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Concomitant Radiochemotherapy with Temozolomide in Non-Selected Patients with Newly Diagnosed High-Grade Gliomas

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Concomitant Radiochemotherapy with Temozolomide in Non-Selected Patients with Newly Diagnosed High-Grade Gliomas ANTICANCER RESEARCH 26: 4959-4964 (2006) Concomitant Radiochemotherapy with Temozolomide in Non-selected Patients with Newly Diagnosed High-grade Gliomas KLAUS H. EBERLEIN1, BRITTA NAGEL1, KEA FRANZ2, DETLEF IMHOFF1, VOLKER SEIFERT2, HEINZ D. BOETTCHER1 and STEPHAN MOSE3 Departments of 1Radiotherapy and Oncology and 2Neurosurgery, Johann Wolfgang Goethe-Universität Frankfurt/Main, Frankfurt; 3Radiotherapy Department, Villingen-Schwenningen Hospital, Villingen-Schenningen, Germany Abstract. Background: Malignant gliomas still present a medical Attempts to produce a meaningful improvement in the challenge, despite decades of continuous extensive research with prognosis through the use of stereotactic or hyperfractionated optimization of surgical techniques, radiotherapy and systemic accelerated radiotherapy techniques have likewise been no treatments. Patients and Methods: From 1999 to 2004, 104 more than moderately successful (31-35). patients with WHO grade III and IV gliomas underwent surgery Clinical trials of new chemotherapeutic agents, such as and received concomitant radiotherapy combined with temozolomide combined with adjuvant or definitive concomitant oral temozolomide. Patients with progressive disease radiotherapy, depending on the resectability of the malignant received sequential 5-day cycles of temozolomide at 28-day glioma, are intended to show whether a significant intervals. Results: The median overall survival was 19.7 and 15.0 improvement of overall survival is possible in the presence of months for patients with WHO grade III versus IV gliomas, a moderate side-effect profile and minimal hospitalization and respectively. Patient compliance was good and toxicity moderate. whether a subgroup might be identified as long-term survivors The overall survival was as long as 18.0 months in a subgroup of in a therapeutic indication that is otherwise associated with a subjects with glioblastoma, performance status >60% and poor prognosis. complete radiochemotherapy. Conclusion: Although our patients Temozolomide is an alkylating agent which selectively had more negative characteristics (age, performance, biopsy only), methylates the base guanine (36). The drug effectively the results confirmed those from recently published optimistic penetrates the blood-brain barrier (cerebrospinal fluid levels phase III trial data and indeed surpassed them in some cases. approximating 20%-40% of serum levels of the drug) (37) and has high bioavailability (almost 100%) (38) after oral dosing in Malignant gliomas are amongst the most aggressive tumors a fasting state. Absorption is approximately 10% lower if the and may be fatal within a few months if left untreated. drug is taken with food (38). The serum half-life is 2 h. Macroscopically complete resection, to the greatest possible Response rates of 35% were seen in phase II trials of extent, post-surgical radiotherapy and chemotherapy help to anaplastic astrocytoma (39). High enzyme activity prolong survival but do not result in a genuinely satisfactory (methylguanine-DNA-methyltransferase and poly-ADP-ribose outlook. Numerous single agents and combinations have been polymerase) may lower the temozolomide effect (40-42). tried out, including the nitrosoureas ACNU, BCNU, CCNU, The aim of our retrospective evaluation was to examine as well as paclitaxel, cis/carboplatin, 5-FU, VP16, irinotecan, whether temozolomide would also produce those satisfactory procarbazine, vincristine, topotecan, mitomycin C, VM26 and responses in non-selected patients. interferons. Chemotherapy regimens employed to date, either had little effect on overall survival or displayed an unfavorable Patients and Methods side-effect profile (1-30). A total of 104 patients with malignant gliomas were treated in the period from 1999 to 2004 (Table I); 86 had WHO grade IV and 18 had WHO grade III disease. Seventy-six patients underwent resection Correspondence to: Klaus H. Eberlein, Radiotherapy and Oncology (WHO IV n=63 and WHO III n=13), 28 merely underwent Department, Johann Wolfgang Goethe-Universität Frankfurt/ stereotactic biopsy (5 with WHO III and 23 with WHO grade IV Main, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany. disease). The age range was 23 to 76 years and the mean age was 54.8 years. Unlike many studies on the treatment of malignant glioma, this Key Words: Malignant glioma, high-grade glioma, glioblastoma trial also enrolled patients with a low Karnofsky performance index multiforme, temozolomide, radiochemotherapy, survival. score, ranging from 40% to 100%. 0250-7005/2006 $2.00+.40 4959 ANTICANCER RESEARCH 26: 4959-4964 (2006) Table I. Patient characteristics. Table II. Side-effects: myelosuppression. All Glioma Glioma Type CTC* Number of patients patients WHO III WHO IV (n=104) (n=18) (n=86) Leucopenia 0 84 I10 Extend of resection II 4 Resection 76 13 63 III 3 Biopsy only 28 5 23 IV 3 Age at diagnosis Thrombopenia <60 years 61 14 47 088 ≥60 years 43 4 39 I5 Karnofsky score II 1 <70% 14 1 13 III 4 ≥70% 90 17 73 IV 6 Anemia Gender male : female = 62 : 42 097 I3 II 2 III 1 IV 1 Patients had a radiotherapy mask fitted followed by intravenous injection of contrast medium and CT-guided 3D conformal *CTC, common toxicity criteria. radiotherapy planning for treatment of the tumor area with a 2-cm safety margin, as far as was acceptable in terms of volume with perifocal edema factored in. Treatment was applied using normal fractionation with 2.0 Gy 5 times per week up to a total focal dose of grade IV glioma had overall and progression-free survival 60.0 Gy. Where there was topographic proximity to at-risk organs, times of 15.0 and 6.3 months, respectively (Figures 1 and 2). the individual dose was reduced to 1.8 Gy, with a total focal dose Broken down by performance index, the total survival in of up to 59.4 Gy. Target volume definition and dosage were in subjects with grade III gliomas and a Karnofsky performance accordance with ICRU 50. score ≥70% was 21.3 months (n=17). The corresponding Percutaneous irradiation was accompanied by oral chemotherapy with temozolomide 75 mg/m2 body surface area every morning, on figure for subjects with a Karnofsky score <70% was 11.8 an empty stomach if possible, unless there were contraindications months, versus 16.4 months (n=73) and 6.2 months (n=13) in in terms of bone marrow, hepatic or renal function, or if the drug subjects with glioblastoma/gliosarcoma and the same was poorly-tolerated. A maximum surface of 2.0 m2 was defined, i.e. performance index. the maximum absolute daily dose was 150 mg. Standard The median overall and progression-free survival in Pneumocystis carinii prophylaxis was not necessary. patients with grade III gliomas ≤60 years of age was 20.6 and The radiochemotherapy was supported by weekly lab tests and 11.9 months. The corresponding figures in older subjects clinical monitoring. Chemotherapy was interrupted in subjects with major (hemato-) toxicity, or discontinued depending on blood (>age 60) were 14.7 and 6.5 months, respectively. The overall markers. and progression-free survival periods for glioblastoma were Post-therapeutic clinical, lab and slice imaging (CT/MRI) 16.3 and 8.5 months, respectively for patients below 60 years monitoring was performed at 3-month intervals as part of post- of age (n=47), and 12.9 and 4.0 months in subjects over 60 cancer care. Salvage treatment with oral temozolomide 150-200 years of age (n=38). mg/m2 body surface area/day from day 1 to 5 was introduced in Of particular interest are the results of patients with a subjects with imaging evidence of recurrent or progressive disease Karnofsky score >60% (n=58) with grade IV glioma who and continued at 4-week intervals, depending on tolerability (43, 44). Concomitant radiochemotherapy was completed with no received a complete series of treatment with no modifications in modifications in 87 out of 104 patients. Treatment had to be their chemoradiotherapy regimen. The median overall survival interrupted or discontinued in the remaining 17 patients, in most in this population was 18.0 months, although this subset also cases due to hematological changes. contained elderly subjects (>60 years of age) and patients who had only undergone biopsy, i.e., no debulking of the primary Results tumor. Fourteen glioblastoma patients survived for 24 months or more. One patient was still alive at 61 months (Table III). The follow-up period ranged from 2 to 61 months. The Although 42 patients were aged 60 or more, there were median period across both grades of malignancy was 16.2 only 3 cases of grade III and IV leukopenia, 6 cases of grade months. The median overall survival was 19.7 months in III and IV thrombocytopenia and 2 cases of grade III and IV subjects with WHO grade III malignant glioma, with a anemia (Table II). One patient died because of a major dosing progression-free survival time of 9.9 months. Patients with error during ambulatory oral second-line Temodal treatment 4960 Eberlein et al: Radiochemotherapy Results in Non-selected High-grade Glioma Patients Figure 1. Progression-free survival from time of diagnosis for patients with grade III and IV malignant glioma. Figure 2. Overall survival from time of diagnosis for patients with grade III and IV malignant glioma. in the presence of progressive disease. The overdose may have with no more than WHO grade II leucopenia. Minor been suicidally intended. Another patient died of intercurrent gastrointestinal symptoms were rarely observed (nausea, pneumonia, which was non-treatment-related in this subject bloating, etc.) and were readily managed by the use of 4961 ANTICANCER RESEARCH 26: 4959-4964 (2006) Table III. Survival from time of diagnosis. Stupp’s study was 70 years) is one of the exclusion criterias. Furthermore, although histology is one of the most important WHO III Glioma WHO IV Glioma prognostic factors (50, 51), often the subtypes histology are Median survival mixed, which might result in misleading survival statistics.
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