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© 2002 American Society for Clinical Oncology Prospective Randomized Trial of Low- Versus High-Dose Radiation Therapy in Adults With Supratentorial Low-Grade Glioma: Initial Report of a North Central Cancer Treatment Group/Radiation Therapy Oncology Group/Eastern Cooperative Oncology Group StudyByFrom the North Central Cancer Treatment Group Operations Office, Rochester, MN; Eastern Cooperative Oncology Group Operations Office, Brookline, MD; and Radiation Therapy Oncology Group Operations Office, Philadelphia, PA. Address reprint requests to E. Shaw, MD, Department of Radiation Oncology, Wake Forest University (WFU) School of Medicine at the WFU Baptist Medical Center, Medical Center Blvd, Winston-Salem, NC 27157-1030; email: eshaw{at}wfubmc.edu
PURPOSE: To compare survival and toxicity in adult patients treated with low-dose (50.4 Gy/28 fractions) versus high-dose (64.8 Gy/36 fractions) localized radiation therapy (RT) for supratentorial low-grade astrocytoma, oligodendroglioma, and mixed oligoastrocytoma. PATIENTS AND METHODS: From 1986 to 1994, 203 eligible/analyzable patients were randomized: 101 to low-dose RT, 102 to high-dose RT. Almost half were younger than 40 years, and 95% had grade 2 tumors. Histologic subtype was astrocytoma (or mixed oligo-astrocytoma with astrocytoma dominant) in 32% of patients and oligodendroglioma (or oligoastrocytoma with oligodendroglioma dominant) in 68%. Tumor diameter was less than 5 cm in 35% of patients, and 41% of tumors showed some degree of contrast enhancement. Extent of resection was gross total in 14% of patients, subtotal in 35%, and biopsy only in 51%. RESULTS: At the time of the present analysis, 83 patients (41%) are dead, and median follow-up is 6.43 years in the 120 who are still alive. Survival at 2 and 5 years is nonsignificantly better with low-dose RT; survival at 2 and 5 years was 94% and 72%, respectively, with low-dose RT and 85% and 64%, respectively, with high-dose RT (log rank P = .48). Multivariate analysis identified histologic subtype, tumor size, and age as the most significant prognostic factors. Survival is significantly better in patients who are younger than 40 years and in patients who have oligodendroglioma or oligo-dominant histology. Grade 3 to 5 radiation neurotoxicity (necrosis) was observed in seven patients, with one fatality in each treatment arm. The 2-year actuarial incidence of grade 3 to 5 radiation necrosis was 2.5% with low-dose RT and 5% with high-dose RT. CONCLUSION: This phase III prospective randomized trial of low- versus high-dose radiation therapy for adults with supratentorial low-grade astrocytoma, oligodendroglioma, and oligoastrocytoma found somewhat lower survival and slightly higher incidence of radiation necrosis in the high-dose RT arm. The most important prognostic factors for survival are histologic subtype, tumor size, and age. The study design of the ongoing intergroup trial in this population will be discussed.
LOW-GRADE GLIOMAS (LGG), the World Health Organization grade 2 tumors, account for approximately 11% of the primary CNS tumors diagnosed each year in the United States. The most common histologic subtypes of LGG include the astrocytomas, oligodendrogliomas, and mixed oligoastrocytomas. They are infiltrative tumors capable of undergoing anaplastic transformation in up to 79% of patients. Because of their infiltrative nature, aggressive behavior, and poor survival (average 10-year survival rate,  30%),1 postoperative radiation therapy has often been used in the management of LGG, particularly in adults, although this has been a controversial issue over the years.2,3 Given that localized radiation treatment fields have historically been used, the key radiotherapeutic issue in the treatment of patients with LGG is total radiation dose. Unlike malignant gliomas, for which prospective clinical trials have shown that survival linearly increases as radiation dose is increased from 50 to 60 Gy,4 the dose-response data in LGG have been mixed. Several retrospective studies have suggested poorer survival with radiation doses greater than 40 to 50 Gy,5,6 whereas several others have suggested better survival with doses of 50 to 53 Gy or greater.1,7 In 1986, the North Central Cancer Treatment Group (NCCTG) opened a phase III prospective randomized clinical trial of low- versus high-dose radiation therapy in adults with LGG. The radiation doses chosen, 50.4 Gy in 28 fractions and 64.8 Gy in 36 fractions, with estimated maximum radionecrosis rates of 1% and 5%,8 respectively, were believed to represent the lowest and highest doses that would be acceptable in clinical practice. Several years after study initiation, the Eastern Cooperative Oncology Group (ECOG) and the Radiation Therapy Oncology Group (RTOG) joined the trial. The intergroup study met its accrual goal in 1994. This article is the first full report of the outcome data.9
The main goals of the study were to determine, in a randomized manner, whether a larger dose of radiation, 64.8 Gy, compared with a lower dose, 50.4 Gy, would improve survival for patients with biopsied, subtotally resected, or totally resected low-grade astrocytomas, oligodendrogliomas, or oligoastrocytomas and to compare the toxicity between the two doses of radiation.
To be eligible, patients had to be 18 years of age or older and have histologic proof of a supratentorial Kernohan grade 1 or 2 astrocytoma, oligodendroglioma, or mixed oligoastrocytoma within 3 months of study entry (pilocytic astrocytomas and other low-grade glioma variants were excluded). Central pathology review was performed by B. Scheithauer, MD, at the Mayo Clinic in Rochester, MN. Patients were randomized to either arm A, 50.4 Gy in 28 fractions over 5.5 weeks, or arm B, 64.8 Gy in 36 fractions over 7 weeks. Stratification factors included the following: Kernohan grade (1 v 2), histology (astrocytoma or oligoastrocytoma [astrocytoma dominant] v oligodendroglioma or oligoastrocytoma [oligodendroglioma dominant]), extent of resection (total resection v subtotal resection v biopsy), age (< 40 years v The radiation therapy treatment fields were localized and included the preoperative tumor volume (as defined by a CT scan in the earlier years of the study and an MRI scan in the later years of the study) with a 2-cm margin treated to a total dose of 50.4 Gy in 28 fractions. Patients who were randomized to arm B received an additional boost of 14.4 Gy in seven fractions to the preoperative tumor volume with a 1-cm margin. After the completion of radiation therapy, the patient’s radiation treatment chart, simulator and port films, radiation treatment plan, and preoperative imaging studies were reviewed for the purpose of quality assurance by the principal investigator (ES). At baseline and after the completion of protocol therapy (every 4 months for 2 years, every 6 months for 3 years, and yearly thereafter until year 15), patients had a physical examination that included a neurologic examination, assessment of Neurologic Function (NF) score, assessment of Mini-Mental Status Examination (MMSE) status,11 assessment of toxicity, recording of antiseizure and steroid medication doses and frequencies, and a CT or MRI scan. Imaging response was determined using the following criteria: complete response, disappearance of all tumor; partial response or regression, greater than 50% reduction in the tumor based on perpendicular diameters or a clear reduction in the tumor; stable, not qualifying for complete or partial response, regression, or progression; and progression, greater than 25% increase in tumor size based on perpendicular diameters or a clear increase in the size of the tumor. Toxicity was assessed using the National Cancer Institute’s common toxicity criteria plus radiation-specific criteria modified from the RTOG. Patients who were coded as having a complete or partial response or regression had their records and imaging studies reviewed by the principal investigator. Patients who were coded as having a progression, grade 3 to 5 toxicity, or death from any cause had their records and imaging studies reviewed by a multidisciplinary team, including neurologists (B.O., R.D.), radiation oncologists (E.S., J.E.), and a statistician (J.O.).
Study Design However, events occurred much more slowly than expected because patient accrual took longer than planned and median survival in the low-dose arm proved to be nearly 10 years, ie, much longer than the 3.78 years assumed by design. Moreover, throughout the trial, both the death rate and the toxicity rate were slightly but consistently higher in the high-dose arm than in the low-dose arm. Therefore, when more than half of the 150 deaths expected for the final analysis had been observed, the NCCTG Data Monitoring Committee recommended early publication of these results on the basis of the following futility rule14: If, when half the required deaths have been observed, the observed death rate in the experimental regimen is higher than the observed death rate in the standard regimen, then the trial may be terminated and the conclusion drawn that an advantage for the experimental regimen has not been established. Note, however, that all patients still alive will continue to be observed for 15 years or until death.
Statistical Methods
From May 1986 through December 1994, 211 patients were accrued and randomized; 108 were assigned to arm A (low-dose radiation), and 103 were assigned to arm B (high-dose radiation). Subsequently, five were found to be ineligible because of incorrect histologic subtype or grade (four on arm A, one on arm B), and three eligible patients refused to begin therapy (three on arm A). Thus, 203 eligible patients began treatment (101 on arm A, 102 on arm B). The number and percentage of assessable patients accrued from each participating institution or cooperative group were as follows: 62 from Mayo Clinic (31%); 66 from other NCCTG institutions (33%); 65 from RTOG (32%), and 10 from ECOG (5%). For the various statistical analyses, institutions were grouped as follows: group 1, Mayo Clinic; group 2, RTOG + ECOG; and group 3, other NCCTG. The patient characteristics for these 203 patients are shown in Table 1. The two treatment groups were similar.
Survival and TTP At the time of this analysis, 83 patients (41%) were dead, 36 (18%) were alive but off study with progression, and the remaining 84 patients (41%) were alive without evidence of progression. A total of 114 progressions had been observed. Median survival was 9.25 years, and median TTP was 5.5 years. The median follow-up time was 6.4 years in the 120 still alive. As shown in Table 2 and Fig 1, there was no significant difference in overall survival between the two treatment arms (log rank P = .48), although the 2- and 5-year survival percentages were somewhat better in the low-dose radiation arm. TTP (Fig 2) was also not significantly different between the two treatment arms (log rank P = .65). In the Cox design models that contained the treatment variable ("High-Dose RT") and the stratification variables, treatment was not significantly associated with either survival (Table 3) or TTP (Table 4) after adjustment for the effects of the stratification factors (log rank P = .19 in both design models). However, the hazard rate for high-dose RT was estimated to be 30% to 35% higher than the hazard rate for low-dose RT.
Univariate analyses of the stratification factors and other key baseline variables (Tables 2 and 3) showed that improved survival was significantly associated with oligodendroglioma or oligo-dominant mixed histology (P = .0001; Fig 3A), smaller tumor size (P = .0008), gross total resection (P = .0116), younger age (P = .0245), high baseline MMSE scores (P = .0030), and good NF scores (P = .0420). Similarly (Table 4), improved TTP was significantly associated with smaller tumor size (P = .0001), oligodendroglioma, oligo-dominant histology (P = .0038), gross total resection (P = .0137), and high MMSE scores (P = .0004).
Exploratory multivariate analyses using CART and Cox models were performed to identify—only preliminarily, given the relative immaturity of the end point data—prognostic factors for overall survival and TTP. CART models were generated first because the robust computer-intensive CART methods can deal successfully with numerous variables and missing values and can often detect interactions (synergistic or antagonistic effects) between pairs of baseline variables. Subsequently, the results of the CART models and univariate log rank tests were used to select smaller sets of baseline variables for Cox modeling, because Cox model methods exclude patients with any missing values and may prove unstable if too many baseline variables are used.
CART modeling was performed using all 203 patients and the independent variables listed in Table 3 to identify subsets of patients with distinctly different survival distributions. CART procedures generate a tree that consists of nodes (subsets of patients) by successively splitting each node into two nodes that correspond to the various ways that the values of each independent baseline variable can be split into two groups. The variable that splits a given node into two subsets with the greatest difference in survival is chosen as the optimum split for that node. The resulting CART model (Fig 4A) identified five survival groups on the basis of histologic subtype, tumor size, age, and MMSE score. When age as a continuous variable was substituted for the dichotomous age stratification variable, the resulting CART model (Fig 4B) identified six distinct groups by classifying the 27 oldest patients as the worst survival group and defining five better groups in the remaining 176 younger patients (age < 55 years) on the basis of tumor size, histologic subtype, and MMSE scores. Similarly (not shown), CART modeling for TTP using the variables listed in Table 4 identified tumor size, extent of resection, histologic subtype, and MMSE as prognostic variables. However, when age as a continuous variable was substituted for the dichotomous age variable, the 27 patients with age
Because baseline MMSE scores were not recorded for 9% of the study patients and Cox model analyses eliminate patients with missing values, a modified MMSE variable was created for the Cox model analyses by assigning all patients with missing values to the low MMSE group. This definition tends to reduce the difference in survival between the low- and high-MMSE groups because many of these patients undoubtedly would have had high MMSE scores had they been measured. The Cox models for survival and TTP are summarized in Tables 3 and 4, respectively. The factors that were identified as valid prognostic factors for overall survival were oligodendroglioma or oligo-dominant histologic subtype, tumor size, age, and institution, whereas the valid prognostic factors for TTP were tumor size, oligodendroglioma or oligo-dominant histologic subtype, MMSE, and year of surgery.
Response
Patterns of Failure
Toxicity Assorted neurotoxicities, including lethargy, headache, dizziness, seizures, radiation necrosis, and radiation encephalitis, in addition to the National Cancer Institute’s common toxicity criteria neurotoxicities, were reported in both arms; six types were reported by 12 patients in arm A, whereas 10 types were reported by 20 patients in arm B. Severe radiation toxicity, defined to be grade 3 to 5 radiation necrosis, radiation encephalitis, or CNS toxicity not otherwise specified was observed in seven patients (one on arm A, six on arm B) including one fatality in each treatment arm. The 2-year actuarial incidence of severe radiation toxicity was 2.5% in arm A and 5% in arm B (Fig 5).
This study failed to demonstrate an advantage for high- versus low-dose radiation in adults with supratentorial LGG in terms of overall survival or TTP. In fact, overall, the survival at 5 years was 72% in the low-dose radiation arm and 65% in the high-dose radiation arm (Fig 1, Table 2). These results are similar to those reported by the European Organization for the Research and Treatment of Cancer (EORTC), in which 379 adults with incompletely resected LGG were randomized to receive either 45 Gy in 25 fractions or 59.4 Gy in 33 fractions, a 14.4 Gy spread in dose similar to that of the present study. In the EORTC study, the 5-year survival rates were 58% and 59% with low- and high-dose radiation, respectively.21 Taken together, the NCCTG and EORTC data do not suggest any radiation dose-response for LGG over the range of 45 to 64.8 Gy. Unfortunately, 28% to 42% of adults with supratentorial LGG are still dying of their disease within 5 years and more than half at 10 years, on the basis of the survival rates from the present study. Three prognostic factors, histologic subtype, tumor size, and age, were most consistently and significantly associated with overall survival in multivariate analysis (Table 3). Significantly better survival was associated with oligodendroglioma or oligo-dominant mixed tumor histology, small tumors (< 5 cm), and/or young age (age < 40), as shown in Fig 3A-3C and Table 2. When combined, histologic subtype and age were particularly powerful predictors of overall survival. The 5-year survival rate of patients who were younger than 40 and had oligodendroglioma was 82%, compared with 32% for those who were 40 or older and had astrocytoma. Histologic subtype and age were also significant prognostic factors for overall survival in the EORTC study, as was extent of surgical resection.21 In the present study, extent of resection was not a significant prognostic factor for overall survival in multivariate analysis (Table 3). The crude incidence of severe, life-threatening, or fatal radiation neurotoxicity (necrosis) was low in both treatment arms, one (1%) of 101 in the low-dose arm and six (6%) of 102 in the high-dose arm (Fig 5), essentially as predicted at the time the study was written. This represents the first carefully conducted prospective evaluation of radiation tolerance to partial brain radiation treatment fields conducted in era of contemporary neuroimaging and radiation treatment planning and delivery. Several observations are worth emphasizing. First, radiation necrosis does occur even at a dose of 50.4 Gy using conventional 1.8-Gy fractions. The one patient who developed neurotoxicity at this dose died of radiation necrosis involving the brainstem, which was partially encompassed in the posteroinferior corner of a rectangular treatment field for a temporal LGG. Second, the 6% incidence of severe or worse neurotoxicity at 64.8 Gy is higher than the TD5/5 (5% likelihood of radionecrosis at 5 years) dose of 50 Gy and 60 Gy quoted by Emami et al8 for partial brain irradiation to two thirds and one third the brain volume, respectively. Besides overt radionecrosis, other forms of radiation-induced toxicity to the brain may be of clinical importance, such as cognitive function. In the present study, 19 of the 62 patients who entered and were treated at the Mayo Clinic in the earlier years of the study underwent neurocognitive testing at baseline and for 3 years after protocol radiation therapy. These data, previously reported by Hammack et al,22 found no significant losses in general intellectual, new learning, or memory function. At the present time, the RTOG is conducting an intergroup trial with NCCTG, ECOG, and the Southwest Oncology Group in which "unfavorable" adults with supratentorial LGG, defined as those younger than 40 years with incompletely resected tumors or those 40 years or older (regardless of the extent of resection), are randomized to receive radiation alone (54 Gy in 30 fractions, a "compromise" dose based on the present data and that of the EORTC) or radiation followed by six cycles of "standard"-dose procarbazine, lomustine, and vincristine (PCV) chemotherapy. The use of PCV in LGG is an extrapolation from the experience with this regimen in anaplastic oligodendroglioma.23 There are also some efficacy data. Buckner et al24 reported a 28% response rate in 29 patients with newly diagnosed low-grade oligodendrogliomas and oligoastrocytomas. Mason et al25 reported a 100% response rate in newly diagnosed low-grade oligodendrogliomas treated with PCV. The RTOG-Intergroup trial also has an observation (ie, delayed radiation) arm for patients who are younger than 40 years and have completely resected supratentorial LGG, in part based on the preliminary report of another EORTC trial in which adults with incompletely resected LGG were randomized to receive radiation therapy with 54 Gy in 30 fractions or observation. The study failed to demonstrate a difference in overall survival, although progression-free survival was significantly better with radiation therapy and two thirds of the patients in the observation arm had local tumor progression and went on to receive radiation therapy.21 In conclusion, this phase III prospective randomized clinical trial of low- versus high-dose radiation therapy for adults with supratentorial LGG found a somewhat lower survival and a slightly higher incidence of radiation neurotoxicity in the high-dose arm. Histologic subtype, tumor size, and age were the most important prognostic factors for survival. An ongoing RTOG Intergroup trial is comparing radiation (54 Gy) with or without PCV chemotherapy (six cycles).
E.S. thanks his mentor, John Earle, MD, for encouraging him to write and conduct this clinical trial. We acknowledge the efforts of Debra Kvittem and Jill Burton, Clinical Research Associates, for expert data management assistance during the conduct of the trial.
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Cairncross JG, Laperriere NJ: Low-grade glioma: To treat or not to treat? Arch Neurol 46: 1238, 1990 (editorial)
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Shaw EG: Low-grade gliomas: To treat or not to treat? A radiation oncologist’s viewpoint. Arch Neurol 47: 1138-1139, 1990 (editorial) 4. Walker MD, Strike TA, Sheline GE: An analysis of dose-effect relationship in the radiotherapy of malignant gliomas. Int J Radiat Oncol Biol Phys 5: 1725-1731, 1979[Medline] 5. Laws ER Jr, Taylor WF, Clifton MB, et al: Neurosurgical management of low-grade astrocytoma of the cerebral hemispheres. J Neurosurg 61: 665-673, 1984[Medline] 6. Rutten E, Kazam I, Slooff JL, et al: Post-operative radiation therapy in the management of brain astrocytomas: Retrospective study of 142 patients. Int J Radiat Oncol Biol Phys 7: 191-195, 1981[Medline] 7. Shibamoto Y, Kitakabu Y, Takahashi M, et al: Supratentorial low-grade astrocytoma: Correlation of computed tomography findings with effect of radiation therapy and prognostic variables. Cancer 72: 190-195, 1992 8. Emami B, Lyman, Brown A, et al: Tolerance of normal tissues to therapeutic irradiation. Int J Radiat Oncol Biol Phys 21:109-122, 1991 9. Shaw EG, Arusell R, Scheithauer B, et al: A prospective randomized trial of low- versus high dose radiation therapy in adults with supratentorial low-grade glioma: initial report of a NCCTG-RTOG-ECOG study. Proc Am Soc Clin Oncol 17: 401a, 1998 (abstr 1545) 10. Pocock SL, Simon R: Sequential treatment assignment with balancing for prognostic factors in the controlled clinical trial. Biometrics 31: 103-115, 1975[CrossRef][Medline] 11. Folstein MF, Folstein SE, McHugh PR: MiniMental State: A practical method for grading of the cognitive state of patients for the clinician. J Psychiatr Res 12: 189-198, 1975[CrossRef][Medline]
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Lan KKG, DeMets DL: Discrete sequential boundaries for clinical trials. Biometrika 70: 659-663, 1983 13. O’Brien PC, Fleming TR: A multiple testing procedure for clinical trials. Biometrics 35: 549-556, 1979[CrossRef][Medline] 14. Wieand HS, Schroeder G, O’Fallon J: Stopping when the experimental regimen does not appear to help. Stat Med 13:1455, 1457, 1994 15. Kaplan EL, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 53: 457-481, 1958[CrossRef] 16. Mantel N: Evaluation of survival data and two new rank order statistics arising in its consideration. Cancer Chemother Rep 50: 163-170, 1966[Medline] 17. LeBlanc M, Crowley J: Relative risk trees for censored survival data. Biometrics 48: 411-425, 1992[CrossRef][Medline] 18. Cox DR: Regression models and life tables. J R Stat Soc (B) 34: 187-220, 1972 19. Efron B: Bootstrap methods: Another look at the jackknife. Ann Stat 7: 1-26, 1979 20. Sauerbrei W, Schumacher M: A bootstrap resampling procedure for model building: Application to the Cox regression model. Stat Med 11: 2093-2109, 1992[Medline] 21. Karim AB, Maat B, Hatlevoll R, et al: A randomized trial on dose-response in radiation therapy of low-grade cerebral glioma: EORTC Study 22844. Int J Radiat Oncol Biol Phys 36: 549-556, 1996[CrossRef][Medline] 22. Hammack J, Shaw E, Ivnik R, et al: Neurocognitive function in patients receiving radiation therapy for supratentorial low-grade glioma: A North Central Cancer Treatment Group prospective study. Proc Am Soc Clin Oncol 14: 151, 1995 (abstr 299)
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Cairncross G, MacDonald D, Ludwins S, et al: Chemotherapy for anaplastic oligodendroglioma. J Clin Oncol 12: 2013-2021, 1994 24. Buckner JC, Smith JS, Nelson DF, et al: Phase II trial of procarbazine, CCNU, and vincristine (PCV) as initial therapy in patients with low-grade oligodendroglioma or oligoastrocytoma: Efficacy results and associations with 1p and 19q loss. Proc Am Soc Clin Oncol 18: 140a, 1999 (abstr 536)
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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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ABSTRACT
INTRODUCTION
40 years), preoperative tumor diameter as measured from the preoperative computed tomography (CT) or magnetic resonance imaging (MRI) scan (< 5 cm v 
2 tests (for unordered variables) were used to compare their distributions. For continuous variables, Wilcoxon tests were used to compare the distributions between subsets of patients who were classified by categorical data (eg, treatment arm, sex). Also, for several continuous variables, categorical variables were defined to create scientifically appropriate groups (eg, MMSE < 28, 
