Promising Survival and Concomitant Radiation Plus Temozolomide Followed by Adjuvant Temozolomide
Authors: Patrick Beauchesne, Roger Stupp, Sandrine Ostermann-Kraljevic, Pierre-Yves Dietrich, René O. Mirimanoff, David Reardon, Darell D. Bigner
Journal: Journal of Clinical Oncology (2002)

Article Tools SPECIAL DEPARTMENTS Article Tools OPTIONS & TOOLS Export Citation Track Citation Add To Favorites Rights & Permissions COMPANION ARTICLES No companion articles ARTICLE CITATION DOI: 10.1200/JCO.2002.20.14.3180 Journal of Clinical Oncology - published online before print November 1, 2016 PMID: 12118035 Promising Survival and Concomitant Radiation Plus Temozolomide Followed by Adjuvant Temozolomide Patrick BeauchesnexPatrick BeauchesneSearch for articles by this author Roger StuppxRoger StuppSearch for articles by this author , Sandrine Ostermann-KraljevicxSandrine Ostermann-KraljevicSearch for articles by this author , Pierre-Yves DietrichxPierre-Yves DietrichSearch for articles by this author , René O. MirimanoffxRené O. MirimanoffSearch for articles by this author David ReardonxDavid ReardonSearch for articles by this author , Darell D. BignerxDarell D. BignerSearch for articles by this author Show More L’Institut National de la Santé et de la Recherche Médicale U453, Lyon, FranceUniversity Hospitals Lausanne and Geneva, SwitzerlandDuke University Medical Center, Durham, NC https://doi.org/10.1200/JCO.2002.20.14.3180 First Page Full Text PDF Figures and Tables © 2002 by American Society of Clinical OncologyjcoJ Clin OncolJournal of Clinical OncologyJCO0732-183X1527-7755American Society of Clinical OncologyjcoJ Clin OncolJournal of Clinical OncologyJCO0732-183X1527-7755American Society of Clinical OncologyResponse15072002Response15072002Reply 1, to Nieder and Beauchesne:Dr Nieder compares the results of two novel strategies in the treatment of malignant glioma, both published in the March 1, 2002, issue of the Journal of Clinical Oncology.1,2 However, comparison of the results should be cautioned. Treatment with 131I-labeled antitenascin antibodies1 requires a surgical resection, whereas chemoradiotherapy with temozolomide2 is applicable to the majority of patients. The median survival of the 49 patients in our study who had some type of surgical debulking was 17 months; more importantly, our patients had an encouraging 2-year survival rate of 42%.2 It is unlikely that this improvement is due only to second-line treatment at recurrence. In our series, only one third of patients received second-line therapy, which was most frequently re-treatment with temozolomide with a continuous administration schedule. As stated by Nieder, for the patients who did not undergo surgical resection, the results with concomitant chemoradiotherapy were not appreciably improved over historical results. However, the heterogeneity of this disease and the small number of patients (n = 15) in this subgroup do not allow for any conclusive statement. Individual patients with an initially good performance status may still benefit from this treatment.Dr Beauchesne warns of a possible selection bias in our study.2 The age distribution of our patient population is comparable to that of a recent meta-analysis: 63% of our patients and 54% in the meta-analysis were 40 to 60 years old, and 23% of our patients were more than 60 years old, compared with 28% in the meta-analysis.3 The Karnofsky performance status in our study was indeed higher than what is commonly reported and may have contributed to the favorable results. However, we compared our results with the Radiation Therapy Oncology Group prognostic classes and could demonstrate a prolonged median and 2-year survival (data shown in the article).4 Beauchesne criticizes the rational for using temozolomide and concomitant radiation therapy. The goal of combining temozolomide with radiation was to use an intrinsically active agent (spatial cooperation) that has a different toxicity profile (toxicity independence) and has shown in vitro additive or synergistic activity (radiosensitization).5-7 Temozolomide is also thought to inhibit signaling of radiation-triggered migration and invasiveness8 and to decrease tumor repopulation.Because we are aware of the limitations of any phase II study, we proceeded to confirm (or infirm) our results in a large, prospective, randomized trial. This European Organization for Research and Treatment of Cancer/National Cancer Institute of Canada trial has now completed accrual of more than 550 patients and will provide an answer regarding the true benefit of this approach.Reply 2:We appreciate the comments of Dr Nieder on our article presenting a phase II study of patients with newly diagnosed malignant glioma treated with 131I-radiolabeled antitenascin monoclonal antibody 81C6.1 As summarized by Nieder, the outcome for most patients with malignant glioma remains dismal despite aggressive multimodality therapeutic strategies incorporating systemic chemotherapy and external-beam radiotherapy. Innovative approaches, including the application of therapeutic agents directed against tumor-associated targets, offer a promising means of more effectively treating these challenging tumors. Furthermore, the administration of such agents directly into the tumor bed maximizes delivery to regions at greatest risk for recurrence2 while minimizing systemic exposure and toxicity. The results of our current phase II trial confirm that the administration of 131I-radiolabeled 81C6 into the surgically created resection cavity clearly provides a significant survival advantage to patients with these tumors.As pointed out by Nieder, patients treated in our study represent a favorable prognostic subgroup of patients with glioblastoma multiforme (GBM) in that all had undergone a gross total resection and had a Karnofsky performance status of 70% or greater. According to a recursive partitioning analysis of prognostic factors among 1,578 patients with newly diagnosed malignant glioma treated on three consecutive Radiation Therapy Oncology Group trials, patients with newly diagnosed GBM over age 50, who also have a Karnofsky performance status greater than 70% and have undergone either a gross total or partial resection, have a median survival of 37 to 46 weeks.3 In comparison, patients in our study with similar prognostic factors had a median survival of 65 weeks. The survival advantage conferred by the administration of 131I-radiolabeled 81C6 was equally significant in patients younger than 50 with newly diagnosed GBM. In the analysis by Curran et al,3 such patients had a median survival of 44 to 72 weeks after the administration of external-beam radiotherapy with or without chemotherapy. In our study, such patients had a median survival of 87 weeks.A further point for emphasis not raised by Nieder is that the survival advantage conferred by 131I-radiolabeled 81C6 was not obtained at the expense of additional morbidity. Only one patient (3%) treated on our study required debulking surgery for radiation necrosis, which is a much lower rate than that associated with either stereotactic radiosurgery or 125I brachytherapy.4For all of these reasons, we wholeheartedly concur with Nieder that a phase III study incorporating 131I-radiolabeled antitenascin monoclonal antibody 81C6 is warranted.1. Reardon DA, Akabani G, Coleman RG, et al: Phase II trial of murine I-labeled antitenascin monoclonal antibody 81C6 administered into surgically created resection cavities of patients with newly diagnosed malignant gliomas. J Clin Oncol 20:: 1389,2002-1397, 131 Link, Google Scholar2. Stupp R, Dietrich PY, Ostermann Kraljevic S, 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:: 1375,2002-1382, Link, Google Scholar3. Stewart LA: Chemotherapy in adult high-grade glioma: A systematic review and meta-analysis of individual patient data from 12 randomised trials. Lancet 359:: 1011,2002-1018, Crossref, Medline, Google Scholar4. Scott CB, Scarantino C, Urtasun R, et al: Validation and predictive power of Radiation Therapy Oncology Group (RTOG) recursive partitioning analysis classes for malignant glioma patients: A report using RTOG 90-06. Int J Radiat Oncol Biol Phys 40:: 51,1998-55, Crossref, Medline, Google Scholar5. Steel GG, Peckham MJ: Exploitable mechanisms in combined radiotherapy-chemotherapy: The concept of additivity. Int J Radiat Oncol Biol Phys 5:: 85,1979-91, Crossref, Medline, Google Scholar6. Wedge SR, Porteous JK, Glaser MG, et al: In vitro evaluation of temozolomide combined with x-irradiation. Anticancer Drugs 8:: 92,1997-97, Crossref, Medline, Google Scholar7. 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:: 779,2000-784, Crossref, Medline, Google Scholar8. Wick W, Wick A, Schulz JB, et al: Prevention of irradiation-induced glioma cell invasion by temozolomide involves caspase 3 activity and cleavage of focal adhesion kinase. Cancer Res 62:: 1915,2002-1919, Medline, Google Scholar1. Reardon DA, Akabani G, Coleman RE, et al: Phase II trial of murine I-labeled antitenascin monoclonal antibody 81C6 administered into surgically created resection cavities of patients with newly diagnosed malignant gliomas. J Clin Oncol 20:: 1389,2002-1397, 131 Link, Google Scholar2. Liang BC, Thornton AF, Sandler HM, et al: Malignant astrocytomas: Focal tumor recurrence after focal external beam radiation therapy. J Neurosurg 75:: 559,1991-663, Crossref, Medline, Google Scholar3. Curran WJ, Scott CB, Horton J, et al: Recursive partitioning analysis of prognostic factors in three Radiation Therapy Oncology Group malignant glioma trials. J Natl Cancer Inst 85:: 704,1993-710, Crossref, Medline, Google Scholar4. Shrieve DC, Alexander E 3rd, Wen PY, et al: Comparison of stereotactic radiosurgery and brachytherapy in the treatment of recurrent glioblastoma multiforme. Neurosurgery 36:275-282, discussion 282-284, 1995 Google Scholar