 The characteristics of the patients in the two groups were = well=20 balanced at baseline (Table=20 1). The median age was 56 years, and 84 percent of = patients had=20 undergone debulking surgery. Slightly more patients in the=20 radiotherapy group than in the radiotherapy-plus-temozolomide = group=20 were receiving corticosteroids at the time of randomization = (75=20 percent vs. 67 percent). Histologic slides were submitted for = 85=20 percent of patients, and central pathological review = confirmed the=20 diagnosis of glioblastoma in 93 percent of the reviewed = cases; 3=20 percent had anaplastic astrocytoma or oligoastrocytoma (WHO = grade=20 III), and in 1 percent submitted material was insufficient = for a=20 definitive diagnosis.

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  		Table 1. Demographic=20 Characteristics of the Patients at Baseline. =

 
Disposition=20 of Patients and Delivery of Treatment

The median time from diagnosis to the start of therapy was 5 = weeks=20 (range, 2.0 to 12.9) in the radiotherapy group and 5 weeks = (range,=20 1.7 to 10.7) in the radiotherapy-plus-temozolomide group. Table=20 2 summarizes the details of treatment. Unplanned interruptions = in=20 radiotherapy were usually brief (median, four days) and = interruptions=20 due to the toxicity of therapy occurred in only 3 percent of=20 the radiotherapy group and 4 percent of the=20 radiotherapy-plus-temozolomide group. The other reasons were = mainly=20 administrative (e.g., holidays, radiotherapy equipment = maintenance,=20 or technical problems). One patient randomly assigned to = radiotherapy=20 alone received radiotherapy plus temozolomide. Among the 287 = patients=20 who were assigned to receive concomitant radiotherapy plus=20 temozolomide, 85 percent completed both radiotherapy and = temozolomide=20 as planned. Thirty-seven patients (13 percent) prematurely=20 discontinued temozolomide because of toxic effects (in 14 = patients),=20 disease progression (in 11), or other reasons (in 12). =

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  		Table 2. Disposition of = Patients=20 and Intensity of Treatment. =

 
Afte= r=20 radiotherapy, 223 patients in the radiotherapy-plus-temozolomide=20 group (78 percent) started adjuvant temozolomide and received = a=20 median of 3 cycles (range, 0 to 7); 47 percent of patients = completed=20 6 cycles. The main reason for not beginning or not completing = adjuvant temozolomide therapy was disease progression. Only 8 = percent=20 of patients discontinued adjuvant temozolomide because of = toxic=20 effects. Beginning with cycle 2, the dose of temozolomide was = increased to 200 mg per square meter in 67 percent of = patients. Only=20 9 percent of patients did not receive the higher dose because = of=20 hematologic toxicity.

Survival and Progression

At a median follow-up of 28 months, 480 patients (84 percent) = had=20 died. The unadjusted hazard ratio for death in the=20 radiotherapy-plus-temozolomide group as compared with the=20 radiotherapy group was 0.63 (95 percent confidence interval, = 0.52 to=20 0.75; P<0.001 by the log-rank test). These data indicate a = 37=20 percent relative reduction in the risk of death for patients = treated=20 with radiotherapy plus temozolomide, as compared with those = who=20 received radiotherapy alone.

The median survival benefit was 2.5 months; the median survival=20 was 14.6 months (95 percent confidence interval, 13.2 to = 16.8)=20 with radiotherapy plus temozolomide and 12.1 months (95 = percent=20 confidence interval, 11.2 to 13.0) with radiotherapy alone (Figure=20 1 and Table=20 3). The two-year survival rate was 26.5 percent (95 = percent=20 confidence interval, 21.2 to 31.7 percent) in the group given = radiotherapy plus temozolomide, as compared with 10.4 percent = (95=20 percent confidence interval, 6.8 to 14.1 percent) with = radiotherapy=20 alone. The median progression-free survival was 6.9 months = (95=20 percent confidence interval, 5.8 to 8.2) with radiotherapy = plus=20 temozolomide and 5.0 months (95 percent confidence interval, = 4.2 to=20 5.5) with radiotherapy alone (hazard ratio for death or = disease=20 progression, 0.54 [95 percent confidence interval, 0.45 to = 0.64];=20 P<0.001 by the log-rank test) (Figure=20 2).


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  		Figure 1. Kaplan=96Meier = Estimates of=20 Overall Survival According to Treatment Group.

The hazard ratio for death among patients treated with=20 radiotherapy plus temozolomide, as compared with those who = received=20 radiotherapy alone, was 0.63 (95 percent confidence = interval, 0.52=20 to 0.75; P<0.001). =

 
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  		Table 3. Overall and=20 Progression-free Survival According to Treatment Group. =

 

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  		Figure 2. Kaplan=96Meier = Estimates of=20 Progression-free Survival According to Treatment Group.

The hazard ratio for death or disease progression among = patients=20 treated with radiotherapy plus temozolomide, as compared = with those=20 treated with radiotherapy alone, was 0.54 (95 percent = confidence=20 interval, 0.45 to 0.64; P<0.001). =

 
The = hazard=20 ratio for death was adjusted by fitting the Cox proportional-hazard = models. In addition to the stratification factors (the extent = of surgery, WHO performance status, and treatment center), = other=20 possible confounding factors =97 age, use or nonuse of = corticosteroids=20 at randomization, sex, score on the MMSE, and tumor location = =97=20 were included. The adjusted hazard ratio for death in the=20 radiotherapy-plus-temozolomide group as compared with the=20 radiotherapy group =97 0.62 (95 percent confidence interval, = 0.51=20 to 0.75) =97 was essentially the same as the unadjusted = hazard=20 ratio.

Survival according to prognostic factors, including age, sex,=20 extent of surgery, WHO performance status, and use or nonuse = of=20 corticosteroids, was also analyzed (see Table 1 in the Suppleme= ntary=20 Appendix, available with the full text of this article at = www.nejm.org). Radiotherapy plus temozolomide was associated = with a=20 significant improvement in median overall survival in nearly = all=20 subgroups of patients (see Figure 1 in the Suppleme= ntary=20 Appendix); the exceptions were the small subgroup of 93 = patients=20 who underwent biopsy only and the 70 patients with a poor = performance=20 status.

Safety

We analyzed adverse events separately during radiotherapy (with = or=20 without concomitant temozolomide), the adjuvant-therapy period, = and=20 the entire study period (from study entry until disease = progression=20 or last follow-up). No grade 3 or 4 hematologic toxic effects = were=20 observed in the radiotherapy group. During concomitant = temozolomide=20 therapy, grade 3 or 4 neutropenia was documented in 12 = patients (4=20 percent), and grade 3 or 4 thrombocytopenia occurred in 9 = patients (3=20 percent) (Table=20 4). Overall, 19 patients (7 percent) had any type of = grade 3 or 4=20 hematologic toxic effect. During adjuvant temozolomide = therapy, 14=20 percent of patients had any grade 3 or 4 hematologic toxic = effect, 4=20 percent had grade 3 or 4 neutropenia, and 11 percent had = grade 3 or 4=20 thrombocytopenia.

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  		Table 4. Grade 3 or 4 = Hematologic=20 Toxic Effects in Patients Treated with Temozolomide. =

 
Duri= ng the=20 radiotherapy period, severe infections occurred in 6 patients = in the=20 radiotherapy group (2 percent) and in 9 patients in the=20 radiotherapy-plus-temozolomide group (3 percent); during = adjuvant=20 temozolomide therapy, 12 patients (5 percent) had severe = infections.=20 The most common nonhematologic adverse event during = radiotherapy was=20 moderate-to-severe fatigue in 26 percent of patients in the=20 radiotherapy group and 33 percent in the = radiotherapy-plus-temozolomide=20 group (Table 2 in the Suppleme= ntary=20 Appendix). Thromboembolic events occurred in 28 patients = (5=20 percent) =97 16 in the radiotherapy group and 12 in the=20 radiotherapy-plus-temozolomide group. Two patients in the=20 radiotherapy-plus-temozolomide group died of cerebral = hemorrhage in=20 the absence of a coagulation disorder or thrombocytopenia. = Pneumonia=20 was reported in five patients in the radiotherapy group and = three in=20 the radiotherapy-plus-temozolomide group. Opportunistic = infections=20 occurred in two patients; one patient treated with = radiotherapy alone=20 had suspected P. carinii pneumonia, and one patient in = the=20 radiotherapy-plus-temozolomide group had proven bacterial and = candida=20 pneumonia.

Treatment after Disease Progression

If disease progression occurred, further treatment was at the=20 physician's discretion. At the cutoff date (May 10, 2004), = 512=20 patients =97 268 in the radiotherapy group (94 percent) = and 244=20 in the radiotherapy-plus-temozolomide group (85 percent) =97 = had=20 disease progression. At the time of progression, 23 percent = of=20 patients in both treatment groups underwent a second surgery, = and 72=20 percent of patients in the radiotherapy group and 58 percent = in the=20 radiotherapy-plus-temozolomide group received chemotherapy. = Salvage=20 chemotherapy consisted of temozolomide in 60 percent of = patients in=20 the radiotherapy group and 25 percent of patients in the=20 radiotherapy-plus-temozolomide group. The response to salvage = chemotherapy was not recorded as part of our study. =

Discussion

For more than 30 years, chemotherapy given as an adjunct to=20 radiotherapy or before radiotherapy has been widely = investigated=20 in patients with malignant glioma. Such treatment has had = limited=20 success.6,7,8,10,25,26,27=20 The present study demonstrates that the addition of = chemotherapy to=20 radiotherapy significantly prolongs survival among patients = with=20 newly diagnosed glioblastoma, with a median increase in = survival of=20 2.5 months or a relative reduction in the risk of death of 37 = percent. Unlike most previous studies, which included = patients with=20 both glioblastoma (WHO grade IV) and anaplastic astrocytoma = (WHO=20 grade III), who have a better prognosis, our study was = designed to=20 include only patients with glioblastoma. At two years, we = found a=20 clinically meaningful increase =97 by a factor of 2.5 =97 in = the=20 survival rate, from 10 percent with radiotherapy alone to 27=20 percent with radiotherapy plus temozolomide, consistent with = the=20 findings of the preceding phase 2 trial.19=20 An exploratory analysis of subgroups defined according to = known=20 prognostic factors demonstrated a survival benefit in nearly = all=20 subgroups.

The outcome for patients treated with radiotherapy alone in = our=20 trial compares favorably with the outcome in other trials.9,11,28=20 Patients being treated with corticosteroids received stable = or=20 decreasing doses before randomization and started radiotherapy = within=20 one week after randomization. These criteria may have served = to=20 exclude patients with the worst prognosis, who may not = benefit from=20 any therapy. Moreover, most patients had undergone debulking = surgery.=20 The relatively long survival after disease progression = (approximately=20 seven months in both groups) is also noteworthy. This = extended=20 survival may reflect either patient selection or the early = detection=20 of tumor progression by means of regular radiographic = assessment.=20 Furthermore, 72 percent of patients in the radiotherapy group = and 58=20 percent of patients in the radiotherapy-plus-temozolomide = group=20 received salvage chemotherapy at the time of = progression.

This trial was designed to determine whether the addition of=20 temozolomide to radiotherapy early in the course of treatment = prolongs survival among patients with glioblastoma, but it = was=20 not designed to distinguish between the effects of = concomitant=20 therapy with radiotherapy plus temozolomide and adjuvant = treatment=20 with temozolomide. At the time the trial was conceived, it = was=20 deemed most important to administer chemotherapy early in the = course of the disease, for a sufficiently long time, and = concurrently=20 with radiotherapy. Temozolomide was given concomitantly with=20 radiotherapy on a continuous schedule for several reasons. = First,=20 daily administration of low doses makes possible an increase = by=20 almost a factor of two in dose intensity, as compared with = the=20 standard regimen, without an increase in toxicity.15=20 Second, continuous administration of an alkylating agent = depletes=20 MGMT,16=20 an enzyme that may be induced by radiotherapy and that is = necessary=20 for repair of damage to DNA caused by alkylating agents.29=20 In a companion translational study also reported in this = issue=20 of the Journal, we observed that methylation of the = MGMT=20 promoter, which results in gene silencing, is associated with = a=20 striking survival benefit in patients treated with = radiotherapy=20 plus temozolomide.30=20 Third, synergy between temozolomide and radiotherapy has been = observed in vitro.31,32,33=20 The spontaneous conversion of temozolomide into the active = metabolite=20 and its ability to cross the blood=96brain barrier also = favors this=20 regimen.34=20 Finally, to ensure sufficient exposure to the drug, we added=20 six cycles of adjuvant temozolomide after the completion of=20 radiotherapy.

In the context of palliative care, chemotherapy-induced toxic=20 effects should be manageable. Nausea was controlled with = standard=20 antiemetic agents. Severe myelosuppression was observed in 16 = percent of patients, leading to the early discontinuation of=20 chemotherapy in 5 percent. Whether the addition of = chemotherapy=20 increases the risk of radiotherapy-induced cognitive deficits = cannot be assessed at this time. However, long-term = monitoring=20 and observational studies of late toxic effects will be = important=20 to guide treatment recommendations in the future. = Furthermore,=20 prolonged chemotherapy with alkylating agents has been = associated=20 with myelodysplastic syndromes and secondary leukemia = occurring=20 years after therapy.35=20 In our trial, at a median follow-up of approximately two = years, there=20 had been no evidence of any increase in treatment-induced = late toxic=20 effects. Such late toxicity may become a greater concern, = however, if=20 this regimen is used in patients with intermediate- or = low-grade=20 glioma, who have a more favorable prognosis in terms of=20 survival.

In conclusion, the addition of temozolomide to radiotherapy = early=20 in the course of glioblastoma provides a statistically = significant=20 and clinically meaningful survival benefit. Nevertheless, the = challenge remains to improve clinical outcomes further. For = this=20 reason, the regimen of radiotherapy plus temozolomide should = serve as=20 the new platform from which to explore innovative regimens = for=20 treating malignant gliomas. Many questions remain unanswered=20 regarding the applications of this regimen to lower grade = gliomas and=20 the optimal combination of radiotherapy and = temozolomide.

Supported by grants (5U10CA11488-30 through=20 5U10CA11488-34) from the National Cancer Institute and by an=20 unrestricted educational grant from Schering-Plough, = Kenilworth,=20 N.J., which also provided the study drugs. The contents of = this=20 article are solely the responsibility of the authors and do = not=20 necessarily represent the views of the National Cancer=20 Institute.

Drs. Stupp, Mason, van den Bent, Brandes, Cairncross, and = Mirimanoff=20 report having received consulting and lecture fees from=20 Schering-Plough; Dr. Stupp also reports consulting fees from = EMD=20 Pharmaceuticals, and Oncomethylome, Dr. van den Bent = consulting fees=20 from Novartis, Dr. Eisenhauer consulting fees from = Schering-Plough,=20 and Dr. Marosi and Dr. Bogdahn lecture fees from=20 Schering-Plough.

We are indebted to the patients and their families for agreeing = to=20 participate in this trial, to the nurses and data managers = for their=20 collaboration, and to the EORTC data center (Linda de Prijck) = and the=20 NCIC Clinical Trials Group office (Marina Djurfeldt). =

* = Participating=20 institutions and investigators are listed in the = Appendix.=20


Source=20 Information

From the Centre Hospitalier Universitaire Vaudois, = Lausanne,=20 Switzerland (R.S., R-C.J., R.O.M.); Princess Margaret Hospital, Toronto=20 (W.P.M.); Daniel den Hoed Oncology Center=96Erasmus University Medical = Center=20 Rotterdam, Rotterdam, the Netherlands (M.J.B.); the University of = T=FCbingen=20 Medical School, T=FCbingen, Germany (M.W.); the University of Western = Ontario,=20 London, Ont., Canada (B.F.); the University Medical Center, Utrecht, the = Netherlands (M.J.B.T.); H=F4pital Notre Dame du Centre Hospitalier = Universitaire,=20 Montreal (K.B.); Azienda-Ospedale Universit=E0, Padova, Italy (A.A.B.); = Medical=20 University of Vienna, Vienna (C.M.); Universit=E4tskliniken, Regensburg, = Germany=20 (U.B.); Inselspital, Bern, Switzerland (J.C.); Queen's University, = Kingston,=20 Ont., Canada (S.K.L.); the European Organisation for Research and = Treatment of=20 Cancer Data Center, Brussels (T.G., A.A., D.L.); the University of = Calgary,=20 Calgary, Alta., Canada (J.G.C.); and the National Cancer Institute of = Canada=20 Clinical Trials Group, Kingston, Ont., Canada (E.E.).

Address reprint requests to Dr. Stupp at the = Multidisciplinary=20 Oncology Center, Centre Hospitalier Universitaire Vaudois, 46, rue du = Bugnon,=20 CH-1011 Lausanne, Switzerland, or at roger.stupp{at}chuv.hospvd.ch .

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Appendix

The following institutions and investigators participated in = the=20 trial: EORTC =97 Algemeen Ziekenhuis Middelheim, Antwerp, = Belgium (D.=20 Van Den Weyngaert); Klinikum Aschaffenburg, Germany (S. = Kaendler);=20 Nervenklink, Bamberg, Germany (P. Krauseneck); Hospital = Clinico y=20 Provincial de Barcelona, Barcelona, Spain (N. Vinolas); = Institut=20 Catala D'Oncologia, Barcelona, Spain (S. Villa);=20 Universitaetsklinikum (Charit=E9)=96Humboldt=96Universit=E4t, = Berlin (R.E.=20 Wurm); Centre Hospitalier R=E9gional de Besan=E7on=96Hopital = Jean Minjoz,=20 Besan=E7on, France (M.-H. Baron Maillot); Ospedale Bellaria, = Bologna,=20 Italy (F. Spagnolli); Institut Bergonie, Bordeaux, France (G. = Kantor); Centre Hospitalier Universitaire de Brest, Brest, = France=20 (J.-P. Malhaire); Cliniques Universitaires St. Luc, Brussels = (L.=20 Renard); Hopital Universitaire Erasme, Brussels (O. De = Witte);=20 Ospedale Sant Anna, Como, Italy (L. Scandolaro); Medisch = Centrum=20 Haaglanden=96Westeinde, Den Haag, the Netherlands (C.J. = Vecht); Centre=20 Georges-Fan=E7ois-Leclerc, Dijon, France (P. Maingon);=20 Universit=E4tsklinikum Freiburg, Freiburg, Germany (J. = Lutterbach);=20 Medical University of Gdansk, Gdansk, Poland (A. Kobierska); = Centre=20 Hospitalier R=E9gional de Grenoble=96La Tronche, Grenoble, = France (M.=20 Bolla); Allgemeines Krankenhaus Hagen, Hagen, Germany (R. = Souchon);=20 Hopital de Jolimont, Haine St. Paul, Belgium (C. Mitine); = Rambam=20 Medical Center, Haifa, Israel (T. Tzuk-Shina, A. Kuten);=20 Henriettenstiftung=96Neurologische Klinik, Hannover, Germany = (G.=20 Haferkamp); Akademisch Ziekenhuis Vrije Universiteit, = Brussels (J. de=20 Greve); Centre Hospitalier D=E9partmental, La Roche sur Yon, = France (F.=20 Priou); Universitaire Ziekenhuizen Gasthuisberg, Leuven, = Belgium (J.=20 Menten); Centre Hospitalier Universitaire Sart-Tilman, Liege, = Belgium=20 (I. Rutten); Centre Hospitalier Universitaire de Limoges, = Limoges,=20 France (P. Clavere); Linkoping University Hospital, = Linkoping,=20 Sweden (A. Malmstrom); Institute of Oncology, Ljubljana, = Slovenia=20 (B. Jancar); Charing Cross Hospital, London (E. Newlands); = Royal=20 Free Hospital, London (K. Pigott); Academisch Ziekenhuis = Maastricht,=20 Maastricht, the Netherlands (A. Twijnstra); Centre = Hospitalier=20 Universitaire de la Timone, Marseille, France (O. Chinot); = Istituto=20 Scientifico Hospedale San Raffaele, Milan (M. Reni); Istituto = Nazionale Neurologico "Carlo Besta," Milan (A. Boiardi); = Centre=20 R=E9gional Lutte contre le Cancer Val d'Aurelle, Montpellier, = France (M. Fabbro); Centre Rene Gauducheau, Nantes St. = Herblain,=20 France (M. Campone); Newcastle General Hospital, Newcastle,=20 United Kingdom (J. Bozzino); Centre Antoine Lacassagne, Nice, = France (M. Frenay); University Medical Centre Nijmegen, = Nijmegen,=20 the Netherlands (J. Gijtenbeek); Azienda-Ospedale = Universit=E0,=20 Padova, Italy (A.A. Brandes); Centre Hospitalier = Universitaire=20 Piti=E9=96Salp=EAtri=E8re, Paris (J.-Y. Delattre); = Universit=E4tskliniken=20 Regensburg, Germany (U. Bogdahn); Ospedale San Pietro=20 Fatebenefratelli, Rome (U. De Paula); Erasmus University = Medical=20 Center, Rotterdam, the Netherlands (M.J. van den Bent); = Centre Henri=20 Becquerel, Rouen, France (C. Hanzen); Ospedale = Civile=96Ospedale S.=20 Maria Misericordia, Rovigo, Italy (G. Pavanato); Centre Paul = Strauss,=20 Strasbourg, France (S. Schraub); Chaim Sheba Medical Center, = Tel=20 Hashomer, Israel (R. Pfeffer); Universit=E0 degli studi di = Torino,=20 Turin, Italy (R. Soffietti); Universit=E4tsklinikum = T=FCbingen,=20 T=FCbingen, Germany (M. Weller, R.D. Kortmann); Universitair=20 Medisch Centrum=96Academisch Ziekenhuis, Utrecht, the = Netherlands=20 (M. Taphoorn); Hospital General Universitario, Valencia, = Spain=20 (J. Lopez Torrecilla); Medical University of Vienna, Vienna = (C.=20 Marosi); Kaiser Franz Josef Spital, Vienna (W. Grisold); = Algemeen=20 Ziekenhuis Sint-Augustinus, Wilrijk, Belgium (P. Huget); NCIC = Clinical Trials Group =97 Tom Baker Cancer Centre, Calgary, = Alta. (P.=20 Forsyth); Cross Cancer Institute, Edmonton, Alta. (D. = Fulton); Nova=20 Scotia Cancer Centre, Halifax, N.S. (S. Kirby); Margaret and = Charles=20 Juravinski Cancer Center, Hamilton, Ont. (R. Wong); British = Columbia=20 Cancer Agency=96Cancer Centre of the Southern Interior, = Kelowna, B.C.=20 (D. Fenton); London Regional Cancer Center, London, Ont. (B. = Fisher,=20 G. Cairncross); Dr. Leon Richard Oncology Centre, Moncton, = N.B. (P.=20 Whitlock); H=F4pital Notre-Dame du Centre Hospitalier=20 Universitaire de Montreal, Montreal (K. Belanger); McGill = University,=20 Montreal (S. Burdette-Radoux); Ottawa Regional Cancer=20 Centre=96Civic Campus, Ottawa (S. Gertler); Saint John = Regional=20 Hospital, St. John, N.B. (S. Saunders); Dr. H. Bliss Murphy = Cancer=20 Centre, St. John, Newf. (K. Laing, J. Siddiqui); British = Columbia=20 Cancer Agency=96Fraser Valley Cancer Centre, Surrey, B.C. = (L.A.=20 Martin); Thunder Bay Regional Health Sciences Centre, Thunder = Bay, Ont. (S. Gulavita); Toronto=96Sunnybrook Regional Cancer = Centre, Toronto (J. Perry); Princess Margaret Hospital, = Toronto=20 (W. Mason); British Columbia Cancer Agency=96Vancouver Cancer = Centre, Vancouver, B.C. (B. Thiessen); British Columbia = Cancer=20 Agency=96Vancouver Island Cancer Centre, Victoria, B.C. = (H. Pai);=20 Windsor Regional Cancer Centre, Windsor, Ont. (Z.Y. Alam); = Cancercare=20 Manitoba, Winnipeg, Man. (D. Eisenstat) =97 all in Canada; = Swiss=20 Cooperative Group for Clinical Cancer Research (SAKK) =97 = Kantonsspital=20 Aarau, Aarau (W. Mingrone); Kantonsspital Basel, Basel (S. = Hofer);=20 Ospedale San Giovanni, Bellinzona (G. Pesce); Inselspital = Bern, Bern=20 (J. Curschmann); Hopital Cantonal Universitaire, Geneva (P.Y. = Dietrich); Centre Hospitalier Universitaire Vaudois, Lausanne = (R.=20 Stupp, R.O. Mirimanoff); Kantonsspital Luzern, Lucerne (P. = Thum);=20 Universit=E4tsspital Zurich, Zurich (B. Baumert) =97 all in = Switzerland;=20 Tasmanian Radiation Oncology Group: Peter MacCallum Cancer = Institute,=20 Melbourne, Australia (G. Ryan).


 
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Treatment = of Brain=20 Tumors
Paulino A. C., Teh B. S., Sadeh M., Seiter K., = Ashby L.,=20 LaRocca R., Ryken T., Aiken R. D., Rutkowski S., Ottensmeier H., Pietsch = T.,=20 Stupp R., Hegi M. E., DeAngelis L. M.
Extract<= /A> | Full = Text | PDF =  
N=20 Engl J Med 2005; 352:2350-2353, Jun 2, 2005. Correspondence =

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