Abstract
The primary objective of this augmental, prospective, uncontrolled phase II multicentre trial was to assess adverse events (AE) associated with malignant glioma resection using 5-aminolevulinic (5-ALA). During accrual, the standard of adjuvant therapy changed to concomitant radiochemotherapy with adjuvant temozolomide (RT/TMZ). Thus, this study also provided a platform for investigating the influence of RT/TMZ on survival in patients with fluorescence-guided resections. Malignant glioma patients, aged 18–75 years and with a Karnofsky performance score (KPS) ≥70%, were eligible. Data were collected on adverse events, KPS, survival and adjuvant therapies. In 243 patients evaluable for safety, 6-week AE incidence was 51.9% (nervous system disorders: 30.0%). Three patients experienced four possibly drug-related AEs. Grade III/IV incidence was 18.9% (nervous system disorders: 10.7%). About 48 h after surgery, AE incidence was 26.3% (9.9% grade III/IV), which was related to overall survival. A total of 219 patients (glioblastoma 206; anaplastic astrocytoma: 13) qualified for efficacy analysis. Median overall survival was 14.1 months (95% CI: 12.0–16.6), but 16.3 (13–19.2) months in 122 glioblastoma patients receiving RT/TMZ compared to 11.9 (9.6–14.1) months in the remaining 84 patients (P = 0.0194). Older patients (≥60 years) had less adjuvant therapies than younger patients. Median survival of older glioblastoma patients with RT/TMZ was also significantly prolonged (16.3; 12.0–17.2 months vs. 11.2; 7.4–14.1, hazard ratio = 0.55; 0.32–0.92). Risks of surgery were similar to past experiences with 5-ALA. Ancillary analyses demonstrated surgical glioblastoma patients, including the elderly, to have derived benefit from RT/TMZ. Thus, older patients should not generally be excluded from accepted therapies (fluorescence-guided resection plus RT/TMZ).
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Stummer W, Pichlmeier U, Meinel T et al (2006) Fluorescence-guided surgery with 5-aminolevulinic acid for resection of malignant glioma: a randomised controlled multicentre phase III trial. Lancet Oncol 7:392–401
Stupp R, Mason WP, van den Bent MJ et al (2005) Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352:987–996
Surawicz TS, McCarthy BJ, Kupelian V et al (1999) Descriptive epidemiology of primary brain and CNS tumors. Results from the central brain tumor registry of the United States, 1990–1994. Neurooncology 1:14–25
Westphal M, Hilt DC, Bortey E et al (2003) A phase 3 trial of local chemotherapy with biodegradable carmustine (BCNU) wafers (Gliadel wafers) in patients with primary malignant glioma. Neuro Oncol 5:79–88
Laws ER, Parney IF, Huang W et al (2003) Survival following surgery and prognostic factors for recently diagnosed malignant glioma: data from the glioma outcomes project. J Neurosurg 99:467–473
Kita D, Ciernik IF, Vaccarella S et al (2009) Age as predictive factor in glioblastomas: population-based study. Neuroepidemiology 33:17–22
Iwamoto FM, Reiner AS, Panageas KS et al (2008) Patterns of care in elderly glioblastoma patients. Ann Neurol 64:628–634
Stummer W, Kamp MA (2009) The importance of surgical resection in malignant glioma. Curr Opin Neurol 22:645–649
Chang SM, Parney IF, McDermott M et al (2003) Glioma outcomes investigators. Perioperative complications and neurological outcomes of first and second craniotomies among patients enrolled in the glioma outcome project. J Neurosurg 98:1175–1181
Hegi ME, Diserens AC, Gorlia T, Hamou MF, de Tribolet N, Weller M, Kros JM, Hainfellner JA, Mason W, Mariani L, Bromberg JE, Hau P, Mirimanoff RO, Cairncross JG, Janzer RC (2005) Stupp R. MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med 352:997–1003
Stupp R, Hegi ME, Mason WP et al (2009) Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in gtlioablastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol 10:459–466
Vuorinen V, Hinkka S, Farkkila M et al (2003) Debulking or biopsy of malignant glioma in elderly people—a randomised study. Acta Neurochir (Wien) 145:5–10
Kelly PJ, Hunt C (1994) The limited value of cytoreductive therapy in elderly patients with malignant glioms. Neurosurgery 34:62–66
Ampil F, Fowler M, Kookmin K (1992) Intracranial astrocytoma in elderly patients. J Neuro-Oncol 12:125–130
Brandes AA, Vastola F, Basso U et al (2003) A prospective study on glioblastoma in the elderly. Cancer 97:657–662
Iwamoto FM, Cooper AR, Reiner AS et al (2009) Glioblastoma in the elderly: the Memorial Sloan-Kettering Cancer Center Experience (1997–2007). Cancer 115:3758–3766
Hutchins LF, Unger JM, Crowley JJ et al (1999) Underrepresentation of patients 65 years of age or older in cancer-treatment trials. N Engl J Med 341:2061–2067
Gross CP, Herrin J, Wong N et al (2005) Enrolling older persons in cancer trials: the effect of socio-demographic, protocol, and recruitment center characteristics. J Clin Oncol 23:4755–4763
Yee KW, Pater JL, Pho L et al (2003) Enrollment of older patients in cancer treatment trials in Canada: why age is a barrier? J Clin Oncol 21:1618–1623
Brandes AA, Franceschi E, Tosoni A et al (2009) Temozolomide concomitant and adjuvant to radiotherapy in elderly patients with glioblastoma: correlation with MGMT promoter methylation status. Cancer 115:3512–3518
Minniti G, De Sanctis V, Muni R et al (2008) Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma in elderly patients. J Neurooncol 88:97–103
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C. Woiciechowsky (Virchow-Klinikum der HU Berlin), M. Brock, T. Kombos, B. Kühn, C. Wille (Universitätsklinikum Benjamin Franklin, Berlin), J.-C. Tonn, C. Goetz (Universitätsklinikum München), V. Seifert, K. Franz (J.W. Goethe Universitätsklinikum, Frankfurt a. M.), W. Hassler, A. Bani, D. Klassen (Klinikum Duisbug gGmbH, Duisburg), F. Weber, U. Langenbach (Klinikum Saarbrücken), M. Westphal, O.W. Heese (Universitätsklinikum Hamburg-Eppendorf), T. Grumme, T. Stretz (Zentralklinikum Augsburg), D. Stolke, S. Asgari, B. El Hamalawi (Universitätsklinikum Essen), R. Steinmeier, S.-A. May, P. Duscha (Klinikum Chemnitz gGmbH, Chemnitz), U. Kehler, M. Kämper (Asklepios Klinik Altona, Hamburg), J. Meixensberger (Universitätsklinikum, Leipzig), B. Meyer, F. Ringel (Klinikum rechts der Isar der TU, München), M. Tatagiba, R. Ritz (Universitätsklinikum, Tübingen), H.-P. Richter, K. Seitz (Bezirkskrankenhaus, Universität Ulm, Günzburg), A. Unterberg (Ruprecht-Karls-Universität, Heidelberg), J. Zentner, J. Vesper, A. Weyerbrock (Albert-Ludwigs-Universität, Freiburg).
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Stummer, W., Nestler, U., Stockhammer, F. et al. Favorable outcome in the elderly cohort treated by concomitant temozolomide radiochemotherapy in a multicentric phase II safety study of 5-ALA. J Neurooncol 103, 361–370 (2011). https://doi.org/10.1007/s11060-010-0400-9
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DOI: https://doi.org/10.1007/s11060-010-0400-9