Brain Tumor Cooperative Group Research Articles

The Brain Tumor Cooperative Group NIH Trial 87-01: A Randomized Comparison of Surgery, External Radiotherapy, and Carmustine versus Surgery, Interstitial Radiotherapy Boost, External Radiation Therapy, and Carmustine

Abstract OBJECTIVE The objective of the Brain Tumor Cooperative Group NIH Trial 87-01 trial was to investigate the effect of additional implanted radiation therapy in newly diagnosed patients with pathologically confirmed malignant gliomas. METHODS The study involved a randomized comparison of surgery, external beam radiotherapy, and carmustine (BCNU) versus surgery, external beam therapy, interstitial radiotherapy boost, and BCNU in newly diagnosed malignant gliomas. 125I was chosen as best suited for this effort because it allowed preimplantation planning and postimplantation quality assurance review. Two hundred ninety-nine patients met the eligibility criteria and were randomized into the two arms of the study between December 1987 and April 1994. Follow-up continued for an additional 3 years. Twenty-nine patients were identified as having committed protocol violations and were excluded, resulting in 270 subjects in the Valid Study Group. One hundred thirty-seven patients received external beam radiation and BCNU, and 133 underwent the 125I implantation plus external beam radiation and BCNU therapy. RESULTS The overall median survival for the Valid Study Group was 64.3 weeks. The median survival for patients receiving additional therapy of 125I was 68.1 weeks, and median survival for those receiving only external beam radiation and BCNU was 58.8 weeks. The cumulative proportion surviving between the two treatment groups was not statistically significantly different (log-rank test, P = 0.101). As in other studies in the literature, age, Karnofsky score, and pathology were predictors of mortality. Additional analyses incorporating an adjustment for these prognostic variables, either in a stratified analysis or Cox proportional hazards model, did not result in statistically significant differences in the cumulative proportion of patients surviving between the two treatment groups. CONCLUSION We conclude that there is no long-term survival advantage of increased radiation dose with 125I seeds in newly diagnosed glioma patients.

The Brain Tumor Cooperative Group NIH Trial 87-01: A Randomized Comparison of Surgery, External Radiotherapy, and Carmustine versus Surgery, Interstitial Radiotherapy Boost, External Radiation Therapy, and Carmustine

The objective of the Brain Tumor Cooperative Group NIH Trial 87-01 trial was to investigate the effect of additional implanted radiation therapy in newly diagnosed patients with pathologically confirmed malignant gliomas. The study involved a randomized comparison of surgery, external beam radiotherapy, and carmustine (BCNU) versus surgery, external beam therapy, interstitial radiotherapy boost, and BCNU in newly diagnosed malignant gliomas. (125)I was chosen as best suited for this effort because it allowed preimplantation planning and postimplantation quality assurance review. Two hundred ninety-nine patients met the eligibility criteria and were randomized into the two arms of the study between December 1987 and April 1994. Follow-up continued for an additional 3 years. Twenty-nine patients were identified as having committed protocol violations and were excluded, resulting in 270 subjects in the Valid Study Group. One hundred thirty-seven patients received external beam radiation and BCNU, and 133 underwent the (125)I implantation plus external beam radiation and BCNU therapy. The overall median survival for the Valid Study Group was 64.3 weeks. The median survival for patients receiving additional therapy of (125)I was 68.1 weeks, and median survival for those receiving only external beam radiation and BCNU was 58.8 weeks. The cumulative proportion surviving between the two treatment groups was not statistically significantly different (log-rank test, P = 0.101). As in other studies in the literature, age, Karnofsky score, and pathology were predictors of mortality. Additional analyses incorporating an adjustment for these prognostic variables, either in a stratified analysis or Cox proportional hazards model, did not result in statistically significant differences in the cumulative proportion of patients surviving between the two treatment groups. We conclude that there is no long-term survival advantage of increased radiation dose with (125)I seeds in newly diagnosed glioma patients.

Meta-analysis of radiation therapy with and without adjuvant chemotherapy for malignant gliomas in adults

The value of chemotherapy after standard postoperative external beam radiation in the treatment of malignant gliomas remains controversial. Despite recent recommendations from the Brain Tumor Cooperative Group that chemotherapy should be considered part of the standard treatment of patients with high-grade astrocytomas, several recent trials have questioned the efficacy of this approach. Using results from 16 randomized clinical trials involving more than 3000 patients, the authors compared the survival rates of patients who received radiation alone or radiation with chemotherapy. The combined data were analyzed using the statistical method of meta-analysis as described by DerSimonian and Laird. The estimated increase in survival for patients treated with combination radiation and chemotherapy was 10.1% at 1 year (95% confidence interval, 6.8, 13.3%) and 8.6% at 2 years (5.2, 12.0%). These absolute increases in survival (treated-control [TC]) in patients treated with chemotherapy represent relative increases (T-C)/C of 23.4% at 1 year (15.8, 30.9%) and 52.4% at 2 years (31.7, 73.2%). This survival advantage is conferred by several different chemotherapeutic agents. When the prognostic variables of age and histology are factored into the analysis, however, the data suggest that the survival benefit from chemotherapy occurs earlier in patients with anaplastic astrocytoma (AA) than in patients with glioblastoma. The authors concluded that chemotherapy is advantageous for patients with malignant gliomas and should be considered part of the standard therapeutic regimen. Additional randomized trials using optimal radiation and chemotherapy may still be needed to precisely define which subgroups of patients, based on prognostic variables, will benefit most from chemotherapy after radiation.

Fractionation in radiation therapy - Part II - Radiobiological emphasis

Introduction: Supratentorial malignant gliomas (anaplastic astrocytomas and glioblastoma multiforme) are associated with an extremely poor prognosis. The Brain Tumor Study Group (now known as the Brain Tumor Cooperative Group) has conducted a number of studies demonstrating a dose response relationship when the radiation dose was increased from 50 to 60 Gy. Chemotherapy (such as BCNU) has had only a modest improvement in survival. Recently, the RTOG has published the results of a dose-searching Phase I/II trial to evaluate hyperfmctionated radiotherapy with total doses up to 81.6 Gy in the treatment of malignant gliomas. Even after doses as high as those used in this trial, local recurrence was the principal mode of failure. Since the vast majority of the recurrences occur within the contrast enhancing region (or within a few centimeters from it), several institutions have performed clinical trials with interstitial implants in an attempt to increase the therapeutic gain. Recently hyperthermia has been used to sensitize gliomas before and after an implant.

Malignant Glioma: Current Treatment Perspectives

Cytoreduction through multimodality therapy is the primary goal in management of malignant gliomas. Clinical trials such as those offered by the Brain Tumor Cooperative Group help to define current standards of care and investigate new therapies. Available therapies are in the medical, surgical, radiation and chemotherapeutic realms.

Clinical Trials: Bringing Research to the Bedside

Over the years, clinical trials with their structured treatment plans and multicenter involvement have been instrumental in developing new treatments and establishing standard of care therapy. While clinical trials strive to advance medical knowledge, they provide scientifically sound, state of the art care and their use should be increased. The Brain Tumor Cooperative Group, one such NCI-sponsored cooperative group, has been the primary group for the treatment of malignant gliomas. As the field of neuro-oncology expands, the neuroscience nurse needs to develop an understanding of clinical trials and their operation. The nurse is in an optimal position to support medical research and the research participant.

Results of a randomized trial comparing BCNU plus radiotherapy, streptozotocin plus radiotherapy, BCNU plus hyperfractionated radiotherapy, and BCNU following misonidazole plus radiotherapy in the postoperative treatment of malignant glioma

In Brain Tumor Cooperative Group Study 77-02, eleven institutions randomized 603 adult patients with supratentorial malignant glioma to one of four treatment groups following surgery: conventional radiotherapy (6000 cGy in 30–35 fractions) + BCNU, conventional radiotherapy + streptozotocin, hyperfractionated (twice daily) radiotherapy (6600 cGy in 60 fractions) + BCNU, and conventional radiotherapy with misonidazole followed by BCNU. Data were analyzed for the total randomized population and for the 557 patients (86% with glioblastoma multiforme) who met protocol eligibility specifications (including confirmed histopathology on central review). Median survival was approximately 10 months following randomization. Overall there was no statistically significant difference in survival among the four groups. Among non-glioblastoma patients, the misonidazole group appeared to have poor survival. Peripheral neuropathy was a dose-limiting toxicity with misonidazole. It is concluded that neither the addition of misonidazole nor hyperfractionated radiotherapy as given in this protocol offered any advantage over conventional radiotherapy plus either BCNU or streptozotocin for treatment of malignant glioma.

The prognostic importance of tumor size in malignant gliomas: a computed tomographic scan study by the Brain Tumor Cooperative Group.

The prognostic importance of tumor size was studied in 510 patients with malignant glioma (80% with glioblastoma multiforme) in the Valid Study Group of Study 80-01 of the Brain Tumor Study Group (now the Brain Tumor Cooperative Group [BTCG]). The endpoint was length of survival from randomization, which occurred within 3 weeks of definitive surgery. Following randomization, patients were scheduled to receive radiotherapy (RT) (6,020 cGy) during a 7-week period, along with continuing courses of chemotherapy. Computed tomographic (CT) scan information was available for 124 patients preoperatively, 300 patients postoperatively (preradiation), and 218 patients 9 weeks post-RT (+/- 3 weeks). Tumor size was determined as area (length x width) on the contrast-enhanced scan and survival was compared by log rank statistics. Preoperative tumor area was unrelated to survival (P = .48), but postoperative area was significantly prognostic (P less than .0001); the smaller the residual tumor, the longer the patient lived. Patients with a 75% or greater resection, as determined by measuring the difference between the preoperative and the postoperative scans, tended to have better survival, but the difference was not significant (P = .16). The post-RT area was strongly related to survival (P less than .00001). The percent change in area between the pre- and post-RT scans was also prognostic. Tumor size was of prognostic importance independent of the other known prognostic variables: age, Karnofsky performance score, and whether the tumor was glioblastoma or anaplastic astrocytoma. We conclude that the amount of tumor remaining after surgery is an important baseline variable at the start of RT, and that the tumor size 9 weeks following RT is also prognostic. Surgical resection is most important when it leaves the least amount of residual tumor.