Correspondence
Treatment of Brain Tumors
N Engl J Med 2005; 352:2350-2353June 2, 2005
- Article
To the Editor:
In the report by Rutkowski et al. (March 10 issue)1 regarding treatment of early childhood medulloblastoma with postoperative chemotherapy alone, 20 of 43 children under the age of three years (46.5 percent) had desmoplastic medulloblastoma, and these 20 children had a five-year progression-free survival rate of 85 percent. The desmoplastic variant is considered to be less aggressive than classic medulloblastoma and occurs mainly in adolescents and adults.2,3 As far as we know, desmoplastic histologic features are not found in a large proportion of children who are younger than three years of age. Could the somewhat higher-than-expected proportion of children with the desmoplastic variant in the study by Rutkowski et al. be secondary to the exclusion of 19 of the 62 patients originally registered in the study? The authors report a worse outcome for children less than two years of age, but they do not mention how many children were in this age group.
3 ReferencesArnold C. Paulino, M.D.
Bin S. Teh, M.D.
Baylor College of Medicine, Houston, TX 77030
apaulino@tmh.tmc. edu 1
Rutkowski S ,Bode U ,Deinlein F , et al. Treatment of early childhood medulloblastoma by postoperative chemotherapy alone. N Engl J Med 2005;352:978-986
Full Text | Web of Science | Medline2
Frost PJ ,Laperriere NJ ,Wong CS ,Milosevic MF ,Simpson WJ ,Pintilie M . Medulloblastoma in adults. Int J Radiat Oncol Biol Phys 1995;32:951-957
CrossRef | Web of Science | Medline3
Chan AW ,Tarbell NJ ,Black PM , et al. Adult medulloblastoma: prognostic factors and patterns of relapse. Neurosurgery 2000;47:623-631
CrossRef | Web of Science | Medline
To the Editor:
The well-documented relation between intrathecal methotrexate and cognitive damage1 is not adequately examined by Rutkowski et al. Only 14 children in their study underwent neuropsychological assessments that tested for nonverbal tasks and that were not highly dependent on language.
A significant correlation between the leukoencephalopathy grade and the cumulative intraventricular methotrexate dose was noted, but the use of intraventricular methotrexate was not identified as an independent prognostic factor — so why use it?
1 ReferencesMichelle Sadeh, Ph.D.
Israel Cancer Association, 53103 Givataim, Israel
smichelle@clalit.org. il 1
Riva D ,Giorgi C ,Nichelli F , et al. Intrathecal methotrexate affects cognitive function in children with medulloblastoma. Neurology 2002;59:48-53
CrossRef | Web of Science | Medline
To the Editor:
Hegi et al. (March 10 issue)1 report on MGMT (O6-methylguanine–DNA methyltransferase) gene silencing in patients with glioblastoma who were treated with radiotherapy with or without temozolomide. The clinical study, reported by Stupp et al. in the same issue,2 showed that patients who received temozolomide plus radiotherapy had improved progression-free survival and overall survival. Patients with the methylated MGMT promoter who received temozolomide had the longest survival. However, irrespective of the treatment group, MGMT promoter methylation was an independent predictor of favorable overall survival. Progression-free survival was similar (and inferior) in all groups except patients with the methylated MGMT promoter who received temozolomide.
These apparently conflicting results can be resolved if one considers the salvage therapy that patients received. It seems likely that patients who did not receive temozolomide during the study received it after the study was completed. It is also likely that these patients and the other patients subsequently received treatment with regimens based on alkylating agents, whose activity is also affected by MGMT status.3,4 Therefore, the improved survival of patients with a methylated MGMT promoter who did not receive temozolomide in the current study could be the result of a response to temozolomide or other alkylating agents given as salvage therapy.
4 ReferencesKaren Seiter, M.D.
New York Medical College, Valhalla, NY 10595
karen_seiter@nymc.edu 1
Hegi ME ,Diserens A-C ,Gorlia T , et al. MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med 2005;352:997-1003
Full Text | Web of Science | Medline2
Stupp R ,Mason WP ,van den Bent MJ , et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 2005;352:987-996
Full Text | Web of Science | Medline3
Jaeckle KA ,Eyre HJ ,Townsend JJ , et al. Correlation of tumor O6 methylguanine-DNA methyltransferase levels with survival of malignant astrocytoma patients treated with bis-chloroethylnitrosourea: a Southwest Oncology Group study. J Clin Oncol 1998;16:3310-3315
Web of Science | Medline4
Balana C ,Ramirez JL ,Taron M , et al. O6-methyl-guanine-DNA methyltransferase methylation in serum and tumor DNA predicts response to 1,3-bis(2-chloroethyl)-1-nitrosourea but not to temozolomide plus cisplatin in glioblastoma multiforme. Clin Cancer Res 2003;9:1461-1468
Web of Science | Medline
To the Editor:
The trial of temozolomide reported by Stupp et al. demonstrates advancement in the treatment of glioblastoma multiforme. However, the authors fail to mention treatment with a biodegradable wafer containing carmustine (Gliadel Wafer, Guilford) approved in 2003 for primary grade III and IV gliomas. In the initial surgery setting, the median survival benefit of 2.3 months with the use of the carmustine wafer is similar to the 2.5-month survival benefit in the temozolomide trial.
Lynn Ashby, M.D.
Barrow Neurological Institute, Phoenix, AZ 85013Renato LaRocca, M.D.
Kentuckiana Cancer Institute, Louisville, KY 40202Timothy Ryken, M.D.
University of Iowa Hospitals and Clinics, Iowa City, IA 52242To the Editor:
I am surprised that Dr. DeAngelis (March 10 issue)1 chose “A New Beginning” as the subtitle of her editorial accompanying the reports by Rutkowski et al., Stupp et al., and Hegi et al. I would have chosen the more sanguine expression “Is That All?” It has been 27 years since Walker et al.2 reported a medial survival of 10 months; now we have Stupp et al. reporting a median survival of 14.6 months. This is not a very auspicious “beginning.” Although there are subgroups that have significantly prolonged survival, as reported by Hegi et al., glioma remains a dismal disease. Despite recent revolutions in brain imaging, surgery, and radiation delivery, there has not been a commensurate increase in survival. Furthermore, long-term survival can be accompanied by significant impairment in the quality of life.3 It should be apparent that we have been barking up the wrong trees.
3 ReferencesRobert D. Aiken, M.D.
Beth Israel Medical Center, New York, NY 10003
raiken@chpnet.org 1
DeAngelis LM . Chemotherapy for brain tumors -- a new beginning. N Engl J Med 2005;352:1036-1038
Full Text | Web of Science | Medline2
Walker MD ,Alexander E Jr ,Hunt WE , et al. Evaluation of BCNU and/or radiotherapy in the treatment of anaplastic gliomas: a cooperative clinical trial. J Neurosurg 1978;49:333-343
CrossRef | Web of Science | Medline3
Aiken RD, Quality-of-life issues in patients with malignant gliomas. Semin Oncol 1994;21:273-275
Web of Science | Medline
Author/Editor Response
We agree with Drs. Paulino and Teh that desmoplastic medulloblastoma occurs more frequently in adolescents and adults than in children. However, to our knowledge there are no population-based studies on the incidence of medulloblastoma variants in very young children.1-3 About 90 percent of children in Germany with a diagnosis of medulloblastoma were registered in our study during the study period. Among the 11 patients with medulloblastoma who were excluded from analysis, 3 children had the desmoplastic subtype, and 8 had medulloblastoma without further classification. Our data suggest that desmoplastic medulloblastoma may have a double-peaked age distribution, and the biology may differ between age groups. Twenty-three of the 43 children were younger than two years of age at diagnosis.
In our study, 20 of 27 patients (74 percent) who were alive 3.9 years or more after diagnosis underwent neurocognitive assessment (14 patients after chemotherapy alone, and 6 patients who received radiotherapy after chemotherapy). Parents of seven of the patients did not answer our request for testing or did not agree to it. The children were also tested for learning abilities, including vocabulary, motor abilities, simple reaction time, and an attention task. The complete neurocognitive data are being analyzed, and a 10-year follow-up is under way. There is evidence that deficits in attention may be more relevant for learning problems than deficits in verbal skills.4 The majority of the 14 children (12) treated with chemotherapy alone are successfully attending a standard regular school; 1 child is attending a school for hearing-impaired children, and 1 a school for physically handicapped children.
Our study was not designed to compare treatment with and without intraventricular methotrexate. The multivariate analysis concerning intraventricular methotrexate as a prognostic factor refers to children receiving different cumulative doses. As compared with the results of other studies using systemic methotrexate, repeated doses of intraventricular methotrexate may have pharmacokinetic advantages.5 Leukoencephalopathy was a clinically asymptomatic finding. In our opinion, the efficacy of our regimen outweighs its toxicity, but the contribution of intraventricular methotrexate should be further assessed.
5 ReferencesStefan Rutkowski, M.D.
Holger Ottensmeier, Ph.D.
Children's University Hospital, 97080 Würzburg, Germany
rutkowski@mail.uni-wuerzburg. de Torsten Pietsch, M.D.
National Reference Center for Brain Tumors, 53105 Bonn, Germany1
Gajjar A, Hernan R, Kocak M, et al. Clinical, histopathologic, and molecular markers of prognosis: toward a new disease risk stratification system for medulloblastoma. J Clin Oncol 2004;984-93.
2
Eberhart CG ,Kepner JL ,Goldthwaite PT , et al. Histopathologic grading of medulloblastomas: a Pediatric Oncology Group study. Cancer 2002;94:552-560
CrossRef | Web of Science | Medline3
Fernandez-Teijeiro A ,Betensky RA ,Sturla LM ,Kim JY ,Tamayo P ,Pomeroy SL . Combining gene expression profiles and clinical parameters for risk stratification in medulloblastomas. J Clin Oncol 2004;22:994-998
CrossRef | Web of Science | Medline4
Reeves CB, Palmer SL, Reddick WE, et al. Attention and memory functioning among pediatric patients with medulloblastoma. J Pediatr Psychol (in press).
5
Fleischhack G ,Jaehde U ,Bode U . Pharmacokinetics following intraventricular administration of chemotherapy in patients with neoplastic meningitis. Clin Pharmacokinet 2005;44:1-31
CrossRef | Web of Science | Medline
Author/Editor Response
Unlike Dr. Aiken, we truly believe that there is a new beginning for treatment and research in malignant glioma. Considering only median survival, an increase of five months since the report by Walker et al. may seem modest, but it represents an increase of 50 percent. Moreover, improved knowledge of the biology of gliomas allows us to identify tumors likely to respond to alkylating agents. If patients are selected on the basis of MGMT promoter methylation and receive temozolomide chemotherapy, two-year survival reaches 46 percent. The important issue of the quality of life, emphasized by Dr. Aiken, was addressed as a secondary end point in our trial. The analysis showed that the addition of chemotherapy to standard radiation therapy had no significant detrimental effect on the quality of life.1
Dr. Seiter suggests that salvage therapy could explain why there was no difference in progression-free survival in the two groups we studied. Indeed, 72 percent of the patients initially treated with radiation therapy alone received salvage chemotherapy with an alkylating agent. Actually, more than 60 percent of patients received temozolomide after progression.
Dr. Ashby and colleagues believe that carmustine-impregnated wafers should be recognized as an alternative treatment. In our opinion, the results with carmustine wafers were disappointing, particularly because all patients had to undergo debulking surgery to implant the wafer to the resection cavity.2 Patients with glioblastoma receiving carmustine wafers had a median survival of 13.5 months, as compared with 11.4 months with placebo, with no significant difference in survival beyond 18 months. In the European Organization for Research and Treatment of Cancer and National Cancer Institute of Canada trial, patients who underwent surgery had a median survival of 12.9 months with initial radiation therapy, as compared with 15.8 months for patients who received treatment with temozolomide during and after radiation therapy (P<0.001). More important, our trial shows an improvement in the two-year survival rate, which we consider meaningful. Malignant glioma is a disease of the brain beyond the visible local extension. Thus, treatments that target only local disease have inherent limitations. There may be a rationale for future trials that combine treatment with carmustine wafers and temozolomide with radiation therapy. The local administration of carmustine could be a strategy to exhaust the MGMT reservoir of the tumor.
2 ReferencesRoger Stupp, M.D.
Monika E. Hegi, Ph.D.
Lausanne University Hospital, CH-1011 Lausanne, Switzerland1
Taphoorn MJB, Stupp R, Osaba D, et al. Joint EORTC Brain Tumour Group/Radiotherapy Group and NCIC CTG phase III randomised controlled trial evaluating health-related quality of life in glioblastoma patients. Proc ESMO, Ann Oncol 2004;15:Suppl 3:206. abstract.
2
Westphal M ,Hilt DC ,Bortey E , et al. A phase 3 trial of local chemotherapy with biodegradable carmustine (BCNU) wafers (Gliadel wafers) in patients with primary malignant glioma. Neurooncol 2003;5:79-88
CrossRef | Web of Science | Medline
Author/Editor Response
In the study by Stupp et al., the addition of temozolomide to radiotherapy prolonged the median survival by 2.5 months and increased the 2-year survival rate from 10.4 percent to 26.5 percent. Dr. Aiken says this is old news and an insignificant improvement. However, recent data indicate that many patients with glioblastoma in the United States receive suboptimal standard care; only 54 percent of patients receive adjuvant chemotherapy, regardless of whether they are treated in the community or at an academic institution.1 Temozolomide is easy to add, has acceptable side effects, and could benefit, although not cure, thousands of patients. Many have called for a new way to treat glioblastoma, but to date, signal-transduction inhibitors, small molecules, and immunotherapy have been disappointing and have not yet led to even the incremental change observed with the addition of the relatively nontoxic temozolomide.2,3 The study by Stupp et al. and the companion tissue analysis by Hegi et al. suggest that glioblastoma is a tractable problem. This will stimulate further research as investigators realize that we are starting to see the forest — and not just the trees.
3 ReferencesLisa M. DeAngelis, M.D.
Memorial Sloan-Kettering Cancer Center, New York, NY 10021
deangell@mskcc.org 1
Chang SM ,Parney IF ,Huang W , et al. Patterns of care for adults with newly diagnosed malignant glioma. JAMA 2005;293:557-564
CrossRef | Web of Science | Medline2
Rich JN ,Reardon DA ,Peery T , et al. Phase II trial of gefitinib in recurrent glioblastoma. J Clin Oncol 2004;22:133-142
CrossRef | Web of Science | Medline3
Puduvalli VK ,Yung WK ,Hess KR , et al. Phase II study of fenretinide (NSC 374551) in adults with recurrent malignant gliomas: a North American Brain Tumor Consortium study. J Clin Oncol 2004;22:4282-4289
CrossRef | Web of Science | Medline
- Citing Articles (4)
Citing Articles
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Zhenhua Li, Jang-Won Lee, Debraj Mukherjee, Jianfei Ji, Sunil P Jeswani, Keith L Black, John S Yu. (2011) Immunotherapy targeting glioma stem cells – insights and perspectives. Expert Opinion on Biological Therapy1-14
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Zhenhua Li, Debraj Mukherjee, Jang-Won Lee, John S. Yu. 2011. Molecular targeting of cancer stem cells. , 202-216.
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Peter B. Dirks. (2010) Brain tumor stem cells: The cancer stem cell hypothesis writ large. Molecular Oncology 4:5, 420-430
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Sonia Maciá Escalante, Álvaro Rodríguez Lescure, José Miguel Segura Ibáñez, Julio Sáez Castán, Carmen Guillén Ponce, Alfredo Carrato Mena. (2006) Patient with resected anaplastic astrocytoma and an image suggestive of relapse. Clinical and Translational Oncology 8:12, 912-914
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