Chemotherapy for Brain Tumors — A New Beginning
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《新英格兰医药杂志》
Primary brain tumors often resist treatment; the most common brain tumor in adults, glioblastoma, kills patients within a median of a year after diagnosis, even with aggressive surgical resection and radiotherapy. This dismal outcome has not substantially improved since the Brain Tumor Study Group published its results more than 25 years ago.1 Numerous phase 3 trials have attempted to demonstrate a better outcome with the addition of chemotherapy (usually with a nitrosourea drug) to radiotherapy, but a significant prolongation of survival has never been observed, despite treatments with a variety of agents and delivery systems. There was a suggestion that 10 percent of patients had prolonged survival with adjuvant chemotherapy, and this finding was confirmed in two meta-analyses, but patients with chemotherapy-sensitive tumors could not be identified on the basis of clinical or pathological characteristics.2,3,4 For decades, many have argued that the existence of this subgroup of patients justified giving adjuvant chemotherapy to all patients with newly diagnosed glioblastoma. This approach was adopted primarily in the United States; most European physicians continued to treat such patients with radiotherapy alone.
In this issue of the Journal, three articles highlight the growing importance of chemotherapy for malignant brain tumors. The companion studies by Stupp et al.5 and Hegi et al.6 focused on adults with glioblastoma, whereas Rutkowski et al.7 report on the use of chemotherapy alone for the treatment of medulloblastoma in very young children. Each report represents a substantial step forward in the treatment of these diseases.
Stupp and his colleagues conducted a randomized phase 3 trial in adults with newly diagnosed glioblastoma, who received radiotherapy alone or radiotherapy with concurrent temozolomide followed by adjuvant temozolomide. The patients who received both radiotherapy and the alkylating agent had significantly longer overall survival and progression-free survival, as well as a significantly higher rate of two-year survival, than the group treated with radiotherapy alone. Furthermore, there were few adverse events associated with the treatment.
Why did this study show a greater benefit of chemotherapy than all previous studies had done? Several factors are probably involved. First, the patients were a relatively healthy group. Almost all were younger than 70 years of age, they had a good performance status, and in 84 percent of them, debulking of the tumor was possible — all favorable prognostic factors. Second, temozolomide may be more effective and is certainly less toxic than the nitrosourea drugs. The incidence of drug-related toxic effects in this study was extremely low, even when temozolomide was administered concomitantly with radiotherapy. Third, the concurrent administration of a chemotherapeutic agent with radiotherapy was a novel approach. Although this study does not distinguish the relative contribution of drug administration during radiotherapy from the contribution of adjuvant therapy, the concurrent administration may have played an important role in enhancing the overall outcome.
For their study, Hegi et al. attempted to identify patients who would benefit from the addition of temozolomide to radiotherapy. Tumor-specific markers that predict responses to treatment in brain tumors were first identified in anaplastic oligodendrogliomas, in which a loss of heterozygosity for chromosomes 1p and 19q indicates a tumor that is likely to respond to treatment, resulting in a better prognosis for the patient.8 Hegi and her colleagues studied O6-methylguanine–DNA methyltransferase (MGMT), an enzyme that repairs the DNA damage caused by alkylating agents such as temozolomide; this injury to DNA culminates in apoptotic cell death. Methylation of the promoter of MGMT turns off transcription of the gene, reducing the intracellular level of MGMT and thereby inhibiting the repair mechanism. In principle, therefore, interference with MGMT should accentuate the antitumor effect of the alkylating agent. The investigators found that the prognosis was better for patients who had tumors in which there was methylation of the MGMT promoter than for patients who had tumors without the methylation. Furthermore, almost all of the benefit of adding temozolomide to radiotherapy occurred within the subgroup of patients who had a methylated promoter. Those with an unmethylated promoter did have significantly longer progression-free survival with chemotherapy plus radiotherapy than with radiotherapy alone, but the benefit was small.
What does this pair of studies tell us? Investigating tumor tissue for MGMT promoter methylation is not an easy technique, and the results are not always informative. Even in the hands of these experienced investigators who were collecting tumor tissue prospectively, specimens were obtained from only half of the patients and were informative in only two thirds of the cases they analyzed. This test is not widely available to most practicing clinicians, and the results reported here must be validated in additional studies. Therefore, it seems reasonable to administer temozolomide with radiotherapy to all patients with newly diagnosed glioblastoma. One can anticipate that in the not-too-distant future, information about the methylation status of the MGMT promoter, along with other tumor-specific markers, will be more readily available to help us choose the patients who are most likely to benefit from this approach. However, the minimal toxicity associated with temozolomide and the clear benefit of its use make it reasonable to give this drug to all patients now. This conclusion, however, does not mean that these data can be applied to patients with glioma of other grades — specifically, anaplastic astrocytoma or other types of primary brain tumors; further study will be required to determine the approach's generalizability.
The work of Rutkowski et al. addresses the treatment of medulloblastoma in very young children. The cornerstone of treatment for medulloblastoma, neuraxis radiotherapy, is highly effective, and the addition of chemotherapy is now recognized to prolong disease-free and overall survival. However, the severe side effects associated with neuraxis irradiation in the very young make it an unacceptable therapeutic option. Clinicians have been exploring chemotherapy as the sole treatment for such young patients in order to defer or eliminate the need for radiotherapy. The study by Rutkowski et al. is the largest that has been conducted in children younger than three years of age. The use of a vigorous combination chemotherapy regimen resulted in an excellent outcome, and most important, radiotherapy was avoided in two thirds of patients who had no evidence of macroscopic metastases at diagnosis. Furthermore, subsequent cognitive function in these patients was better than that reported in studies of similar patients treated with radiotherapy, validating the hypothesis that radiotherapy may be withheld in the very young without compromising disease control.
All three of these studies emphasize the importance of enrolling patients with brain tumors in clinical trials. We still have a long way to go in the treatment of malignant brain tumors, but progress will come only through clinical research, and we must encourage our patients to participate. In the meantime, we can enjoy the victories reported here. The studies by Stupp et al. and Hegi et al. represent landmarks in the diagnosis and treatment of malignant glial tumors. As we come to understand these diseases better and identify biologic markers that will enable us to subclassify this otherwise clinically and pathologically homogeneous population, we will improve life for our patients.
Source Information
From the Department of Neurology, Memorial Sloan-Kettering Cancer Center, New York.
References
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.
Fine HA, Dear KB, Loeffler JS, Black PM, Canellos GP. Meta-analysis of radiation therapy with and without adjuvant chemotherapy for malignant gliomas in adults. Cancer 1993;71:2585-2597.
Stewart LA. Chemotherapy in adult high-grade glioma: a systematic review and meta-analysis of individual patient data from 12 randomised trials. Lancet 2002;359:1011-1018.
DeAngelis LM, Burger PC, Green SB, Cairncross JG. Malignant glioma: who benefits from adjuvant chemotherapy? Ann Neurol 1998;44:691-695.
Stupp R, Mason WP, van den Brent MJ, et al. Radiotherapy plus concomitant and adjuvant temozolomide for newly diagnosed glioblastoma. N Engl J Med 2005;352:987-996.
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.
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.
Cairncross JG, Ueki K, Zlatescu MC, et al. Specific genetic predictors of chemotherapeutic response and survival in patients with anaplastic oligodendrogliomas. J Natl Cancer Inst 1998;90:1473-1479.(Lisa M. DeAngelis, M.D.)
In this issue of the Journal, three articles highlight the growing importance of chemotherapy for malignant brain tumors. The companion studies by Stupp et al.5 and Hegi et al.6 focused on adults with glioblastoma, whereas Rutkowski et al.7 report on the use of chemotherapy alone for the treatment of medulloblastoma in very young children. Each report represents a substantial step forward in the treatment of these diseases.
Stupp and his colleagues conducted a randomized phase 3 trial in adults with newly diagnosed glioblastoma, who received radiotherapy alone or radiotherapy with concurrent temozolomide followed by adjuvant temozolomide. The patients who received both radiotherapy and the alkylating agent had significantly longer overall survival and progression-free survival, as well as a significantly higher rate of two-year survival, than the group treated with radiotherapy alone. Furthermore, there were few adverse events associated with the treatment.
Why did this study show a greater benefit of chemotherapy than all previous studies had done? Several factors are probably involved. First, the patients were a relatively healthy group. Almost all were younger than 70 years of age, they had a good performance status, and in 84 percent of them, debulking of the tumor was possible — all favorable prognostic factors. Second, temozolomide may be more effective and is certainly less toxic than the nitrosourea drugs. The incidence of drug-related toxic effects in this study was extremely low, even when temozolomide was administered concomitantly with radiotherapy. Third, the concurrent administration of a chemotherapeutic agent with radiotherapy was a novel approach. Although this study does not distinguish the relative contribution of drug administration during radiotherapy from the contribution of adjuvant therapy, the concurrent administration may have played an important role in enhancing the overall outcome.
For their study, Hegi et al. attempted to identify patients who would benefit from the addition of temozolomide to radiotherapy. Tumor-specific markers that predict responses to treatment in brain tumors were first identified in anaplastic oligodendrogliomas, in which a loss of heterozygosity for chromosomes 1p and 19q indicates a tumor that is likely to respond to treatment, resulting in a better prognosis for the patient.8 Hegi and her colleagues studied O6-methylguanine–DNA methyltransferase (MGMT), an enzyme that repairs the DNA damage caused by alkylating agents such as temozolomide; this injury to DNA culminates in apoptotic cell death. Methylation of the promoter of MGMT turns off transcription of the gene, reducing the intracellular level of MGMT and thereby inhibiting the repair mechanism. In principle, therefore, interference with MGMT should accentuate the antitumor effect of the alkylating agent. The investigators found that the prognosis was better for patients who had tumors in which there was methylation of the MGMT promoter than for patients who had tumors without the methylation. Furthermore, almost all of the benefit of adding temozolomide to radiotherapy occurred within the subgroup of patients who had a methylated promoter. Those with an unmethylated promoter did have significantly longer progression-free survival with chemotherapy plus radiotherapy than with radiotherapy alone, but the benefit was small.
What does this pair of studies tell us? Investigating tumor tissue for MGMT promoter methylation is not an easy technique, and the results are not always informative. Even in the hands of these experienced investigators who were collecting tumor tissue prospectively, specimens were obtained from only half of the patients and were informative in only two thirds of the cases they analyzed. This test is not widely available to most practicing clinicians, and the results reported here must be validated in additional studies. Therefore, it seems reasonable to administer temozolomide with radiotherapy to all patients with newly diagnosed glioblastoma. One can anticipate that in the not-too-distant future, information about the methylation status of the MGMT promoter, along with other tumor-specific markers, will be more readily available to help us choose the patients who are most likely to benefit from this approach. However, the minimal toxicity associated with temozolomide and the clear benefit of its use make it reasonable to give this drug to all patients now. This conclusion, however, does not mean that these data can be applied to patients with glioma of other grades — specifically, anaplastic astrocytoma or other types of primary brain tumors; further study will be required to determine the approach's generalizability.
The work of Rutkowski et al. addresses the treatment of medulloblastoma in very young children. The cornerstone of treatment for medulloblastoma, neuraxis radiotherapy, is highly effective, and the addition of chemotherapy is now recognized to prolong disease-free and overall survival. However, the severe side effects associated with neuraxis irradiation in the very young make it an unacceptable therapeutic option. Clinicians have been exploring chemotherapy as the sole treatment for such young patients in order to defer or eliminate the need for radiotherapy. The study by Rutkowski et al. is the largest that has been conducted in children younger than three years of age. The use of a vigorous combination chemotherapy regimen resulted in an excellent outcome, and most important, radiotherapy was avoided in two thirds of patients who had no evidence of macroscopic metastases at diagnosis. Furthermore, subsequent cognitive function in these patients was better than that reported in studies of similar patients treated with radiotherapy, validating the hypothesis that radiotherapy may be withheld in the very young without compromising disease control.
All three of these studies emphasize the importance of enrolling patients with brain tumors in clinical trials. We still have a long way to go in the treatment of malignant brain tumors, but progress will come only through clinical research, and we must encourage our patients to participate. In the meantime, we can enjoy the victories reported here. The studies by Stupp et al. and Hegi et al. represent landmarks in the diagnosis and treatment of malignant glial tumors. As we come to understand these diseases better and identify biologic markers that will enable us to subclassify this otherwise clinically and pathologically homogeneous population, we will improve life for our patients.
Source Information
From the Department of Neurology, Memorial Sloan-Kettering Cancer Center, New York.
References
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.
Fine HA, Dear KB, Loeffler JS, Black PM, Canellos GP. Meta-analysis of radiation therapy with and without adjuvant chemotherapy for malignant gliomas in adults. Cancer 1993;71:2585-2597.
Stewart LA. Chemotherapy in adult high-grade glioma: a systematic review and meta-analysis of individual patient data from 12 randomised trials. Lancet 2002;359:1011-1018.
DeAngelis LM, Burger PC, Green SB, Cairncross JG. Malignant glioma: who benefits from adjuvant chemotherapy? Ann Neurol 1998;44:691-695.
Stupp R, Mason WP, van den Brent MJ, et al. Radiotherapy plus concomitant and adjuvant temozolomide for newly diagnosed glioblastoma. N Engl J Med 2005;352:987-996.
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.
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.
Cairncross JG, Ueki K, Zlatescu MC, et al. Specific genetic predictors of chemotherapeutic response and survival in patients with anaplastic oligodendrogliomas. J Natl Cancer Inst 1998;90:1473-1479.(Lisa M. DeAngelis, M.D.)