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ANTICANCER RESEARCH 26: 4959-4964 (2006)

Concomitant Radiochemotherapy with in Non-selected Patients with Newly Diagnosed High-grade

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 , 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 , 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 (36). The drug effectively the results confirmed those from recently published optimistic penetrates the blood-brain barrier ( 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 (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 help to anaplastic (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 ACNU, BCNU, CCNU, The aim of our retrospective evaluation was to examine as well as , cis/, 5-FU, VP16, , whether temozolomide would also produce those satisfactory , , , , 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 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 (, pneumonia, which was non-treatment-related in this subject bloating, etc.) and were readily managed by the use of

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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. Progression-free* 9.88 19.73 In contrast, it was the aim of our trial to strictly evaluate Overall * 6.34 15 the efficacy of combined therapy in patients representing an Number of patiens alive unselected collective admitted to radiotherapy, also including ≥18 months 61% (n=11) 37.2% (n=32) patients with negative charateristics (low performance status, ≥24 months 27.7% (n=5) 16.28% (n=14) higher age and a high percentage of biopsy-only patients). *months. However, to obtain data considering the tumor histology we separately evaluated WHO grade III and WHO grade IV tumors. Considering these criteria, our data yield interesting supportive treatment with , such as 5-HT3 results although they were obtained retrospectively. antagonists or by taking temozolomide after breakfast rather Compared to the EORTC trial where 17% of patients had than on an empty stomach. These symptoms did not mandate no radical resection, we report about 27% with biopsy only. discontinuation of treatment. In our collective, 13% of the WHO grade IV glioma patients On the other hand, numerous patients displayed declining were older than 70 years, whereas in the EORTC trial for the platelet or white blood cell counts toward the end of radiochemotherapy patients the limit was 70 years. combination radiochemotherapy. As a result, routine Furthermore, in the EORTC trial the performance status of sequential continuation of oral temozolomide chemotherapy patients was higher (87% WHO performance status 0 and 1, after combined radiochemotherapy was not done in all i.e., Karnofsky 100 to 80%) than in our patients (69% patients, but only when progressive disease occurred. Karnofsky 100% to 80%). Our results corroborate the EORTC and NCIC trial results Discussion published by Stupp et al. despite the high rate of patients who had negative characteristics. Our large percentage of Treatment of malignant glioma consistently failed to produce glioblastoma patients who lived ≥24 months (16.3%, n=14) satisfactory responses in the past. Despite escalation of is likewise remarkable. radiation doses and limiting treatment to conformal radiation A subgroup of patients with a Karnofsky score >60% who of the tumor area with a safety margin and departure from the received their full course of radiochemotherapy with no practice of whole brain irradiation (45), the use of stereo- interruptions or discontinuations had a median survival period tactic radiotherapy (46), hyperfractionated accelerated of as long as 18.0 months. treatment regimens (47-49) and adjunctive use of various chemotherapy drugs, there was either no meaningful Conclusion prolongation of overall survival, or the survival benefit did not justify the additional distress and hospitalization required. Combined adjuvant radiochemotherapy with temozolomide The use of oral temozolomide chemotherapy in an after resection of malignant glioma, or after stereotactic ambulatory setting, with only moderate toxicity (apart from biopsy, improved median overall survival in our patient occasional reports of major thrombocytopenia/leucopenia) in population by approximately 3 months as compared with the combination with definitive or postoperative radiotherapy for literature in the presence of good patient compliance, low approximately 6 weeks, followed by sequential single-agent toxicity and close hematological monitoring, and usually with Temodal therapy (150-200 mg/m2 body surface area / day, day no need for hospitalization. A subgroup of patients with an at 1 to 5, repeated every 28 days depending on tolerability) upon least satisfactory state of health who underwent the full development of progressive disease, raised median overall treatment series achieved benefited by as much as 6 months. survival in our patient population to 15.0 months versus Future progressive treatment regimens involving historical control cohorts of patients with grade IV malignant combinations of chemo-, immuno- and target therapies (e.g. glioma. However, it should be pointed out that in most studies, against VEGF) will have to measure up against these results especially in the EORTC trial by Stupp et al. (44) evaluating in terms of survival, toxicity and practicability. the efficacy of combined temozolomide and radiotherapy References selected patients were included. Therefore, these data are mostly based on patients with good and/or moderate 1 Anders K, Grabenbauer GG, Schuchardt U, Fahlbusch R, performance status who have undergone radical resection or at Fietkau R, Sauer R and Krauseneck P: Accelerated radiotherapy least large tumor debulking. Often age >70 (the maximum age with concomitant ACNU/Ara-C for the treatment of malignant in the combined therapy "irradiation+temozolomide" group in glioma. J Neurooncol 48: 63-73, 2000.

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