As recurrences are largely local and in field following surgery and radiation, there have been several studies exploring the role of dose-escalation to improve tumor control. Unfortunately, these studies have failed to demonstrate improvement in outcome with the use of higher doses of radiotherapy for low-grade gliomas.
The two radiation doses were 45 Gy in 25 fractions delivered within 6 weeks or Radiotherapy techniques were variable and included simple two-field treatment to multifield treatments encompassing the enhancing tumor and nonenhancing tumor with margins.
In this patient population treated with postoperative radiotherapy, prognostic factors associated with better OS and PFS on multivariable analysis included smaller tumor volume, gross total resection and neurological status.
Age under 40 years was also associated with better survival, as shown in other studies regardless of the management approach. The radiation in the high-dose arm incorporated a lower dose to a larger volume with margin around the tumor with a conformal boost directed to the pre-operative tumor to the total dose of But dose-escalation up to Similarly, small studies exploring the role of altered fractionation schemes have not demonstrated greater survival outcomes than conventional radiotherapy.
There was a Phase II study investigating the efficacy and toxicity of hyperfractionated radiation dose-escalation in 37 adult patients with incompletely resected supratentorial low-grade gliomas. The hyperfractionated radiation regimen was composed of several phases with shrinking volumes such that the tumor plus 2 cm margin was treated with 55 Gy in 50 fractions delivered in 25 treatment days over 5 weeks, then the tumor plus 1 cm margin was treated with an additional At the time of publication, median survival time and median time to tumor progression had not yet been reached.
Studies of radiotherapy for low-grade glioma have used variable target volumes with variable margins intended to treat microscopic disease in the peritumoral region.
Definition of the target volume has varied from the pre-operative tumor volume to the postoperative surgical bed along with residual tumor, and it is our personal recommendation that the latter be utilized. Although low-grade gliomas are not expected to grow within weeks of surgery, the timing of image acquisition for radiotherapy planning may impact the radiotherapy treatment, as there can be substantial changes in the surgical cavity during the early postoperative period, and for this reason we recommend postoperative MRI images be obtained at the time of treatment planning.
Patients are typically immobilized in a thermoplastic mask, which they wear for the CT simulation and daily treatments. In general the target volume includes the surgical cavity and any visible residual tumor, which appears hyperintense on the FLAIR images along with a margin to encompass the region most likely to contain further microscopic tumor Figure 1.
Using the available image sets, organs at risk OARs are delineated and dose thresholds are respected during the planning process. These OARs include but are not limited to the lenses, orbits, optic nerves and chiasm, brainstem, cochlea, lacrimal glands and parotid glands. A Representative image of a radiotherapy plan delivering 50 Gy in 25 fractions to a large bifrontal oligodendroglioma.
Gross tumor volume is in red, clinical target volume in green and planning target volume in blue. B Representative images of the tumor at the time of radiotherapy and 4 months postradiotherapy. Most radiotherapy centers currently use 3D-conformal or intensity modulated radiotherapy IMRT techniques for the treatment of low-grade gliomas Figure 1. If available, centers may use cone-beam CT to guide online correction and ensure that any displacements in patient positioning are within 2 mm, prior to treatment delivery.
Although practice has evolved in most centers to exploit the readily available technology, there is no prospective data to show that advanced imaging and treatment techniques have survival impact.
Several studies have reported both the benefit and toxicity associated with the use of protons and carbon ions to treat low-grade gliomas. Fitzek et al. Median age at diagnosis was Tumor recurrence was the cause of death in three of seven patients with grade 2 tumors and eight of 13 patients with grade 3 tumors.
The incidence of radionecrosis was remarkably high with evidence of radionecrosis in two of seven patients with grade 2 tumors and four of 13 patients with grade 3 tumors of which one patient likely died from radionecrosis [ 14 ]. Fourteen patients with diffuse astrocytoma were treated with two doses of carbon ion radiotherapy, either a lower dose of There were nine patients enrolled at the lower dose but seven patients received the entire dose of Five patients were enrolled and received the total higher dose of As none of the patients developed grade 3 or higher acute or late reactions, it was concluded that toxicities were acceptable with this treatment.
These findings provide early provocative data to raise the question of whether high-dose carbon ion radiotherapy may lead to better PFS and OS, although this experience must be interpreted with caution in view of the small patient numbers.
Adding chemotherapy to radiotherapy for patients with low-grade glioma has so far resulted in modest benefits, observed in prior trials that largely evaluated nitrosurea-based chemotherapy [ 16 , 17 ]. However, the combination of chemotherapy with radiotherapy had failed to demonstrate significant survival benefit over radiotherapy alone for grade 2 or 3 glioma in any prospective randomized trial until recently.
This trial failed to show a significant survival advantage in the PCV arm, although the trend was toward improved survival with PCV hazard ratio 0. The RTOG study randomized patients to dose-intense PCV followed by radiotherapy versus radiotherapy alone and did not result in significantly better OS with median survival of 4. After a median follow-up of 5. It was also noted that the separation of the survival curves for both PFS and OS only presented after 2 years of follow-up suggesting that there is a delayed benefit with PCV, and a larger OS benefit is anticipated with longer follow-up.
Although many of the more recent studies have emphasized investigation with PCV in combination with RT, a retrospective study reviewing the outcomes of several prior RTOG trial regimens demonstrated no difference in survival outcome between BCNU and PCV in combination with RT in patients with anaplastic astrocytomas [ 23 ].
Therefore, both PCV and BCNU likely have a favorable impact but one chemotherapy regimen is not likely superior to the other when used in combination with radiotherapy. PFS, toxicities, cognition, and quality of life were also compared. Anticonvulsants, antiemetics, and corticosteroids were prescribed as needed for symptom control. The status of chromosomes 1p and 19q was assessed by fluorescence in situ hybridization.
Baseline evaluations included blood counts, pulmonary and biochemistry screening, MRI or computed tomography CT , neurologic assessment, and mini-mental status examination MMSE. During RT, patients were reviewed weekly. Follow-up MRI or CT scans were performed before each cycle and 4 to 6 weeks after RT; thereafter, scans were done at increasing intervals, and after 5 years, annually, or as needed.
Progression was defined using standard criteria. Survival was analyzed by the Kaplan-Meier method with two-sided log-rank statistics. OS was the time from randomization to death from any cause, and PFS was the time from randomization to progression or death. Only case-eligible results are presented. Cox proportional hazards models were fitted to adjust for stratification factors and confounding clinical and chromosomal variables. Likelihood ratio tests were performed to determine the increase in predictive ability of a given model after inclusion of chromosomal status and its interaction with treatment.
All P values are two-tailed and have not been adjusted for multiple comparisons. The median duration of follow-up was For the entire cohort, long-term follow-up revealed that PCV plus RT did not prolong the median survival time, which was 4. Baseline clinical features and treatment were evaluated in Cox proportional hazards models of OS. The likelihood ratio test for the interaction of treatment with codeletion status was not statistically significant, however. Kaplan-Meier estimates of overall survival by treatment group.
In data not shown, IDH status, an important prognostic factor, 2 was balanced between the arms. Kaplan-Meier estimates of overall survival by genotype for procarbazine, lomustine, and vincristine plus radiotherapy arm. Kaplan-Meier estimates of overall survival by genotype for radiotherapy arm. The median survival was The median PFS was 8. For patients with noncodeleted tumors, there were no median survival differences.
Their median survival was 2. Clinical features and therapy were evaluated in Cox models of OS. For patients with noncodeleted tumors, treatment was not statistically significant in the Cox model. Patients who were randomly assigned to PCV plus RT had more acute toxicities; the most frequent and serious toxicities were myelosuppression, cognitive or mood change, peripheral or autonomic neuropathy, vomiting, hepatic dysfunction, and allergic rash.
Serious immediate toxicities related to RT were uncommon, as were serious late toxicities. No instances of leukemia, severe dementia, or radionecrosis have been reported in either treatment arm. Different treatments were prescribed at progression, including surgery, reirradiation, PCV, temozolomide, and investigational therapies. Two aspects of RTOG , dose-intense and pre-RT chemotherapy, were unusual at the time in brain cancer trials, but reflected schools of thought that were prevalent in oncology in the early s when RTOG began: better tumor control with higher drug doses, therapeutic synergy when drugs accompany RT, and better drug delivery to nonirradiated tumors.
Although the idea of dose-intensity has faded, the goal of combining traditional chemotherapeutics and targeted agents optimally with radiation treatment remains an important therapeutic concept. This interpretation is made cautiously, however, because RTOG was not powered for a subgroup analysis, and retrospective stratification by codeletion status was also unplanned.
When RTOG was planned, molecular heterogeneity, interactions with therapy, and consequences for clinical trials were not considered in designing randomized studies. This knowledge is now incorporated into clinical trial design.
Perhaps temozolomide plus RT, as prescribed for GBM, 10 will be a more acceptable if untested new standard. This is important because studies, like RTOG , that take 20 years to complete are impractical. First, the survival curves for patients with codeleted tumors did not diverge for 5 years, long after RT with or without PCV, suggesting that not all patients with codeleted tumors benefited equally from PCV plus RT, or that some were effectively treated with salvage therapy at progression.
Whether this reflects errors in codeletion testing and incorrect assignment, benefit from PCV plus RT in the absence of visible codeletion, or other factors is unknown at this time.
How do we interpret such findings, and how do they guide care and research? Indeed, such was the experience in GBM, where O6-methyguanine-DNA methyltransferase promoter methylation status did not emerge as a predictive clinical test, especially because it failed to identify all patients with GBM who would have longer survival after temozolomide plus RT. We thank the patients who participated in this multiyear clinical trial and their families. We also thank the late Bernd Scheithauer, MD, who was the central pathologist.
Kaplan-Meier estimates of progression-free survival by treatment group. Kaplain-Meier estimates of progression-free survival by genotype for procarbazine, lomustine, and vincristine plus radiotherapy arm. HR, hazard ratio. See accompanying editorial on page and article on page The contents of this article are the sole responsibility of the authors and do not necessarily represent the views of the National Cancer Institute or Canadian Cancer Society.
Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article. Conception and design: Gregory Cairncross, Edward Shaw. Layout table for investigator information Study Chair: J.
More Information. Cognition and quality of life after chemotherapy plus radiotherapy RT vs. RT for pure and mixed anaplastic oligodendrogliomas: radiation therapy oncology group trial Epub Sep Anaplastic oligodendroglial tumors: refining the correlation among histopathology, 1p 19q deletion and clinical outcome in Intergroup Radiation Therapy Oncology Group Trial Brain Pathol.
Epub Mar Phase III trial of chemotherapy plus radiotherapy compared with radiotherapy alone for pure and mixed anaplastic oligodendroglioma: Intergroup Radiation Therapy Oncology Group Trial J Clin Oncol. Pilot evaluation of 1p and 19q deletions in anaplastic oligodendrogliomas collected by a national cooperative cancer treatment group. Am J Clin Oncol. Epub Oct National Library of Medicine U.
National Institutes of Health U. Department of Health and Human Services. The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Brain and Central Nervous System Tumors. Drug: lomustine Drug: procarbazine hydrochloride Drug: vincristine sulfate Radiation: radiation therapy.
Phase 3. Study Type :. Interventional Clinical Trial. Actual Enrollment :. Actual Study Start Date :. Actual Primary Completion Date :.
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