Randomized Phase II Study of Temozolomide and Radiotherapy Compared With Radiotherapy Alone in Newly Diagnosed Glioblastoma Multiforme
http://www.100md.com
《临床肿瘤学》
the St Savas Cancer Hospital, First Radiation Oncology Department
Metaxa Cancer Hospital, First and Second Radiation Oncology Departments
IASO Hospital, Radiation Oncology Department
General Army Hospital, Radiation Oncology Department, Athens
Papageorgiou Hospital, Radiation Oncology Department, Thessaloniki, Greece
ABSTRACT
PURPOSE: Surgery remains the standard treatment for glioma, followed by radiotherapy (RT) with or without chemotherapy. Despite multidisciplinary approaches, the median survival time for patients with glioblastoma multiform (GBM) remains at less than 1 year from initial diagnosis. Temozolomide (TMZ), an oral alkylating agent, has shown promising activity in the treatment of malignant gliomas. We conducted a multicenter randomized phase II study comparing the efficacy and safety of TMZ administered concomitantly and sequentially to RT versus RT alone in patients with newly diagnosed GBM.
PATIENTS AND METHODS: One hundred thirty patients with pathologically confirmed, newly diagnosed GBM were randomly assigned (110 assessable patients) to receive either TMZ 75 mg/m2/d orally, concomitantly with RT (60 Gy in 30 fractions; group A, n = 57), followed by six cycles of TMZ (150 mg/m2 on days 1 through 5 and 15 to 19 every 28 days), or RT alone (60 Gy in 30 fractions; group B, n = 53).
RESULTS: Median time to progression was 10.8 months in group A and 5.2 months in group B (P = .0001). One-year progression-free survival rate was 36.6% in group A and 7.7% in group B. Median overall survival (OS) time was also significantly better in group A versus group B (13.4 v 7.7 months, respectively; P < .0001), as was the 1-year OS at 56.3% v 15.7% (P < .0001), respectively. Toxicity was mainly hematologic. One patient with grade 4 myelotoxicity died as a result of sepsis. The other side effects were mild.
CONCLUSION: TMZ combined with RT (concomitantly and sequentially) seems to be more effective than RT alone in patients with newly diagnosed GBM. The combined-modality treatment was well tolerated.
INTRODUCTION
Glioblastoma multiforme (GBM) is the most common and aggressive neoplasia of the brain in adults. These tumors account for 45% to 50% of all gliomas. Their clinical course is usually rapid and fatal, with a median survival of less than 1 year. Multimodality treatment with surgical resection followed by radiotherapy (RT) alone or in association with adjuvant chemotherapy has produced poor results, with long-term survival rates of less than 5%.1 Two large, randomized, multicenter trials confirmed that postoperative brain RT provided a significant survival advantage compared with surgery alone.2,3
The effectiveness of adjuvant chemotherapy in malignant gliomas remains controversial. Only one randomized trial performed in the past 30 years has shown a survival benefit for the use of adjuvant chemotherapy, consisting of a nitrosourea-based regimen.4 A recent meta-analysis of 12 randomized trials (3,000 individual patients) has shown a modest increase in survival (40% RT alone v 46% RT plus chemotherapy at 1 year) with the addition of adjuvant chemotherapy.5 Considering the extremely poor prognosis of malignant glioma, continuous research and development of new treatment modalities and chemotherapeutic agents is urgently needed.
Temozolomide (TMZ) is a novel, oral, second-generation, alkylating agent that has demonstrated activity in malignant gliomas. TMZ has nearly 100% bioavailability and readily crosses the blood-brain barrier, resulting in CNS concentrations that are approximately 40% of those observed in the plasma.6 TMZ is approved for the treatment of recurrent malignant glioma but also has activity in patients with newly diagnosed malignant glioma.7-10
Resistance of TMZ is mediated in part through O6-alkylguanine-DNA-alkyltransferase (AGAT). Rapid dose-dependent AGAT depletion was noted in peripheral-blood mononuclear cells by prolonged TMZ exposure.11-14 Newer schedules of prolonged and continuous TMZ administration have been developed, allowing for dose increments of up to two-fold without increasing toxicity.9,15
The concurrent administration of TMZ and radiation has been explored in vitro and in vivo. In vitro studies have shown that, depending on the cell line, treatment of glioma cells with TMZ and x-rays can have either an additive or synergistic effect. The glioma cell line U373MG, with a low level of the repair enzyme AGAT, was particularly sensitive to the combination, whereas a colon cell line with high levels of AGAT expression was more resistant.16 Van Rijn et al17 investigated prolonged TMZ exposure followed by single-dose and fractionated irradiation in two glioma cell lines.17 Prolonged treatment with TMZ and fractionated irradiation in the cell line D384 caused a stronger potentiation. In contrast, no enhancement of cytotoxicity was observed in irradiated U251 cells. A number of possible mechanistic explanations have been suggested for the interaction between TMZ and x-rays.18
In a phase II study by Stupp et al,9 demonstrated that concomitant RT plus continuous daily TMZ followed by adjuvant TMZ is well tolerated and improves survival in patients with newly diagnosed GBM. A recently completed phase III study by the European Organisation for Research and Treatment of Cancer (EORTC) has confirmed this data.19 On the basis of this evidence, we initiated this study to compare the efficacy and safety of TMZ administered concomitantly and sequentially to RT versus RT alone in patients with newly diagnosed GBM.
PATIENTS AND METHODS
Study Objectives
The primary study end points were progression-free survival (PFS) and overall survival (OS) of patients with GBM treated with TMZ concurrent with cranial RT and six cycles of adjuvant TMZ. A secondary end point was to document the treatment-related toxicity.
Eligibility
The eligibility requirements included patients 18 years with histologically confirmed GBM based on WHO classification. Other eligibility criteria included Karnofsky performance score (KPS) 60, adequate bone marrow reserve (hemoglobin 10 g/dL, absolute neutrophil count 1,500/μL, and platelet count 100,000/μL), normal renal function (serum creatinine level < 1.5 mg/dL), and normal hepatic function (bilirubin < 1.5 x the upper limit of laboratory normal, AST < 2.5 x the upper limit of laboratory normal, and alkaline phosphatase < 2 x the upper limit of laboratory normal). Patients were not eligible if they were in poor medical condition because of nonmalignant systemic disease or acute infection or if they had any medical condition that could interfere with the oral administration of TMZ. All patients were required to give written informed consent. The protocol was reviewed and approved by the local ethics committee.
Treatment
Patients eligible for study inclusion were randomly assigned to receive cranial RT and TMZ (concomitantly and sequentially) or RT alone. All patients received RT to limited fields once daily at 2 Gy per fraction, 5 days a week, for a total of 60 Gy, and the dose was prescribed according to the guidelines of the International Commission of the Radiological Units. The patients were treated with thermoplastic immobilization masks to ensure adequate immobilization during therapy and reproducibility. The treatment volumes for both the initial volume and the boost volume were based on preoperative computed tomography (CT) and/or magnetic resonance imaging (MRI) scans. For the first 46 Gy, the initial treatment volume was determined by the volume of contrast-enhancing tumor and surrounding edema calculated from CT and/or MRI scan plus a 2-cm margin or 2.5-cm margin if no surrounding edema was present. After 46 Gy, the treatment volume was reduced to include the contrast-enhancing tumor (without edema) on the preoperative CT and/or MRI scan plus a 2.5-cm margin to a total dose of 60 Gy. All patients were planned using three-dimensional techniques.
Patients randomly assigned to the combined-modality group received TMZ (75 mg/m2 for 7 days a week), concomitantly with RT, 1 hour before irradiation and in the morning on days without RT. Four weeks after RT, patients received six cycles of adjuvant TMZ. We administered a novel schedule (150 mg/m2 of TMZ on days 1 through 5 and 15 to 19 every 28 days), aiming at dose intensification. Prophylactic antiemetics were used routinely. Anticonvulsants and corticosteroids were administered as needed.
Assessments
Patients were assessed weekly during RT for toxicity. CBC counts were performed weekly during treatment, and blood chemistry was performed monthly. During adjuvant TMZ cycles, neurologic examinations, serum chemistry, anticonvulsant levels, and toxicity evaluations were performed at each TMZ cycle and at every follow-up appointment in the RT alone group (every 2 months during the first year and every 3 months during the second year after study entry). CT or MRI scans with or without contrast were performed before the first adjuvant treatment cycle and then every 2 months during the first year and 3 months during the second year. Disease progression was defined as radiologic (25% or greater increase in the size of the product of the largest perpendicular diameters of contrast-enhancing tumor or any new tumor on MRI or CT), neurologic, or clinical. There was no central review. Toxicity was assessed according to National Cancer Institute Common Toxicity Criteria (version 2.0).
Statistical Analysis
The main objectives were to evaluate time to progression (TTP) and OS using the Kaplan-Meier product-limit method.20 OS was estimated from starting date of RT to the date of death or the last contact date. TTP was the interval between the starting date of RT and tumor progression or the moment of withdrawal from the study for any other reason. The log-rank test21 was used to compare OS and TTP among group, and 95% CIs were computed using S-plus (Version 3.3; Statistical Sciences, Seattle, WA).
A multivariate Cox proportional hazards model was used to compare the hazard ratios of the two groups taking into account some patient characteristics. These were age, the KPS of the patient, and whether the patient had undergone total or partial resection or biopsy. Age and KPS were included in the model as binary variables ( 50 years v > 50 years and 80 v > 80, respectively). The model was fit for both TTP and OS.
The comparison of patient characteristics was carried out using the 2 test for the categoric variables (sex, resection, and so on) and using a t test for the continuous variables (time from diagnosis to treatment). Age and KPS were transformed to binary variables with cutoff points of 50 years and KPS of 80, respectively.
RESULTS
Patient Characteristics
January 2000 through December 2002, 130 patients were randomized onto this study, of which 110 were assessable for response. Twenty patients were found to be ineligible; five patients were randomized but not treated, six had ineligible histology (anaplastic astrocytoma), and nine were treated with hyperfractionated RT. Fifty-seven patients received RT + TMZ (group A), whereas 53 patients received RT alone (group B). There were no major differences in the demographic and baseline characteristics of the two treatment groups (Table 1). The majority of patients (82%) was more than 50 years old and had a KPS 80. Forty-two percent of the patients underwent biopsy, 42% underwent subtotal resection, and 16% underwent gross total resection. However, postoperative CT within 48 hours of surgery was not performed in all patients. The median time from diagnosis to the start of treatment was 35.6 days in the RT + TMZ group and 34.4 days in the RT alone group. The mean RT duration was 42.1 days in the RT + TMZ group and 42.2 days in the RT alone group (P = .91). All but four patients received the planned 60 Gy of RT (group A: one patient because of disease progression and one patient because of toxic death; group B: two patients because of disease progression). The median follow-up of the patients was 11.2 months (range, 3.4 to 27.0 months). In group B (RT alone), 10 patients received TMZ at the time they developed disease progression, whereas no patient in group A (RT + TMZ) received second-line chemotherapy at the time they developed disease progression.
TTP and Survival
The median TTP was 10.8 months for the RT + TMZ group (95% CI, 8.08 to 14.69 months) and 5.2 months for the RT alone group (95% CI, 3.94 to 7.36 months). The log-rank test disclosed a significant difference in TTP between the two groups (P < .0001; Fig 1). The TTP survival rates at 6, 12, and 18 months are listed in Table 2.
The median OS was 13.41 months (95% CI, 9.53 to 17.13 months) for the RT + TMZ group and 7.7 months (95% CI, 5.32 to 9.20 months) for the RT alone group. The log-rank test disclosed a significant difference in survival between the two groups (P < .0001; Fig 2). The OS rates at 6, 12, and 18 months are listed in Table 2.
Prognostic Factors
A multivariate Cox proportional hazards regression model was used to test the effect of age, extent of surgery, KPS, and treatment group on TTP and OS (Table 3). Administration of TMZ (hazard ratio = 0.68; P = .0008) and KPS more than 80 (hazard ratio = 0.60; P = .03) were significant prognostic factors for TTP, whereas type of resection and age were not statistically significant.
Concerning OS, both administration of TMZ (hazard ratio = 0.66; P = .0003) and KPS (hazard ratio = 0.47; P = .042) were significant. Type of surgery was not statistically significant, whereas age was very close to the significance level (P = .058; Table 3).
Because of the relatively high proportion (60%) of patients with poor performance status (KPS 80) included in our study, we separately analyzed this group. No significant difference was found between TMZ + RT and RT alone for TTP (P = .26). Concerning OS, it seems that there is a trend in favor of the TMZ + RT group, but the difference is not significant (P = .065).
Toxicity
All 110 eligible patients were evaluated for toxicity. The combination TMZ + RT (concomitant and sequential) was well tolerated. The main side effect was myelosuppression. During the concomitant RT + TMZ phase, grade 3 and 4 leukopenia occurred in two patients (3.5%), and grade 3 and 4 thrombocytopenia occurred in three patients (5.2%). One patient with grade 3 and 4 myelotoxicity experienced serious infection and died as a result of sepsis.
Two hundred forty cycles of adjuvant TMZ were administered, with a mean of 4.2 cycles per patient. The median time from end of RT to start of adjuvant TMZ was 32 days. Eleven patients in the combined-therapy group did not receive at least one cycle of adjuvant TMZ (disease progression, n = 4; toxicity, n = 1; toxic death, n = 1; lost, n = 4; and patient's denial, n = 1). Thirty-five patients (61.4%) completed six cycles of treatment as planned. We observed grade 3 thrombocytopenia in 12 cycles (5%) and grade 3 leukopenia in five cycles (2%). Nine patients had a dose reduction or delay because of myelotoxicity.
Nonhematologic toxicity was mild. In the combined-therapy group, three patients (5%) experienced treatment-related rash, two patients (3.5%) experienced constipation, and one patient (1.5%) experienced arthralgias. Late neurologic side effects were not assessed because of the short duration of follow-up.
DISCUSSION
RT remains the standard of care for high-grade glioma after resection and seems necessary because extensive tumor infiltration into normal brain structures makes resection of the entire primary tumor impossible in most cases. In the late 1970s, several clinical trials showed that postoperative RT significantly improved survival.22,23 Despite the advances in neuroimaging and in neurosurgical and RT techniques, the prognosis of patients with GBM remains poor, and the search of more effective chemotherapeutic agents is of great interest.
TMZ seems to be an effective agent in the treatment of malignant gliomas, offering a favorable safety profile compared with nitrosoureas. A number of studies have demonstrated the radiosensitizing properties of TMZ in vitro and in vivo.16,17
Our randomized study confirms the efficacy and safety of the combination of RT and TMZ (concomitant and sequential) in patients with newly diagnosed GBM and the superiority of this combined regimen over RT alone, which supports the earlier data of Stupp et al.9 An EORTC phase III trial included 573 patients with newly diagnosed GBM who were randomly assigned to either standard RT (60 Gy in 30 daily fractions of 2 Gy) or the same RT and TMZ, concomitant and sequential.19 The trial demonstrated that the combined treatment, compared with RT alone, significantly improved PFS (5 v 7.2 months, respectively; P < .0001) and OS (12 v 15 months, respectively; P < .0001; 2-year survival, 8% v 26%, respectively; P < .0001) in GBM patients. The results of our study also support the benefit of the combination of RT + TMZ in patients with GBM.
PFS and OS, the primary end points of the study, were significantly longer with RT + TMZ than with RT alone (median PFS, 10.8 v 5.2 months, respectively; median OS, 13.4 v 7.7 months, respectively). In the RT alone group, PFS and OS are relatively low compared with other series, but our study was limited to patients with GBM. Furthermore, considering age, KPS, and type of surgery, the majority of our patients had unfavorable baseline characteristics. However, the combined therapy demonstrated encouraging PFS and OS despite the fact that a significant proportion of these patients (60%) had a KPS 80 (Table 1). By contrast, only 36% of the GBM patients had a KPS 80 in the trial by Stupp et al,9 in which a median survival time of 15.8 months was reported. The proportion of patients with poor performance status was also much lower in our study compared with that of the EORTC study.19 This could explain the poorer results for our control group compared with that of Stupp et al.9
The benefit in PFS in the TMZ + RT group versus the RT alone group (TTP, 10.8 v 5.2 months, respectively) that was demonstrated in our study is superior to that of the EORTC study (PFS, 7.2 v 5 months). Two possible explanations are the different patient populations or the more accurate estimation of radiologic progression in the EORTC study.
The multivariate analysis of prognostic factors in all patients demonstrated that the administration of TMZ was the most significant prognostic factor in TTP and OS. Age and KPS proved to be significant, whereas our study failed to demonstrate a statistically significant difference for the type of surgery (biopsy and incomplete and gross total resection). Stupp et al9 demonstrated an increased median survival with debulking surgery compared with biopsy. The lack of a significant difference in our study could possibly be explained by the fact that immediate (within 48 to 72 hours) postoperative CT or MRI was not performed in all patients, and consequently, the estimation of surgical extent is possibly suboptimal. A separate analysis of patients with poor KPS (KPS of 70 to 80) demonstrated that the administration of TMZ did not significantly improve TTP in this group of patients, whereas the improvement in OS was close to the significance level (P = .065).
The schedule-dependent antitumor activity of TMZ has been shown in preclinical studies.24 An extended schedule enables a greater dose of TMZ to be administered per unit of time. Currently, the standard schedule of TMZ in malignant glioma patients is 200 mg/m2 for 5 days every 28 days.7,8,25 A number of different dosing schedules have been investigated to determine whether more frequent administration of TMZ can improve the treatment outcome without increasing toxicity.11,12,26,27 We administered a novel schedule of TMZ (150 mg/m2 of TMZ on days 1 through 5 and 15 to 19 every 28 days) in the adjuvant phase of treatment, aiming at dose intensification.
The main side effect in both the concomitant and the adjuvant phase of the RT + TMZ group was myelosuppression that was reversible and noncumulative, which allowed for nearly continuous therapy. The concomitant administration of RT + TMZ was well tolerated, with low percentages of grade 3 and 4 leukopenia (3.5%) and thrombocytopenia (5.2%). However, one patient in this group died as a result of sepsis. Overall compliance in the adjuvant phase was satisfactory; 46 (80%) of 57 patients had at least one cycle of therapy, and 35 (61.4%) 57 patients completed six cycles of adjuvant TMZ. The extended schedule that was administered in the adjuvant phase demonstrated favorable toxicity because grade 3 and 4 leukopenia was observed in only 2% of cycles and grade 3 and 4 thrombocytopenia was observed in 5% of cycles. Prior concomitant RT + TMZ treatment did not increase toxicity in the adjuvant phase. Nonhematologic adverse effects occurred with low frequency. Grade 3 and 4 nausea and vomiting were virtually eliminated with standard antiemetics.
In summary, the results of our study suggest that concomitant RT + TMZ followed by six cycles of adjuvant TMZ (extended schedule) is superior to RT alone in patients with newly diagnosed GBM. This regimen seems to ameliorate the TTP and OS of the patients. In addition, TMZ was safe and well tolerated, and patients were able to sustain intense, continuous therapy. The recently presented international EORTC phase III trial has demonstrated a similar benefit.19
Authors' Disclosures of Potential Conflicts of Interest
The authors indicated no potential conflicts of interest.
NOTES
Authors' disclosures of potential conflicts of interest are found at the end of this article.
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Walker MD, Strike TA, Sheline GE: An analysis of dose effect relationship in the radiotherapy of malignant gliomas. Int J Radiat Oncol Biol Phys 5:1725-1731, 1979
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Stupp R, Ostermann S, Leyvrav S, et al: Cerebrospinal fluid levels of temozolomide as a surrogate marker for brain penetration. Proc Am Soc Clin Oncol 20:59a, 2001 (abstr 232)
Brada M, Hoang-Xuan K, Rampling R, et al: Multicenter phase II trial of temozolomide in patients with glioblastoma multiforme at first relapse. Ann Oncol 12:259-266, 2001
Yung WK, Prados MD, Yaya-Tur R, et al: Multicenter phase II trial of temozolomide in patients with anaplastic astrocytoma or anaplastic oligoastrocytoma at first relapse. J Clin Oncol 17:2762-2771, 1999
Stupp R, Dietrich PY, Kraljevic SO, 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
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Denis L, Tolcher A, Figueroa J, et al: Protracted daily administration of Temozolomide is feasible: A phase I pharmacokinetic-pharmacodynamic study. Proc Am Soc Clin Oncol 19:202a, 2000 (abstr 786)
Figueroa J, Tolcher A, Denis L, et al: Protracted cyclic administration of temozolomide is feasible: A phase I, pharmacokinetic and pharmacodynamic study. Proc Am Soc Clin Oncol 19:222a, 2000 (abstr 868)
Tolcher A, Felton S, Gerson S, et al: Persistent and marked inactivation of O-6-alkylguanine-DNA alkyltransferase (AGAT), a mechanism of resistance to alkylators, with protracted low-dose oral schedules of temozolomide. Proc Am Soc Clin Oncol 19:175a, 2000 (abstr 680)
Tolcher A, Gerson SL, Denis L, et al: Marked inactivation of O6-alkylguanine-DNA alkyltransferase activity with protracted temozolomide schedules. Br J Cancer 88:1004-1011, 2003
Brock CS, Newlands ES, Wedge SR, et al: Phase I trial of temozolomide using an extended continuous oral schedule. Cancer Res 58:4363-4367, 1998
Wedge SR, Porteous JK, Glaser MG, et al: In vitro evaluation of temozolomide combined with X-irradiation. Anticancer Drugs 8:92-97, 1997
van Rijn J, Heimans JJ, van den Berg J, et al: Survival of human glioma cells treated with various combination of temozolomide and x-rays. Int J Radiat Oncol Biol Phys 47:779-784, 2000
Hirose Y, Berger MS, Pieper RO: Abrogation of the Chk-mediated G(2) checkpoint pathway potentiates temozolomide-induced toxicity in a p53-independant manner in human glioblastoma cells. Cancer Res 61:5843-5849, 2001
Stupp R, Mason WP, van den Bent MJ, et al: Concomitant and adjuvant temozolomide (TMZ) and radiotherapy (RT) for newly diagnosed glioblastoma (GMB): Conclusive results of a randomized phase III trial by the EORTC Brain & RT Groups and NCIC Clinical Trials Group. Proc Am Soc Clin Oncol 23:1, 2004 (abstr 2)
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Salazar OM, Rubin P, Feldstein ML, et al: High dose radiation therapy in the treatment of malignant gliomas: First report. Int J Radiat Oncol Biol Phys 5:1733-1740, 1979
Stevens MF, Hickman JA, Langdon SP, et al: Antitumor activity and pharmacokinetics in mice of 8-carbamoyl-3-methyl-imidazo(5.1-d)-1.2.3.5-tetrazin-4(3 H)-one (CCRG 81045: M & B 39831), a novel drug with potential as an alternative to dacarbazine. Cancer Res 47:5846-5852, 1987
Yung WK, Albright RE, Olsen J, et al: A phase II study of temozolomide vs. procarbazine in patients with glioblastoma multiform at first relapse. Br J Cancer 83:588-593, 2000
Wurm R, Roeschel L, Scheffler D, et al: Phase I-II study with continuous dose-escalated 21-day schedule temozolomide in recurrent high-grade glioma. Proc Am Soc Clin Oncol 19:164a, 2000 (abstr 634)
Raymond E, Vera K, Djafari L, et al: Safety profile and activity of high-dose temozolomide given daily x 3 every 2 weeks in patients with primary tumors. Proc Am Soc Clin Oncol 21:78a, 2002 (abstr 310)(Helen Athanassiou, Maria )
Metaxa Cancer Hospital, First and Second Radiation Oncology Departments
IASO Hospital, Radiation Oncology Department
General Army Hospital, Radiation Oncology Department, Athens
Papageorgiou Hospital, Radiation Oncology Department, Thessaloniki, Greece
ABSTRACT
PURPOSE: Surgery remains the standard treatment for glioma, followed by radiotherapy (RT) with or without chemotherapy. Despite multidisciplinary approaches, the median survival time for patients with glioblastoma multiform (GBM) remains at less than 1 year from initial diagnosis. Temozolomide (TMZ), an oral alkylating agent, has shown promising activity in the treatment of malignant gliomas. We conducted a multicenter randomized phase II study comparing the efficacy and safety of TMZ administered concomitantly and sequentially to RT versus RT alone in patients with newly diagnosed GBM.
PATIENTS AND METHODS: One hundred thirty patients with pathologically confirmed, newly diagnosed GBM were randomly assigned (110 assessable patients) to receive either TMZ 75 mg/m2/d orally, concomitantly with RT (60 Gy in 30 fractions; group A, n = 57), followed by six cycles of TMZ (150 mg/m2 on days 1 through 5 and 15 to 19 every 28 days), or RT alone (60 Gy in 30 fractions; group B, n = 53).
RESULTS: Median time to progression was 10.8 months in group A and 5.2 months in group B (P = .0001). One-year progression-free survival rate was 36.6% in group A and 7.7% in group B. Median overall survival (OS) time was also significantly better in group A versus group B (13.4 v 7.7 months, respectively; P < .0001), as was the 1-year OS at 56.3% v 15.7% (P < .0001), respectively. Toxicity was mainly hematologic. One patient with grade 4 myelotoxicity died as a result of sepsis. The other side effects were mild.
CONCLUSION: TMZ combined with RT (concomitantly and sequentially) seems to be more effective than RT alone in patients with newly diagnosed GBM. The combined-modality treatment was well tolerated.
INTRODUCTION
Glioblastoma multiforme (GBM) is the most common and aggressive neoplasia of the brain in adults. These tumors account for 45% to 50% of all gliomas. Their clinical course is usually rapid and fatal, with a median survival of less than 1 year. Multimodality treatment with surgical resection followed by radiotherapy (RT) alone or in association with adjuvant chemotherapy has produced poor results, with long-term survival rates of less than 5%.1 Two large, randomized, multicenter trials confirmed that postoperative brain RT provided a significant survival advantage compared with surgery alone.2,3
The effectiveness of adjuvant chemotherapy in malignant gliomas remains controversial. Only one randomized trial performed in the past 30 years has shown a survival benefit for the use of adjuvant chemotherapy, consisting of a nitrosourea-based regimen.4 A recent meta-analysis of 12 randomized trials (3,000 individual patients) has shown a modest increase in survival (40% RT alone v 46% RT plus chemotherapy at 1 year) with the addition of adjuvant chemotherapy.5 Considering the extremely poor prognosis of malignant glioma, continuous research and development of new treatment modalities and chemotherapeutic agents is urgently needed.
Temozolomide (TMZ) is a novel, oral, second-generation, alkylating agent that has demonstrated activity in malignant gliomas. TMZ has nearly 100% bioavailability and readily crosses the blood-brain barrier, resulting in CNS concentrations that are approximately 40% of those observed in the plasma.6 TMZ is approved for the treatment of recurrent malignant glioma but also has activity in patients with newly diagnosed malignant glioma.7-10
Resistance of TMZ is mediated in part through O6-alkylguanine-DNA-alkyltransferase (AGAT). Rapid dose-dependent AGAT depletion was noted in peripheral-blood mononuclear cells by prolonged TMZ exposure.11-14 Newer schedules of prolonged and continuous TMZ administration have been developed, allowing for dose increments of up to two-fold without increasing toxicity.9,15
The concurrent administration of TMZ and radiation has been explored in vitro and in vivo. In vitro studies have shown that, depending on the cell line, treatment of glioma cells with TMZ and x-rays can have either an additive or synergistic effect. The glioma cell line U373MG, with a low level of the repair enzyme AGAT, was particularly sensitive to the combination, whereas a colon cell line with high levels of AGAT expression was more resistant.16 Van Rijn et al17 investigated prolonged TMZ exposure followed by single-dose and fractionated irradiation in two glioma cell lines.17 Prolonged treatment with TMZ and fractionated irradiation in the cell line D384 caused a stronger potentiation. In contrast, no enhancement of cytotoxicity was observed in irradiated U251 cells. A number of possible mechanistic explanations have been suggested for the interaction between TMZ and x-rays.18
In a phase II study by Stupp et al,9 demonstrated that concomitant RT plus continuous daily TMZ followed by adjuvant TMZ is well tolerated and improves survival in patients with newly diagnosed GBM. A recently completed phase III study by the European Organisation for Research and Treatment of Cancer (EORTC) has confirmed this data.19 On the basis of this evidence, we initiated this study to compare the efficacy and safety of TMZ administered concomitantly and sequentially to RT versus RT alone in patients with newly diagnosed GBM.
PATIENTS AND METHODS
Study Objectives
The primary study end points were progression-free survival (PFS) and overall survival (OS) of patients with GBM treated with TMZ concurrent with cranial RT and six cycles of adjuvant TMZ. A secondary end point was to document the treatment-related toxicity.
Eligibility
The eligibility requirements included patients 18 years with histologically confirmed GBM based on WHO classification. Other eligibility criteria included Karnofsky performance score (KPS) 60, adequate bone marrow reserve (hemoglobin 10 g/dL, absolute neutrophil count 1,500/μL, and platelet count 100,000/μL), normal renal function (serum creatinine level < 1.5 mg/dL), and normal hepatic function (bilirubin < 1.5 x the upper limit of laboratory normal, AST < 2.5 x the upper limit of laboratory normal, and alkaline phosphatase < 2 x the upper limit of laboratory normal). Patients were not eligible if they were in poor medical condition because of nonmalignant systemic disease or acute infection or if they had any medical condition that could interfere with the oral administration of TMZ. All patients were required to give written informed consent. The protocol was reviewed and approved by the local ethics committee.
Treatment
Patients eligible for study inclusion were randomly assigned to receive cranial RT and TMZ (concomitantly and sequentially) or RT alone. All patients received RT to limited fields once daily at 2 Gy per fraction, 5 days a week, for a total of 60 Gy, and the dose was prescribed according to the guidelines of the International Commission of the Radiological Units. The patients were treated with thermoplastic immobilization masks to ensure adequate immobilization during therapy and reproducibility. The treatment volumes for both the initial volume and the boost volume were based on preoperative computed tomography (CT) and/or magnetic resonance imaging (MRI) scans. For the first 46 Gy, the initial treatment volume was determined by the volume of contrast-enhancing tumor and surrounding edema calculated from CT and/or MRI scan plus a 2-cm margin or 2.5-cm margin if no surrounding edema was present. After 46 Gy, the treatment volume was reduced to include the contrast-enhancing tumor (without edema) on the preoperative CT and/or MRI scan plus a 2.5-cm margin to a total dose of 60 Gy. All patients were planned using three-dimensional techniques.
Patients randomly assigned to the combined-modality group received TMZ (75 mg/m2 for 7 days a week), concomitantly with RT, 1 hour before irradiation and in the morning on days without RT. Four weeks after RT, patients received six cycles of adjuvant TMZ. We administered a novel schedule (150 mg/m2 of TMZ on days 1 through 5 and 15 to 19 every 28 days), aiming at dose intensification. Prophylactic antiemetics were used routinely. Anticonvulsants and corticosteroids were administered as needed.
Assessments
Patients were assessed weekly during RT for toxicity. CBC counts were performed weekly during treatment, and blood chemistry was performed monthly. During adjuvant TMZ cycles, neurologic examinations, serum chemistry, anticonvulsant levels, and toxicity evaluations were performed at each TMZ cycle and at every follow-up appointment in the RT alone group (every 2 months during the first year and every 3 months during the second year after study entry). CT or MRI scans with or without contrast were performed before the first adjuvant treatment cycle and then every 2 months during the first year and 3 months during the second year. Disease progression was defined as radiologic (25% or greater increase in the size of the product of the largest perpendicular diameters of contrast-enhancing tumor or any new tumor on MRI or CT), neurologic, or clinical. There was no central review. Toxicity was assessed according to National Cancer Institute Common Toxicity Criteria (version 2.0).
Statistical Analysis
The main objectives were to evaluate time to progression (TTP) and OS using the Kaplan-Meier product-limit method.20 OS was estimated from starting date of RT to the date of death or the last contact date. TTP was the interval between the starting date of RT and tumor progression or the moment of withdrawal from the study for any other reason. The log-rank test21 was used to compare OS and TTP among group, and 95% CIs were computed using S-plus (Version 3.3; Statistical Sciences, Seattle, WA).
A multivariate Cox proportional hazards model was used to compare the hazard ratios of the two groups taking into account some patient characteristics. These were age, the KPS of the patient, and whether the patient had undergone total or partial resection or biopsy. Age and KPS were included in the model as binary variables ( 50 years v > 50 years and 80 v > 80, respectively). The model was fit for both TTP and OS.
The comparison of patient characteristics was carried out using the 2 test for the categoric variables (sex, resection, and so on) and using a t test for the continuous variables (time from diagnosis to treatment). Age and KPS were transformed to binary variables with cutoff points of 50 years and KPS of 80, respectively.
RESULTS
Patient Characteristics
January 2000 through December 2002, 130 patients were randomized onto this study, of which 110 were assessable for response. Twenty patients were found to be ineligible; five patients were randomized but not treated, six had ineligible histology (anaplastic astrocytoma), and nine were treated with hyperfractionated RT. Fifty-seven patients received RT + TMZ (group A), whereas 53 patients received RT alone (group B). There were no major differences in the demographic and baseline characteristics of the two treatment groups (Table 1). The majority of patients (82%) was more than 50 years old and had a KPS 80. Forty-two percent of the patients underwent biopsy, 42% underwent subtotal resection, and 16% underwent gross total resection. However, postoperative CT within 48 hours of surgery was not performed in all patients. The median time from diagnosis to the start of treatment was 35.6 days in the RT + TMZ group and 34.4 days in the RT alone group. The mean RT duration was 42.1 days in the RT + TMZ group and 42.2 days in the RT alone group (P = .91). All but four patients received the planned 60 Gy of RT (group A: one patient because of disease progression and one patient because of toxic death; group B: two patients because of disease progression). The median follow-up of the patients was 11.2 months (range, 3.4 to 27.0 months). In group B (RT alone), 10 patients received TMZ at the time they developed disease progression, whereas no patient in group A (RT + TMZ) received second-line chemotherapy at the time they developed disease progression.
TTP and Survival
The median TTP was 10.8 months for the RT + TMZ group (95% CI, 8.08 to 14.69 months) and 5.2 months for the RT alone group (95% CI, 3.94 to 7.36 months). The log-rank test disclosed a significant difference in TTP between the two groups (P < .0001; Fig 1). The TTP survival rates at 6, 12, and 18 months are listed in Table 2.
The median OS was 13.41 months (95% CI, 9.53 to 17.13 months) for the RT + TMZ group and 7.7 months (95% CI, 5.32 to 9.20 months) for the RT alone group. The log-rank test disclosed a significant difference in survival between the two groups (P < .0001; Fig 2). The OS rates at 6, 12, and 18 months are listed in Table 2.
Prognostic Factors
A multivariate Cox proportional hazards regression model was used to test the effect of age, extent of surgery, KPS, and treatment group on TTP and OS (Table 3). Administration of TMZ (hazard ratio = 0.68; P = .0008) and KPS more than 80 (hazard ratio = 0.60; P = .03) were significant prognostic factors for TTP, whereas type of resection and age were not statistically significant.
Concerning OS, both administration of TMZ (hazard ratio = 0.66; P = .0003) and KPS (hazard ratio = 0.47; P = .042) were significant. Type of surgery was not statistically significant, whereas age was very close to the significance level (P = .058; Table 3).
Because of the relatively high proportion (60%) of patients with poor performance status (KPS 80) included in our study, we separately analyzed this group. No significant difference was found between TMZ + RT and RT alone for TTP (P = .26). Concerning OS, it seems that there is a trend in favor of the TMZ + RT group, but the difference is not significant (P = .065).
Toxicity
All 110 eligible patients were evaluated for toxicity. The combination TMZ + RT (concomitant and sequential) was well tolerated. The main side effect was myelosuppression. During the concomitant RT + TMZ phase, grade 3 and 4 leukopenia occurred in two patients (3.5%), and grade 3 and 4 thrombocytopenia occurred in three patients (5.2%). One patient with grade 3 and 4 myelotoxicity experienced serious infection and died as a result of sepsis.
Two hundred forty cycles of adjuvant TMZ were administered, with a mean of 4.2 cycles per patient. The median time from end of RT to start of adjuvant TMZ was 32 days. Eleven patients in the combined-therapy group did not receive at least one cycle of adjuvant TMZ (disease progression, n = 4; toxicity, n = 1; toxic death, n = 1; lost, n = 4; and patient's denial, n = 1). Thirty-five patients (61.4%) completed six cycles of treatment as planned. We observed grade 3 thrombocytopenia in 12 cycles (5%) and grade 3 leukopenia in five cycles (2%). Nine patients had a dose reduction or delay because of myelotoxicity.
Nonhematologic toxicity was mild. In the combined-therapy group, three patients (5%) experienced treatment-related rash, two patients (3.5%) experienced constipation, and one patient (1.5%) experienced arthralgias. Late neurologic side effects were not assessed because of the short duration of follow-up.
DISCUSSION
RT remains the standard of care for high-grade glioma after resection and seems necessary because extensive tumor infiltration into normal brain structures makes resection of the entire primary tumor impossible in most cases. In the late 1970s, several clinical trials showed that postoperative RT significantly improved survival.22,23 Despite the advances in neuroimaging and in neurosurgical and RT techniques, the prognosis of patients with GBM remains poor, and the search of more effective chemotherapeutic agents is of great interest.
TMZ seems to be an effective agent in the treatment of malignant gliomas, offering a favorable safety profile compared with nitrosoureas. A number of studies have demonstrated the radiosensitizing properties of TMZ in vitro and in vivo.16,17
Our randomized study confirms the efficacy and safety of the combination of RT and TMZ (concomitant and sequential) in patients with newly diagnosed GBM and the superiority of this combined regimen over RT alone, which supports the earlier data of Stupp et al.9 An EORTC phase III trial included 573 patients with newly diagnosed GBM who were randomly assigned to either standard RT (60 Gy in 30 daily fractions of 2 Gy) or the same RT and TMZ, concomitant and sequential.19 The trial demonstrated that the combined treatment, compared with RT alone, significantly improved PFS (5 v 7.2 months, respectively; P < .0001) and OS (12 v 15 months, respectively; P < .0001; 2-year survival, 8% v 26%, respectively; P < .0001) in GBM patients. The results of our study also support the benefit of the combination of RT + TMZ in patients with GBM.
PFS and OS, the primary end points of the study, were significantly longer with RT + TMZ than with RT alone (median PFS, 10.8 v 5.2 months, respectively; median OS, 13.4 v 7.7 months, respectively). In the RT alone group, PFS and OS are relatively low compared with other series, but our study was limited to patients with GBM. Furthermore, considering age, KPS, and type of surgery, the majority of our patients had unfavorable baseline characteristics. However, the combined therapy demonstrated encouraging PFS and OS despite the fact that a significant proportion of these patients (60%) had a KPS 80 (Table 1). By contrast, only 36% of the GBM patients had a KPS 80 in the trial by Stupp et al,9 in which a median survival time of 15.8 months was reported. The proportion of patients with poor performance status was also much lower in our study compared with that of the EORTC study.19 This could explain the poorer results for our control group compared with that of Stupp et al.9
The benefit in PFS in the TMZ + RT group versus the RT alone group (TTP, 10.8 v 5.2 months, respectively) that was demonstrated in our study is superior to that of the EORTC study (PFS, 7.2 v 5 months). Two possible explanations are the different patient populations or the more accurate estimation of radiologic progression in the EORTC study.
The multivariate analysis of prognostic factors in all patients demonstrated that the administration of TMZ was the most significant prognostic factor in TTP and OS. Age and KPS proved to be significant, whereas our study failed to demonstrate a statistically significant difference for the type of surgery (biopsy and incomplete and gross total resection). Stupp et al9 demonstrated an increased median survival with debulking surgery compared with biopsy. The lack of a significant difference in our study could possibly be explained by the fact that immediate (within 48 to 72 hours) postoperative CT or MRI was not performed in all patients, and consequently, the estimation of surgical extent is possibly suboptimal. A separate analysis of patients with poor KPS (KPS of 70 to 80) demonstrated that the administration of TMZ did not significantly improve TTP in this group of patients, whereas the improvement in OS was close to the significance level (P = .065).
The schedule-dependent antitumor activity of TMZ has been shown in preclinical studies.24 An extended schedule enables a greater dose of TMZ to be administered per unit of time. Currently, the standard schedule of TMZ in malignant glioma patients is 200 mg/m2 for 5 days every 28 days.7,8,25 A number of different dosing schedules have been investigated to determine whether more frequent administration of TMZ can improve the treatment outcome without increasing toxicity.11,12,26,27 We administered a novel schedule of TMZ (150 mg/m2 of TMZ on days 1 through 5 and 15 to 19 every 28 days) in the adjuvant phase of treatment, aiming at dose intensification.
The main side effect in both the concomitant and the adjuvant phase of the RT + TMZ group was myelosuppression that was reversible and noncumulative, which allowed for nearly continuous therapy. The concomitant administration of RT + TMZ was well tolerated, with low percentages of grade 3 and 4 leukopenia (3.5%) and thrombocytopenia (5.2%). However, one patient in this group died as a result of sepsis. Overall compliance in the adjuvant phase was satisfactory; 46 (80%) of 57 patients had at least one cycle of therapy, and 35 (61.4%) 57 patients completed six cycles of adjuvant TMZ. The extended schedule that was administered in the adjuvant phase demonstrated favorable toxicity because grade 3 and 4 leukopenia was observed in only 2% of cycles and grade 3 and 4 thrombocytopenia was observed in 5% of cycles. Prior concomitant RT + TMZ treatment did not increase toxicity in the adjuvant phase. Nonhematologic adverse effects occurred with low frequency. Grade 3 and 4 nausea and vomiting were virtually eliminated with standard antiemetics.
In summary, the results of our study suggest that concomitant RT + TMZ followed by six cycles of adjuvant TMZ (extended schedule) is superior to RT alone in patients with newly diagnosed GBM. This regimen seems to ameliorate the TTP and OS of the patients. In addition, TMZ was safe and well tolerated, and patients were able to sustain intense, continuous therapy. The recently presented international EORTC phase III trial has demonstrated a similar benefit.19
Authors' Disclosures of Potential Conflicts of Interest
The authors indicated no potential conflicts of interest.
NOTES
Authors' disclosures of potential conflicts of interest are found at the end of this article.
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