PRIMARY BRAIN TUMORS comprise only approximately

Promising Survival for Patients With Newly Diagnosed Glioblastoma Multiforme Treated With Concomitant Radiation Plus Temozolomide Followed by Adjuvant...
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Promising Survival for Patients With Newly Diagnosed Glioblastoma Multiforme Treated With Concomitant Radiation Plus Temozolomide Followed by Adjuvant Temozolomide By Roger Stupp, Pierre-Yves Dietrich, Sandrine Ostermann Kraljevic, Alessia Pica, Ivan Maillard, Phillipe Maeder, Reto Meuli, Robert Janzer, Gianpaolo Pizzolato, Raymond Miralbell, Franc¸ois Porchet, Luca Regli, Nicolas de Tribolet, Rene´ O. Mirimanoff, and Serge Leyvraz Purpose: Temozolomide is a novel oral alkylating agent with demonstrated efficacy as second-line therapy for patients with recurrent anaplastic astrocytoma and glioblastoma multiforme (GBM). This phase II study was performed to determine the safety, tolerability, and efficacy of concomitant radiation plus temozolomide therapy followed by adjuvant temozolomide therapy in patients with newly diagnosed GBM. Patients and Methods: Sixty-four patients were enrolled onto this open-label, phase II trial. Temozolomide (75 mg/m2/d ⴛ 7 d/wk for 6 weeks) was administered orally concomitant with fractionated radiotherapy (60 Gy total dose: 2 Gy ⴛ 5 d/wk for 6 weeks) followed by temozolomide monotherapy (200 mg/m2/d ⴛ 5 days, every 28 days for six cycles). The primary end points were safety and tolerability, and the secondary end point was overall survival. Results: Concomitant radiation plus temozolomide therapy was safe and well tolerated. Nonhematologic toxicities were rare and mild to moderate in severity.

During the concomitant treatment phase, grade 3 or 4 neutropenia, thrombocytopenia, or both were observed in 6% of patients, including two severe infections with Pneumocystis carinii. During adjuvant temozolomide, 2% and 6% of cycles were associated with grade 3 and 4 neutropenia or thrombocytopenia, respectively. Median survival was 16 months, and the 1and 2-year survival rates were 58% and 31%, respectively. Patients younger than 50 years old and patients who underwent debulking surgery had the best survival outcome. Conclusion: Continuous daily temozolomide and concomitant radiation is safe. This regimen of concomitant chemoradiotherapy followed by adjuvant chemotherapy may prolong the survival of patients with glioblastoma. Further investigation is warranted, and a randomized trial is ongoing. J Clin Oncol 20:1375-1382. © 2002 by American Society of Clinical Oncology.

RIMARY BRAIN TUMORS comprise only approximately 2% of all malignant diseases. However, with an incidence of 5 per 100,000 persons, more than 17,000 cases are diagnosed every year in the United States, with approximately 13,000 associated deaths.1 In adults, the most common histologies are grade 3 anaplastic astrocytoma (AA) and grade 4 glioblastoma multiforme (GBM).2,3 The standard management of malignant gliomas involves cytoreduction through surgical resection, when feasible, followed by radiotherapy (RT) with or without adjuvant chemotherapy.4,5 Despite this multidisciplinary approach, the prognosis for patients with GBM remains poor. The median survival rates for GBM are typically in the range of 9 to 12 months, with 2-year survival rates in the range of only6,7 8% to 12%. Nitrosoureas are the main chemotherapeutic agents used in the treatment of malignant brain tumors; however, they have shown only modest antitumor activity.7,8 Although frequently prescribed in the United States, the benefit of adjuvant chemotherapy with single-agent carmustine (BCNU) or lomustine or the combination regimen procarbazine, lomustine, and vincristine has never been conclusively demonstrated. A meta-analysis on published data

suggested a possible benefit of adjuvant chemotherapy, mainly for AA.9 However, in a large randomized trial conducted by the British Medical Research Council, adjuvant combination regimen procarbazine, lomustine, and vincristine chemotherapy was of no benefit to AA or GBM patients, with a median survival of only 10 months.10 The absence of chemotherapeutic efficacy in this and other clinical trials may be due in part to the inability of these agents to sufficiently penetrate the blood-brain barrier.

P

From the Departments of Medical Oncology, Radiation Therapy, Neurosurgery, Pathology, and Radiology, Centre Hospitalier Universitaire Vaudois, Lausanne, and Hoˆpital Universitaire Genevois, Geneva, Switzerland. P.Y.D. and S.O.K. contributed equally to this study. Submitted July 26, 2001; accepted October 12, 2001. Supported in part by an unrestricted educational grant by ScheringPlough Research Institute, Kenilworth, NJ. Address reprint requests to Roger Stupp, MD, Centre Hospitalier Universitaire Vaudois, Multidisciplinary Center for Oncology, Rue du Bugnon 46, CH-1011 Lausanne, Switzerland; email: [email protected] .hospvd.ch. © 2002 by American Society of Clinical Oncology. 0732-183X/02/2005-1375/$20.00

Journal of Clinical Oncology, Vol 20, No 5 (March 1), 2002: pp 1375-1382

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Temozolomide (Temodal, Temodar; Schering-Plough, Kenilworth, NJ) is a novel alkylating agent that has demonstrated activity in recurrent gliomas.11-16 After oral administration, temozolomide is rapidly absorbed with almost 100% bioavailability.17 It readily crosses the blood-brain barrier and achieves effective concentrations in the CNS with a reported plasma-CSF ratio of approximately 30% to 40%.18,19 In a phase II trial in patients with recurrent GBM, the objective response rate was only 8%; however, an additional 45% of patients had disease stabilization, suggesting that 53% of patients experienced a clinical benefit with temozolomide treatment.20 The 6-month progressionfree survival rate for temozolomide-treated patients was 18%, and the 6-month overall survival rate was 46%. In a large randomized phase II trial in patients with recurrent GBM, the efficacy of temozolomide was compared with that of procarbazine.16 In this study, the 6-month progressionfree survival rate was 21% for patients treated with temozolomide, compared with only 8% for patients treated with procarbazine (P ⬍ .008). In all these trials, temozolomide was administered at a dose of 150 to 200 mg/m2/d ⫻ 5 days, every 28 days. This treatment is usually well tolerated, with grade 3 and 4 thrombocytopenia and neutropenia occurring in fewer than 10% of patients. Resistance of temozolomide is mediated in part through O6-alkylguanine DNA alkyltransferase (AGT). This repair enzyme, also known as methylguanine-DNA methyltransferase, was found to be a major determinant of temozolomide cytotoxicity in vitro; continuous exposure to temozolomide leads to depletion of this enzyme.21 Therefore, a continuous administration schedule for temozolomide has been investigated, and a dose of 75 mg/m2 daily for 6 to 7 weeks seems safe.22 The rationale for combining temozolomide with RT is based on preclinical data suggesting additive or perhaps synergistic activity. Temozolomide with concurrent irradiation demonstrated additive cytotoxicity against the U373MG glioblastoma cell line with low AGT expression, whereas this effect was absent in a colorectal cell line that expresses high levels of AGT.23 Van Rijn et al24 investigated prolonged temozolomide exposure followed by single-dose and fractionated irradiation in two glioma cell lines. No enhancement of cytotoxicity could be demonstrated in the U251 cell line, but prolonged exposure to temozolomide and fractionated irradiation enhanced cytotoxicity in the D384 cell line. It has been shown that temozolomide induces a G2-M arrest in glioma cells, thus synchronizing the cell cycle in a radiosensitive phase.25 On the basis of this preclinical evidence and the clinical experience with temozolomide in recurrent gliomas, we initiated this study to investigate the safety, tolerability, and

survival of concomitant RT plus temozolomide therapy followed by adjuvant temozolomide therapy in patients with newly diagnosed GBM. PATIENTS AND METHODS

Patients This two-center, open-label, phase II pilot study was conducted in patients (ⱖ 18 years) with newly diagnosed and histologically proven GBM. All histology was reviewed by a second neuropathologist (R.J. and G.P.) and graded according to the World Health Organization classification. Patients were required to have an Eastern Cooperative Oncology Group performance status ⱕ 2 and adequate hematologic, renal, and hepatic functions, defined as absolute neutrophil count ⱖ 1.5 ⫻ 109 cells per liter; platelet count ⱖ 100 ⫻ 109 cells per liter; hemoglobin more than 90 g/L; serum creatinine and total serum bilirubin ⱕ 1.5 times the upper limit of normal; aspartate aminotransferase or alanine aminotransferase less than 2.5 times the upper limit of normal; and alkaline phosphatase less than 2.5 times the upper limit of normal. Study enrollment had to be within 28 days from diagnostic biopsy or resection. Eligible patients were also required to have no other severe underlying disease (including human immunodeficiency virus and chronic hepatitis B or C infection). All patients gave written informed consent. Exclusion criteria included any medical condition that could interfere with the oral administration of temozolomide or any previous or concurrent malignancies at other sites, with the exception of surgically cured carcinoma-in-situ of the cervix and nonmelanoma skin cancer. The protocol was reviewed and approved by the local ethics committees.

Treatment Patients received temozolomide (75 mg/m2/d ⫻ 7 d/wk) for 6 to 7 weeks in a fasting state, 1 hour before RT, and in the morning on days without RT. The first 16 patients treated received temozolomide only on days of RT. Concomitant focal RT was delivered once daily at 2 Gy per fraction, 5 d/wk, for a total of 60 Gy, and was prescribed according to the guidelines of the International Commission on Radiological Units. Adequate immobilization masks were required to ensure reproducibility. Treatment volumes were determined on the basis of preoperative contrast-enhanced computed tomography (CT) or gadoliniumenhanced magnetic resonance imaging (MRI) of the brain. Treatment volume generally included the contrast-enhancing lesion plus a 2- to 3-cm margin, depending on the location. Planning for RT always included dedicated CT, three-dimensional reconstruction with treatment planning computation, and beam eye’s view for the choice of treatment field number, size, and shape. RT was delivered with ⱖ 6-MV photons from linear accelerators. Four weeks after RT, patients received adjuvant temozolomide chemotherapy (200 mg/m2 daily ⫻ 5, every 28 days for six cycles). Prophylactic antiemetics were used only as required during concomitant RT plus temozolomide therapy. Prophylactic antiemetics, including 5-hydroxytryptamine-3 antagonists (pediatric dose: ondansetron 4 mg or granisetron 1 mg), were routinely prescribed once a day before adjuvant temozolomide. After concomitant RT plus temozolomide therapy was administered to 15 patients, prophylaxis against Pneumocystis carinii pneumonia was introduced and consisted of pentamidine inhalations during the first and fifth week of RT. Anticonvulsants and corticosteroids were administered as needed.

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CONCOMITANT TEMOZOLOMIDE AND RT FOR GLIOBLASTOMA Table 1.

Patient Evaluation Baseline evaluations were performed within 14 days (28 days for imaging) from study entry and included a complete medical history, physical examination, determination of performance status, hematology and clinical chemistry assessments, and gadolinium-enhanced MRI or contrast-enhanced CT of the brain. During RT, complete blood counts were checked weekly, and blood chemistry was checked monthly. During adjuvant temozolomide treatment, patients underwent at least one monthly physical examination. Complete blood counts and blood chemistry were drawn before each cycle; the complete blood count was also checked on day 21 (⫾ 48 hours). Gadolinium-enhanced MRI was performed before the first adjuvant treatment cycle and then every 2 months during the first year and every 2 to 3 months during the second year after study entry.

Statistical Methods Toxicity was graded according to the common toxicity criteria (version 2.0). Safety and toxicity are reported for all treated patients. Overall survival was calculated from the time of study entry until death or last follow-up according to the Kaplan-Meier method with SPSS statistical software (release 7.5, 1996; SPSS Inc, Chicago, IL). The 95% confidence intervals were calculated as follows: survival ⫾ 1.96 ⫻ SE. Survival analysis is reported for all patients enrolled onto the study (intent-to-treat [ITT] population) and separately for eligible patients with confirmed glioblastoma.

Patient Demographics and Baseline Disease Characteristics Intent-to-Treat Parameter

No.

Total no. of patients, n Age, years Median Range Sex Male Female ECOG performance status 0 or 1 2 Karnofsky performance status 90%-100% ⱕ 80% Prior surgery Complete resection Incomplete resection Biopsy Time from diagnosis to treatment, days Median Range

64

%

52 24-70 39 25

61 39

55 9

86 14

41 23

64 36

27 22 15

42 34 23 25 14-45

Abbreviation: ECOG, Eastern Cooperative Oncology Group.

RESULTS

Patient Characteristics Sixty-four patients were enrolled (ITT population). Six patients were ineligible, not treated, or incorrectly treated: reasons included treatment refusal (n ⫽ 1), chronic hepatitis B (n ⫽ 1), ineligible histology (n ⫽ 3; one AA and two anaplastic oligoastrocytoma), and toxic death caused by chemotherapy overdose (n ⫽ 1). Of the 64 patients, 62 were treated with temozolomide and were analyzed for safety in the concomitant RT plus temozolomide phase, and 49 patients who received at least one cycle of adjuvant temozolomide were assessable for safety in the adjuvant temozolomide phase. Patient demographics and baseline disease characteristics are listed in Table 1. The median age was 52 years, and the majority of patients had an Eastern Cooperative Oncology Group performance status ⱕ 1. Thirty-six percent of patients had a Karnofsky score of ⱕ 80. Two thirds (66%) of the patients were ⱖ 50 years old, and 20% of the patients were between 40 and 50 years old. The majority (77%) of patients had undergone prior debulking surgery, with 42% being considered macroscopically complete resections; however, immediate postoperative imaging was not performed in all patients. Fifteen patients (23%) had a stereotactic biopsy only. The median time from diagnosis to the start of therapy with RT plus temozolomide was 25 days (range, 14 to 45 days).

Sixty-two patients were treated with concomitant RT plus temozolomide (Fig 1). Two of the 64 patients enrolled onto the study received RT alone; one patient refused treatment with temozolomide, and one patient was ineligible because of chronic hepatitis. Temozolomide was discontinued early during RT in four patients because of toxicity (two patients with an infection and two patients with grade 3 thrombocytopenia after 4 to 5 weeks). All but four patients received the planned 60 Gy of RT; disease progressed in three patients and infection progressed in one patient. The majority of patients completed their RT within the prescribed 6 weeks (42 ⫾ 3 days). In 19 patients, the duration of RT was more than 6.5 weeks (maximum, 52 days), and in two of these patients RT was delayed because of grade 3 or 4 hematologic toxicities

Fig 1.

Treatment scheme. TMZ, temozolomide; RT, radiotherapy.

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STUPP ET AL Table 2.

Hematologic Toxicities and Infection

RT With Continuous TMZ (62 patients) Grade 3 Adverse Event

No. of Patients

Anemia Neutropenia Thrombocytopenia Lymphocytopenia Infection*

2 2 3 14 1

Adjuvant TMZ Cycle 1 (49 patients)

Grade 4 %

No. of Patients

3 3 5 23 2

0 2 1 35 2

Grade 3 %

No. of Patients

0 3 2 57 3

1 1 5 14 0

Adjuvant TMZ All Cycles (216 cycles)

Grade 4 %

No. of Patients

2 2 10 29 0

0 2 2 20 0

Grade 3 %

No. of Cycles

0 4 4 41 0

1 3 12 78 0

Grade 4 %

No. of Cycles

%

⬍1 1 6 36 0

0 2 2 60 0

0 1 1 28 0

Abbreviation: TMZ, temozolomide. *Pneumocystis carinii pneumonia (n ⫽ 2); craniotomy scar infection/osteomyelitis (n ⫽ 1).

(leukocytopenia and thrombocytopenia). All other RT delays were due to holidays or accelerator downtime. Adjuvant temozolomide was administered to 49 patients for a total of 216 cycles. The median time from the completion of RT and the beginning of adjuvant temozolomide treatment was 29 days (range, 20 to 63 days). Adjuvant therapy was delayed in three patients because of grade 3 or 4 leukopenia or thrombocytopenia. The median number of adjuvant cycles per patient was 5.5. Adjuvant chemotherapy was discontinued early because of progressive disease in 24 patients (39%). Twenty-four patients (39%) received all concomitant and adjuvant temozolomide as planned in the protocol. Safety and Tolerability Hematologic toxicity and infection. In both intermittent and continuous administration of temozolomide monotherapy, the dose-limiting toxicity is myelosuppression. However, the hematologic toxicities of concomitant RT plus temozolomide therapy have not been previously reported. Herein, we report the hematologic toxicities associated with concomitant RT and temozolomide therapy (continuous temozolomide schedule) separately from hematologic toxicities associated with adjuvant temozolomide treatment (the approved intermittent daily ⫻ 5 temozolomide schedule). Concomitant phase of treatment. During the concomitant RT plus temozolomide phase, grade 3 or 4 neutropenia occurred in four patients (6%) (Table 2), and grade 3 or 4 thrombocytopenia occurred in four patients (6%), with two patients experiencing platelet counts of less than 25,000 cells per cubic millimeter. Only one patient experienced platelet counts less than 10,000 cells per cubic millimeter. Grade 3 or 4 lymphocytopenia occurred in 49 patients (79%). Three patients had infections that required hospitalization and treatment interruption. Analysis indicated that two of the three patients developed P carinii pneumonia. Both of

these patients were receiving corticosteroids and experienced grade 3 or 4 neutropenia and lymphocytopenia at the time of infection. After these two episodes of opportunistic infections occurred, we introduced prophylactic pentamidine inhalations during the concomitant treatment phase. No additional opportunistic infections were observed with prophylaxis in place. One patient required surgical revision of a scar infection and osteomyelitis 3 weeks after RT. However, this patient’s blood counts were within normal limits during treatment. Adjuvant temozolomide. During the adjuvant temozolomide phase, grade 3 or 4 neutropenia or thrombocytopenia occurred in 2% and 6% of cycles, respectively. Twelve patients required a dose reduction or delay because of grade 3 or 4 thrombocytopenia. One patient received daily temozolomide 200 mg/m2 for 30 days instead of for 5 days and died subsequent to profound thrombocytopenia, neutropenia, and septicemia. Nonhematologic Toxicities Nonhematologic toxicities were mild to moderate (Table 3). During the concomitant RT plus temozolomide phase, prophylactic antiemetics were required in 39% of patients; however, only seven patients (11%) received antiemetics for longer then the first week of the concomitant treatment. During the adjuvant temozolomide phase, 30% of patients required antiemetic therapy. One patient experienced a treatment-induced rash that resulted in early discontinuation of temozolomide after 7 days of concomitant chemoradiotherapy. Moderate to severe fatigue was reported in eight patients during the concomitant RT plus temozolomide phase (grade 3; two patients) and in eight patients during the adjuvant temozolomide phase (grade 3; one patient). The short duration of follow-up precludes definitive assessment of late radiation toxicity; only 14 patients were alive with a follow-up longer than 18 months. However, signs of leukoencephalopathy, without evident clinical impairment, were apparent on MRI in all of these patients. One

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CONCOMITANT TEMOZOLOMIDE AND RT FOR GLIOBLASTOMA Table 3.

Nonhematologic Toxicities

RT With Continuous TMZ (62 patients) Grade 2

Adjuvant TMZ (49 patients)

Grade 3

Grade 4

Grade 2

Grade 3

Grade 4

Adverse Event

No.

%

No.

%

No.

%

No.

%

No.

%

No.

%

Nausea/vomiting Rash Fatigue

5 0 6

8 0 10

2 1 2

3 2 3

0 0 0

0 0 0

5 0 7

10 0 14

3 0 1

6 0 2

0 0 0

0 0 0

Abbreviations: RT, radiation therapy; TMZ, temozolomide.

patient developed intracranial hypertension, refractory seizures, and loss of vision 33 months after beginning RT. The loss of vision may in part be due to prior RT. Subsequent work-up indicated a spinal dissemination of the disease with positive CSF cytology and no evidence of local recurrence. A second patient developed neurologic deterioration with progressive short-term memory loss and hemiplegia 17 months after beginning RT. At 26 months, this patient was still alive without evidence of tumor progression. The remaining patients with follow-up longer than 18 months are doing well without any clinical signs of neurologic impairment. Survival ITT and eligible patient populations. At the time of this analysis, 38 patients had died. The median duration of follow-up was 23 months, with a minimum follow-up for surviving patients of 10 months. On the basis of KaplanMeier estimates, the median survival for the ITT population was 16 months (95% confidence interval, 11 to 21 months) (Fig 2). Fifty-eight percent and 31% of ITT patients were alive at 1 and 2 years, respectively (Table 4). The median survival in the eligible patient population was also 16 months. There was no difference in 1- and 2-year survival between the ITT and the eligible patient populations. Prognostic factors. We separately analyzed the median survival and survival rates of both the ITT and eligible patient populations in relation to prognostic indicators. Because there is no significant difference in outcome, we report only the results for the ITT population (Table 4). In patients younger than 50 years old, the median survival was not reached at 18 months in the ITT population, with 56% of these patients still alive at 18 months. In patients ⱖ 50 years old, the median survival was only 11 months. Patients who underwent debulking surgery had a median survival of 17 months. However, for patients who did not undergo debulking surgery, survival time was 5 months. We also analyzed our patients according to the recursive partitioning analysis (RPA) prognostic classes,26 which are based on a large Radiation Therapy Oncology Group (RTOG) database of patients with malignant gliomas27 (Table 5). In particular, younger patients and patients whose

tumor could be resected seem to have an improved outcome. Patients classified as RPA III (⬍ 50 years old) had longer 1-year and 18-month survival rates than patients classified as RPA V or VI (ⱖ 50 years old). DISCUSSION

GBM is the most common primary brain tumor in adults. Despite surgery and RT with or without adjuvant chemotherapy, malignant glioma remains an almost uniformly fatal disease characterized by a rapid and devastating clinical course. The value of RT was established in randomized trials in the late 1970s and is now considered the standard of care4,5,28; however, concomitant or adjuvant chemotherapy has never been conclusively demonstrated to have a clear clinical benefit. The concept of RT concomitantly with chemotherapy has been explored by using several agents with radiosensitizing properties, recently with topotecan and tirapazamine. A RTOG phase I trial, in which 47 GBM patients were treated

Fig 2. Kaplan-Meier estimates of median survival of all patients (intent-to-treat).

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STUPP ET AL Table 4.

Variable

Median Survival and Survival Rates

Patients (n)

Survival, Median (months)

1-Year Survival (%)

18-Month Survival (%)

2-Year Survival (%)

64

16.0 10.9-21.2

58 46-70

36 24-50

31 19-44

22 42

18.8 11.1

73 50

56 25

50 20

27 22 15

18.8 16.0 5.3

73 61 18

52 35 9

47 35 0

n 95% Confidence interval Age ⬍ 50 years ⱖ 50 years Prior surgery Complete resection Partial resection Biopsy only

with concomitant RT plus topotecan, reported a median survival of 9.7 months.29 Similarly, 124 GBM patients treated with concomitant RT plus tirapazamine, a hypoxiaselective cytotoxin, had a median survival of approximately 10 months.30 Furthermore, Kleinberg et al31 reported a median survival of 12.8 months for patients treated with concomitant RT plus cisplatin and BCNU. Because most recurrences in malignant gliomas occur within 2 cm of the previous resection, local chemotherapy with biodegradable polymers has been investigated in patients with recurrent gliomas.32 In a randomized phase III trial with newly diagnosed glioma patients, BCNU polymers were implanted during the initial resection, and then patients were subsequently treated with standard RT. Preliminary analysis indicated that patients implanted with BCNU polymers had a prolonged median survival (13.9 months; P ⫽ .08) compared with patients implanted with placebo polymers (11.6 months).33 In this study, we examined the safety and efficacy of concomitant RT plus temozolomide therapy followed by adjuvant temozolomide in patients with newly diagnosed GBM. Our study confirms the overall excellent tolerability of temozolomide both with a continuous and intermittent

Table 5.

administration regimen. Myelosuppression, in particular thrombocytopenia, was the predominant toxicity. Hematologic toxicity during the adjuvant temozolomide treatment phase was in agreement with previous reports.15,16,20 The prior concomitant radiochemotherapy did not appreciably increase the incidence of myelosuppression compared with previous reports administering temozolomide to chemotherapy-naive patients.16 Lymphocytopenia is often observed with temozolomide treatment but may, in part, be due to the frequent administration of corticosteroids. In this study, lymphocytopenia was more common with continuous exposure to temozolomide, as was previously described in the phase I trial of this regimen.22 Although lymphocytopenia occurs frequently, it is not typically associated with clinical sequelae. However, two of the first 15 patients we treated with concomitant RT plus temozolomide therapy developed P carinii pneumonia. The frequency of opportunistic infections in a similar patient population treated with RT alone is unknown. Nonetheless, after the subsequent introduction of prophylactic administration of aerosolized pentamidine, no further episodes of P carinii pneumonia or other opportunistic infections were observed.

Comparison of Survival According to Recursive Partitioning Analysis Criteria Present Study

RPA Class

III 95% CI IV 95% CI V 95% CI

Patients (n)†

Survival, Median (months)

18

⬎ 24

28

13.8 9.9-17.7 9.2 6.2-12.3

14

RTOG 90-06* 2-Year Survival (%)

51 26-76 32 12-51 0

Patients (n)

Survival (median)

2-Year Survival (%)

105

17.5 15.6-20.2 11.5 10.8-12.7 7.4 6.2-9.1

30 21-39 17 12-22 8 3-12

240 150

Abbreviation: CI, confidence interval. *Data from Scott et al.27 †One patient RPA class II and three patients RPA class VI were not reported.

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CONCOMITANT TEMOZOLOMIDE AND RT FOR GLIOBLASTOMA

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Late toxicity resulting from long-term exposure to alkylating agents or combined modality treatment remains a concern. Concomitant RT plus temozolomide therapy did not increase late toxicities associated with RT during the 18 months of follow-up; however, follow-up remains too short to make any conclusions with regard to late toxicities resulting from treatment with temozolomide. Survival results in this pilot study are encouraging. Indeed, the median survival of 15.8 months compares favorably with most other reported regimens. Furthermore, most reports in the literature include patients with more favorable histologic grades of glioma, whereas our study was limited to patients with histologically confirmed GBM. Performance status is considered an important prognostic factor and might be somewhat higher in this study compared with that in other reported series. Nevertheless, this treatment protocol was offered to all patients treated with radiation therapy at our two institutions, and most patients accepted participation in the trial. The performance status in our trial may also be somewhat overestimated, because the scoring was based on the initial assessment of residents rotating through the oncology department. Age and extent of resection are the most important prognostic factors for GBM. As expected, younger patients and patients with debulked disease had substantially better survival rates than patients who had a biopsy only. However, we could not demonstrate a statistically significant difference between patients who had a gross complete or subtotal resection. Nonrandomized comparisons between trials have to be approached with caution. Differences in study protocols and changes in response evaluations, pathologic classifications, imaging techniques, and standard and supportive care make comparing trials difficult. The prognostic classes model

from RPA of the RTOG database of malignant glioma patients may overcome some of the shortcomings associated with comparing trials.26,27 RPA suggests that patients in this study compared favorably with patients in the RTOG database who were treated on a randomized trial in the early 1990s (Table 5). In summary, the results of this trial demonstrate that concomitant RT plus continuous daily temozolomide therapy followed by additional cycles of the standard regimen of adjuvant temozolomide therapy is well tolerated and may prolong survival in patients with malignant glioma. However, it remains unclear whether the improved survival resulted from the continuous administration schedule of temozolomide (which depletes AGT), an additive cytotoxic effect of combined RT and temozolomide, or simply because of adjuvant therapy with an active agent. The survival benefits may also be attributed to the ability of temozolomide to penetrate the CNS to a greater extent than many other chemotherapy agents. Temozolomide and concurrent RT, followed by adjuvant temozolomide chemotherapy, is a promising regimen for patients with malignant glioma. This regimen is currently being compared with standard RT alone in an international randomized trial coordinated by the European Organization for Research and Treatment of Cancer and the National Cancer Institute of Canada. ACKNOWLEDGMENT We thank Sally Willcox, RN, for dedicated care; Drs P. Coucke, A. Telenti, and P.A. Despland for advice; Drs C. Collao, N. Doser, R. Greiner, A. Hottinger, B. Rilliet, J.G. Villemure, D. Wellmann, and A. Zouhair for treating patients; M.C. Verbist and A. Magraouhi for administrative support; and Essex/Schering-Plough (H. Egger, PhD; S. Zaknoen, MD) for providing temozolomide.

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Principles and Practice of Oncology. Philadelphia, PA, LippincottRaven, 1997, pp 2022-2082 7. Galanis E, Buckner J: Chemotherapy for high-grade gliomas. Br J Cancer 82:1371-1380, 2000 8. DeAngelis LM: Brain tumors. N Engl J Med 344:114-123, 2001 9. Fine HA, Dear KB, Loeffler JS, et al: Meta-analysis of radiation therapy with and without adjuvant chemotherapy for malignant gliomas in adults. Cancer 71:2585-2597, 1993 10. Randomized trial of procarbazine, lomustine, and vincristine in the adjuvant treatment of high-grade astrocytoma: A Medical Research Council trial. J Clin Oncol 19:509-518, 2001 11. Newlands ES, Stevens MF, Wedge SR, et al: Temozolomide: A review of its discovery, chemical properties, pre-clinical development and clinical trials. Cancer Treat Rev 23:35-61, 1997 12. Stupp R, Gander M, Leyvraz S, et al: Current and future developments in the use of temozolomide for the treatment of brain tumors. Lancet Oncol 2:552-560, 2001

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