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© 2002 American Society for Clinical Oncology
Promising Survival and Concomitant Radiation Plus Temozolomide Followed by Adjuvant TemozolomideL’Institut National de la Santé et de la Recherche Médicale U453, Lyon, France To the Editor:Stupp et al1 have reported a phase II study of concomitant radiation therapy plus temozolomide therapy followed by adjuvant temozolomide therapy in the treatment of patients with newly diagnosed glioblastoma multiforme. At the time of study design, cranial radiation therapy followed by adjuvant chemotherapy as a nitrosourea was considered to be potentially the best standard of care for patients with malignant glioma.2,3 This clinical study indicated that this type of concomitant regimen could prolong survival in patients with malignant glioma. The authors conclude that this "is a promising regimen . . . . This regimen is currently being compared with standard [radiation therapy] alone in an international randomized trial . . . ." We would like to downplay the authors’ enthusiasm.
As is well known, the specific prognostic factors such as age, performance status, histologic grade, and extent of tumor resection predicted significantly the survival of patients with malignant glioma.4,5 A younger age, a high performance status, an anaplastic astrocytoma, and a complete tumor resection are considered the best prognostic factors and authorize a prolonged survival for patients, whatever the type of oncologic treatment used.4,5 Of particular interest in the study by Stupp et al1 is that their population was younger (median age, 52 years) than we could expect for this type of study. Indeed, the incidence peak of malignant gliomas is 65 years old.3 The authors said, "Two thirds . . . of the patients were
Regarding trial entry criteria, we also regret that there was a high percentage of included patients in whom there was the possibility that chemotherapy would be too beneficial: "The majority (77%) of patients had undergone prior debulking surgery, with 42% being considered macroscopically complete resections. . . . Fifteen patients (23%) had a stereotactic biopsy only." Two thirds (64%) of the patients had a high Karnofsky score, Finally, we congratulate the authors for demonstrating that a concurrent combination of radiation therapy and chemotherapy was feasible and safe. Toxicity was acceptable, and no late toxicity was seen. However, the rationale for combining temozolomide with radiation therapy is poor, and preclinical data did not clearly demonstrate additive or perhaps synergistic activity. Currently, the best radiosensitizers are cisplatin, etoposide, and paclitaxel.6 In our clinical study testing a concomitant-to-sequential use of etoposide and radiotherapy for newly diagnosed malignant gliomas, the median survival for patients with glioblastoma multiforme was 13.9 months.6 However, our population included a high percentage of patients with unfavorable prognostic factors, such as residual tumor (41.1% of the population had stereotactic biopsy and 25.4% had incomplete tumor resection, as shown by postsurgery computed tomography scans) and age (median age was 61 years).6 However, the results of this study, in our opinion, do not justify the development of a phase III study, and do not offer a beneficial effect for patients with malignant glioma. REFERENCES
1. 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: 1375-1382, 2002 2. Prados MD, Levin V: Biology and treatment of malignant glioma. Semin Oncol 27: 1-10, 2000[Medline] 3. Fine HA, Dear KBG, Loeffler JS, et al: Meta-analysis of radiotherapy with and without adjuvant chemotherapy for malignant gliomas in adults. Cancer 71: 2585-2597, 1993[CrossRef][Medline] 4. Black PL: Brain tumors, first part. N Engl J Med 21: 1471-1476, 1991
5. Curran WJ, Scott CB, Horton J, et al: Recursive partitioning analysis in three Radiation Oncology Thearpy Group malignant gliomas trials. J Natl Cancer Inst 85: 704-711, 1993 6. Beauchesne P, Soler C, Boniol M, et al: Response to a phase II study of concomitant-to-sequential use of etoposide and radiation therapy in newly diagnosed malignant gliomas. Radiat Oncol Invest (in press)
ResponseUniversity Hospitals Lausanne and Geneva, Switzerland Reply 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. REFERENCES
1. Reardon DA, Akabani G, Coleman RG, et al: Phase II trial of murine 131I-labeled antitenascin monoclonal antibody 81C6 administered into surgically created resection cavities of patients with newly diagnosed malignant gliomas. J Clin Oncol 20: 1389-1397, 2002
2. 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: 1375-1382, 2002 3. Stewart LA: Chemotherapy in adult high-grade glioma: A systematic review and meta-analysis of individual patient data from 12 randomised trials. Lancet 359: 1011-1018, 2002[CrossRef][Medline] 4. 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: 51-55, 1998[CrossRef][Medline] 5. Steel GG, Peckham MJ: Exploitable mechanisms in combined radiotherapy-chemotherapy: The concept of additivity. Int J Radiat Oncol Biol Phys 5: 85-91, 1979[Medline] 6. Wedge SR, Porteous JK, Glaser MG, et al: In vitro evaluation of temozolomide combined with x-irradiation. Anticancer Drugs 8: 92-97, 1997[CrossRef][Medline] 7. 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: 779-784, 2000[CrossRef][Medline]
8. 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: 1915-1919, 2002
ResponseDuke University Medical Center, Durham, NC 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.4 For all of these reasons, we wholeheartedly concur with Nieder that a phase III study incorporating 131I-radiolabeled antitenascin monoclonal antibody 81C6 is warranted. REFERENCES
1. Reardon DA, Akabani G, Coleman RE, et al: Phase II trial of murine 131I-labeled antitenascin monoclonal antibody 81C6 administered into surgically created resection cavities of patients with newly diagnosed malignant gliomas. J Clin Oncol 20: 1389-1397, 2002 2. Liang BC, Thornton AF, Sandler HM, et al: Malignant astrocytomas: Focal tumor recurrence after focal external beam radiation therapy. J Neurosurg 75: 559-663, 1991[CrossRef][Medline]
3. 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: 704-710, 1993 4. 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
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Copyright © 2002 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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50 years old, and 20% of the patients were between 40 and 50 years old." From the statistical analysis used and data given, we could maintain that the second quartile, 
52 years old, is more important than other quartiles and explain why this population is too young compared with the others reported in the literature.
