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Conformal irradiation for pure and mixed oligodendroglioma: The experience of Centre Leon Berard Lyon
Int. J. Radiation Oncology Biol. Phys., Vol. 56, No. 1, pp. 296 –303, 2003 Copyright © 2003 Elsevier Inc. Printed in the USA. All rights reserved 0360-3016/03/$–see front matter
doi:10.1016/S0360-3016(03)00089-0
3D-CRT
CONFORMAL IRRADIATION FOR PURE AND MIXED OLIGODENDROGLIOMA: THE EXPERIENCE OF CENTRE LEON BERARD LYON M. P. SUNYACH, M.D.,* P. POMMIER, M.D.,* I. MARTEL LAFAY, M.D.,* J. GUYOTAT, M.D., PH.D.,† G. GINESTET,* E. JOUANNEAU, M.D.,† A. JOUVET, M.D., PH.D.,‡ M. SINDOU, M.D., PH.D.,† P. BRET, M.D.,† C. CARRIE, M.D.,* AND D. FRAPPAZ, M.D.* *Department of Radiotherapy, Centre Leon Berard, Lyon, France; Departments of †Neurosurgery and ‡Neuropathology, Hoˆpital Wertheimer, Lyon, France Purpose: To assess whether conformal radiotherapy (CRT) after incomplete surgery or biopsy for pure oligodendrogliomas and mixed gliomas results in decreased long-term sequelae without impairing local control and while reducing irradiated volume. Materials and Methods: Twenty-six consecutive patients who presented with pure (21) or mixed (5) oligodendrogliomas and who were given incomplete resections were treated according 3 different strategies: CRT alone (12), chemotherapy followed by CRT (4), and chemotherapy and delayed CRT at the time of tumor progression (10). CRT consisted of multiple noncoplanar fields. Median dose was 60 Gy. Quality of CRT was assessed using tumor and normal tissue conformal indexes. The location of recurrences was assessed with MRI and dosimetric data. Late sequelae were assessed by a questionnaire exploring professional outcome, and also by a Mini Mental State Examination test. Results: The mean overall survival was 5.2 years. Fifteen patients experienced a local relapse. All but 1 occurred in the 95% isodose. Among 11 nonevolutive patients, 6 have a full-time or part-time job. Conclusion: Despite CRT, infield recurrence was a common feature in patients with oligodendrogliomas and mixed tumors. Further research, including molecular biology typing of tumors and type of treatment, is warranted to improve survival and quality of life. © 2003 Elsevier Inc. Gliomas, Oligodendrogliomas, Conformal, Radiotherapy.
Oligodendrogliomas are rare glial tumors, although their prevalence may probably be underestimated. According to Coons et al. (1) and Daumas-Duport et al. (2), the proportion of oligodendrogliomas may represent as much as 25– 33% of glial tumors. Recognizing an oligodendroglial tumor is of utmost importance, because it is widely published that they frequently show sensitivity to chemotherapy at diagnosis (3, 4) and even at the time of recurrence (5–7). This is especially true when a 1p 19 q deletion is found by molecular biology (8). Survival of patients with oligodendrogliomas or mixed tumors is significantly higher compared with survival of patients with pure high-grade astrocytomas. In a review of RTOG 83– 02, Donahue et al. reported a median survival of patients with oligodendrogliomas or mixed tumors of 7.3 years compared with a median survival of 3.4 years for pure anaplastic astrocytomas (9). Leighton et al. reviewed the
records of patients with supratentorial low-grade fibrillary astrocytoma, oligodendroglioma, and mixed glioma treated at a regional cancer center in Canada between 1979 and 1995. Overall and progression-free survivals were longer for patients with an oligodendroglioma or mixed glioma than with astrocytoma (median 13 vs. 7.5 years, p ⫽ 0.003; median progression-free 5.6 vs. 4.4 years) (10). There is no clear demonstration in the current literature that frontline radiotherapy is always effective in improving survival in the subgroup of oligodendrogliomas. For lowgrade gliomas treated with frontline radiotherapy, randomized prospective trials by European Organization for Research and Treatment of Cancer (EORTC) (11) and by Mayo/North Central Cancer Treatment Group (12) demonstrated that low doses (range: 45–50.4 Gy) were as effective as higher doses (range: 59.4 – 64.8 Gy), but it is important to note that in these studies, oligodendrogliomas were not segregated from astrocytomas. An EORTC randomized trial
Reprint requests to: Dr. Sunyach, Radiotherapy Department, Centre Leon Berard, 28 rue Laennec, 69373, Lyon, France. E-mail: [email protected] Presented at the 3rd S. Takahashi Memorial International Work-
shop on 3-Dimensional Conformal Radiotherapy, December 8 –10, 2001, Nagoya, Japan. Received Feb 18, 2002, and in revised form Sep 28, 2002. Accepted for publication Oct 11, 2002.
INTRODUCTION
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(13) showed no overall difference in 5-year survival when comparing postoperative irradiation of 54 Gy with observation in low-grade gliomas. However, immediate vs. delayed radiation did significantly prolong the 5-year progressionfree survival (44% vs. 37%, p ⫽ 0.02). Oligodendrogliomas were not segregated from astrocytomas in this study. In contrast, it is demonstrated that radiotherapy prolongs the overall survival in high-grade gliomas. Randomized study comparing radiation with best supportive care after surgery and radiation combined to chemotherapy, to chemotherapy alone in high-grade glioma, confirmed a modest overall survival improvement with radiotherapy (14, 15). But here again, these studies included high-grade oligodendrogliomas and other high-grade gliomas. When the subgroup of oligodendrogliomas is specifically analyzed, some studies confirm the improved survival with the use of radiotherapy (16, 17), whereas others do not (18, 19). All those series are retrospective. To date, no randomized study has assessed the role of radiotherapy in treating oligodendrogliomas. Prolonged survival is possible for at least some patients treated for oligodendrogliomas. The 5-year overall survival rate ranged from 55% to 83%, and the 10-year survival rate ranged from 29% to 46% in a series of oligodendrogliomas treated with surgery and radiotherapy (16 –19). When longterm survival is achieved, neurocognitive sequelae of radiotherapy may be detected, and their consequences on quality of life may become a major handicap. Conformal radiotherapy is supposed to be a tool to decrease late toxicity, because its aim is to spare normal tissue while focusing on tumoral tissues; however, controversy exists regarding the definition of the target. The optimal protocol of radiotherapy is not well established. This may be crucial for a disease in which prolonged survival may be expected. Conformational radiotherapy has been available at Centre Leon Berard since 1995 and has been used to treat all oligodendrogliomas and Grade 2 or 3 mixed tumors. In this report, we present our experience at Centre Leon Berard with pure and mixed oligodendrogliomas using this technique.
PATIENTS AND METHODS Between January 1996 and January 2001, 26 patients (16 men and 10 women) were treated with conformal radiotherapy for oligodendrogliomas at Centre Leon Berard, Lyon. The median age was 43 years (range: 19 – 63 years). All patients had a median Karnofsky index performance status of 90 (range: 60 –100). The tumor involved frontal lobe (10 patients), temporal lobe (3 patients), parietal lobe (10 patients), occipital lobe (2 patients), and thalamus (1 patient). Initial symptoms were seizures only (8 patients), headache only (1 patient), and seizures and headache (2 patients); focal symptoms were motor deficits and/or visual impairment and/or aphasia (15 patients). The extent of the tumor was assessed before radiotherapy by enhanced computer-
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ized tomography scan (3 patients) and MRI (23 patients). Twenty-two patients presented a contrast enhancement. Pathologic diagnosis and grading were established by one expert neuropathologist (A.J.). Twenty-one patients presented with pure oligodendrogliomas and 5 with mixed tumor. Among 21 patients with pure oligodendrogliomas, 15 had a Grade 3, and 6 had a Grade 2 according to the WHO classification. Out of the 5 patients with mixed oligoastrocytomas, 2 were Grade 2, and 3 were Grade 3 according to the WHO classification (20). Treatment Eleven patients had a biopsy, and 15 had a partial removal at the time of the initial surgery. Six patients had been previously treated with serial complete removal without immediate adjuvant therapy. Twelve patients received first-line chemotherapy (procarbazine CCNU vincristine: PCV) immediately followed by conformal radiotherapy (Group 1), 10 patients were treated by conformal radiotherapy at the time of relapse after chemotherapy (Group 2), and 4 patients underwent exclusive conformal irradiation (Group 3). Radiotherapy Dose delivered was 54 – 64 Gy (median dose: 60 Gy). Radiation was given with 2 Gy per fraction, 5 fractions per week. Irradiation was delivered with an Elekta linear accelerator with multileaf collimator. X-rays of 6 to 10 MeV were used. Patients were immobilized in the supine position in a thermoplastic face mask. The immobilization on the table was obtained with a carbon mask holder, which does not disturb the dose repartition. Unenhanced planning scans were performed with 5-mm slices from the top to the lower part of the brain. For gross target volume (GTV), only tumor (T1 sequence on MRI or, for 3 patients, hypodensity on CT scanning) was taken into account; edema was excluded (T2 sequence on MRI). Target volume was not limited to the contrast enhancement. When radiotherapy was delivered after chemotherapy (Group 1: 12 patients), the irradiated volume was the postchemotherapy volume. A merged image was obtained for the last 3 patients. The technique became available at the Center in January 2000. A 0.5–1-cm safety margin was added to the GTV for a clinical target volume (CTV), except for 4 patients with evolutive disease after chemotherapy, for whom a 1.5- or 2-cm margin was chosen. A 3-mm setup margin was added to the CTV for the planning target volume (PTV). The dose to the chiasma, the optic nerve, and the brainstem was limited to 54 Gy (even if the treated volume had to be decreased at this site). Multiple isocentric, noncoplanar paired fields (median: 8 fields) were used to deliver homogenous high doses to the PTV, sparing the normal brain. Dose–volume histograms were performed for the tumor and normal brain. The tumor volume conformity index, TCI, normal tissue (brain) conformity index, NTCI, and global conformality index, GCI, were calculated as follows:
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Fig. 1. Overall survival.
95% TCI ⫽ PTV volume in the 95% isodose/PTV volume 95% NTCI ⫽ PTV volume in the 95% isodose/ 95% isodose volume 95% GCI ⫽ 95% TCI ⫻ 95% NTCI 1/ 2 Normal tissue complication probability (21) was calculated. All irradiation fields were controlled at the initiation of treatment. Two orthogonal port films were performed every week to check the position of the isocenter. Follow-up by clinical examination and MRI was performed every 3 months the first year and every 6 months afterward. At the time of analysis, target volume was reviewed with preradiotherapy MRI or scan when available. For the patients who recurred, the initial target volume and site of recurrence were reviewed with preradiotherapy MRI or scanner and MRI at the time of recurrence. The site of recurrence was compared to dosimetric data to determine whether the recurrence occurred in the 95% isodose or outside the treated volume. Control port films were reviewed for the patients who recurred to assess the quality of repositioning. A Mini Mental Test was sent through the mail to the 11 patients who were disease free at the time of analysis. They were advised to either fill out the questionnaire with a proxy or to return to Centre Leon Berard for an interview. Statistics Overall and disease-free survival rates were calculated using the Kaplan-Meier method. Survival was calculated
from the end of radiotherapy even for patients treated with frontline chemotherapy. RESULTS With a median follow-up of 65 months, the mean overall survival rate was 5.2 years. Five-year overall survival was 63.4% (Fig. 1) . Forty-seven percent of patients were alive and disease free 5 years after the end of radiotherapy (Fig. 2). At the last follow-up, 16 patients were alive (11 without disease, 5 with progressive disease), and 10 patients died from tumor progression. In Group 1, 4 out of the 12 patients (chemotherapy followed by conformal radiotherapy) relapsed. Among the 4 patients in Group 2 (exclusive radiotherapy), 2 recurred. Among the 10 patients treated with radiotherapy at the time of recurrence (Group 3), only 1 is disease free 18 months after irradiation; 9 patients recurred. Two out of 5 patients presenting with a mixed tumor recurred. Three out of 6 patients presenting with a pure Grade 2 oligodendroglioma recurred, and 10 out of 15 presenting with a Grade 3 pure oligodendroglioma relapsed. Fifteen patients presented a Karnofsky index of 90 to 100, and of these, 8 recurred, whereas 7/11 recurred when the initial Karnofsky index was less than 80. One out of 3 patients who received a dose of radiotherapy less than 60 Gy (range: 54 –56 Gy) recurred. Fourteen out of 23 patients recurred when the dose was 60 Gy or more. Analysis of site of recurrence shows that 14 patients recurred in the 95% isodose (12 in the field, and 2 at its border), and 1 patient presented 2 recurrences in the 90% and 80% isodoses. For this patient, the treated volume had to be decreased because of chiasma. Analysis of port films controlled for patients who presented recurrent disease did not show any deviation that could explain the recurrence.
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Fig. 2. Disease-free survival.
Dosimetric results CT scan performed for dosimetries were printed, so analysis of site of recurrence was available for all 26 patients. However, dosimetric analysis was performed for 15 patients, because of loss of the dosimetric data for the 11 first patients treated initially, because of modifications of the dosimetric system. Normal tissue conformity index was 0.4 – 0.94 (mean: 0.92), tumor conformity index was 0.87–1 (mean: 0.82), and global conformity index was 0.66 – 0.91 (mean: 0.86). Clinical results and dosimetric data for all patients are
reported in Table 1.The patient with normal tissue conformity index 0.4 had a very small target volume. Social adaptation and analysis of late toxicities Eleven patients are alive without disease at the last follow-up and have received no further treatment after radiotherapy. Four of them have a full-time job, and 2 have a part-time job. In contrast, 2 patients required considerable assistance (Karnofsky 60 –50), and another 3 patients did not require assistance but were unable to work (Karnofsky 80)—1 because of blindness present before irradiation and 1
Table 1. Results of dosimetrics
Patients
Dose (Gy)
Volume of isodose 95% (cc)
1 2 3 4 5
60 64 60 60 50 ⫹ 10
198 74 123 135 –
29,7 30,7 23,3 34,5 65,6
0.91 0.94 0.93 0.92 –
0.88 0.4 0.86 0.81 –
0.90 0.66 0.90 0.86 –
0.95 0.77 0.36 – 5.53
6 7 8 9 10 11 13 14 15 12
56 54 60 60 60 60 60 60 60 60
205 281 472 315 142 – 516 357 454 –
35,6 36,0 63,20 59,14 39,4 37,4 75,22 61,11 68,15 47,9
0.94 0.91 0.87 1 0.88 – 0.96 0.93 0.87 –
0.89 0.88 0.88 0.73 0.94 – 0.85 0.66 0.83 –
0.91 0.90 0.88 0.85 0.91 – 0.90 0.78 0.85 –
1.44 0.8 10.22 4.77 1.31 –2.58 13.87 6.22 9.03 3.03
V30 (5) V60 (%)
TCI 95%
NTCI 95%
GCI 95%
NTCP 95%
Evolution Recurrence isodose 95% Disease free Disease free Death evolutive disease Recurrence isodose 90% ⫹ second loc 80% Evolutive disease isodose 95% Disease free Dependent disease free Recurrence isodose 95% Evolutive disease Disease free Evolutive disease Evolutive disease Disease free Disease free
Abbreviations: TCI ⫽ tumor conformity index; NICI ⫽ normal tissue conformity index; GCI ⫽ global conformity index; NTCP ⫽ normal tissue complication probability.
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Table 2. Results for the 8 patients who performed MMSE test Age at the time of RT 50 30 19 49 26 49 39 39
years years years years years years years years
Volume of V95
Total dose
V30; V60
60 60 60 60 60 60 60 60
68%; 15% 47%; 9% 30%; 7% 23%; 11%
454 cc
39%; 4%,
142 cc
74 cc 114 cc
63%; 20%
because of seizures; the last one started working after treatment, but stopped after 4 years because of fatigue. No radionecrosis was observed during the follow-up Mini Mental Test has been proposed for the 11 patients who were disease free at the last follow-up. Two patients were unable to answer the questionnaire. One of them needed a ventricular derivation for late radiation-induced toxicity. One patient refused to perform the test. Results for the 8 patients are reported in Table 2. Patients with a long follow-up show bad performance on the Mini Mental State Examination (MMSE) test (mean: 27, range: 20 – 30). One patient treated when he was 19 years old had limited irradiated volume but tumor located in the temporal region. His result on the MMSE test shows high impairment in cognitive function. DISCUSSION We report our experience with conformal radiotherapy in the treatment of oligodendroglioma or oligoastrocytoma. Therapeutic strategies have changed dramatically during the last decade, so 20 patients received radiotherapy as adjuvant treatment, and 6 received radiotherapy as second-line treatment. Overall survival at 5 years after radiotherapy is 63%, and 5-year disease-free survival is 47%. These results are consistent with other reports in the literature. Five-year overall survival rate ranges from 55% to 83%, and 10-year survival ranges from 29% to 49% in a series of oligodendrogliomas treated with surgery and radiotherapy (16 –19, 22). Celli et al. suggested that the benefit for radiation exists, but probably not for all patients (23). They reported in a series of 137 oligodendrogliomas a significantly better survival with exclusive radiation therapy in multivariate analysis, except in the subgroup of patients with histories of seizures, who were neurologically healthy at diagnosis. Bad performance status (19), high-grade subtype (16, 18), and hemiparesis (16) have been reported as poor prognostic factors. There remains considerable heterogeneity in clinical outcomes among patients with oligodendrogliomas. Molecular markers have now been shown to have prognostic value in the case of oligodendrogliomas. Tumors with chromosome loss of 1p have better response to chemotherapy (24), better response to radiotherapy (25), and longer survival (23).
1.5 6 7 3 7 3 7 2
years years years years years years years years
NTCP
Localization
Results of MMES test
9%
Perietal Frontal Temporal Occipital Parietal Frontal Frontal Frontal
27 28 23 27 22 30 20 24
0.77 0.36 1.31 10
After radiotherapy, the median progression-free survival was 55 months for patients who harbored allelic loss of chromosome 1p vs. 6.2 months for those who did not (p ⬎ 0.001). Those with loss of 1p and 19 q have particularly favorable outcomes (26). Ino et al. suggested the presence of four relevant groups of histologically defined anaplastic oligodendrogliomas (27). Radiation protocols and timing of irradiation will have to be adapted to such prognostic factors in the future. For patients with low-grade glioma, timing of radiotherapy may not be important. Leighton et al. (28). retrospectively reported the experience of a regional cancer center in Canada between 1979 and 1995. In their experience, radiotherapy deferred until tumor progression vs. immediate radiotherapy was associated with longer survival on univariate analysis. However, patients with the worse prognostic factors were more likely to be treated with radiotherapy. EORTC randomized trial (13) showed no overall difference in 5-year survival comparing postoperative irradiation of 54 Gy with observation in low-grade gliomas. However, immediate vs. delayed radiation did significantly prolong the 5-year progression-free survival (44% vs. 37%, p ⫽ 0.02). In these studies, oligodendrogliomas were not segregated from astrocytomas. Though dramatic advances have occurred in chemotherapy (3– 6) over the past decade, radiotherapy still plays an important role in the treatment of oligodendrogliomas. But according to several authors (29, 30), radiotherapy may be delayed and administered at the time of recurrence. Our experience was reported at the ASTRO meeting in 2001 (31): 116 patients were treated in our department between 1982 and 1999 with chemotherapy or radiotherapy after complete surgery or biopsy for oligodendroglioma or mixed tumor. Delay before further treatment is significantly longer after radiotherapy: 52 months after exclusive radiotherapy, 23 months after exclusive chemotherapy, and 37 months after chemotherapy followed by radiotherapy (p ⫽ 0.0001), but no significant difference was found for overall survival. This suggests that disease-free survival is shorter when radiotherapy is not delivered as first-line treatment, but that deleterious effects of radiotherapy may be postponed without decreasing survival rate. The target volume is an important parameter that impacts on treatment outcome. Decreasing the irradiated volume may induce an increase of local recurrence, because of the
Conformal RT in oligodendrogliomas
infiltrative nature of primary brain tumor. Pu et al. (32) reported a series of 46 low-grade gliomas treated with conformal radiotherapy. The GTV was defined as T2 volume if MRI was available or area of enhancement or if absent low attenuation on CT. CTV was equal to GTV, plus a 1–3 cm margin. After 45 to 50 Gy, margins were reduced to 0 –2 cm. All 11 recurrences occurred in the boost region. Rudoler et al. (33) reviewed 30 patients with low-grade gliomas treated this partial brain fields encompassing tumor plus edema and a more than 2-cm margin. Fifty-three patients recurred. All recurrences were located in fields. Mansur et al. (34) reported results of 28 patients treated with limited-field irradiation encompassing the tumor bed and a 2-cm margin; 46% of patients relapsed. All recurrences were in the initial treated volume. In our series, 15 patients among the 26 presented a local evolution. Fourteen recurrences were localized within the 95% isodose, but 2 patients presented a recurrence in the limit of fields. Another patient presented a recurrence in the 80% and 90% isodose, but for this patient, the chiasmatic region was protected, and relapse occurred at this site. Thus, limiting the GTV to the tumor as defined on the T1 sequence of MRI does not seem to downgrade the rate of local control. The question of target volume after chemotherapy is a matter of debate. Among the 11 patients treated with chemotherapy followed by conformational radiotherapy delivered to the postchemotherapy volume, there were 4 relapses, all of which occurred in the 95% isodose. Considering residual volume as target volume did not seem to increase the failure rate. In the present study, high conformal irradiation, assessed with conformal indexes for PTV and normal tissues, was achieved. Median tumor conformity index was 0.82. Late neurocognitive defects in patients who have received radiation therapy to the central nervous system are well documented (35). Clinical syndrome of white matter injury may occur as a consequence of therapeutic irradiation. White matter injury includes nonspecific symptoms: personality changes, deficits in intelligence, or dementia. In contrast, brain necrosis symptoms include motor or sensitive deficits. In the series reported by Olson et al. (36), radiation necrosis, diagnosed in 9 patients (15%), occurred in a median time of 52 months after radiotherapy for lowgrade gliomas. Delayed cognitive impairment due to radiotherapy was noted in 13 patients, and 6 required ventriculoperitoneal derivation. Curran et al. (37) reported the results of quality of life in the EORTC trial comparing low vs. high dose of radiotherapy in low-grade glioma. Patients receiving higher doses reported lower levels of functioning. Kleinberg et al. (38) measured the employment history and memory function 1 year after treatment of 30 gliomas surviving more than 1 year. Memory deficits occurred in 43% of patients receiving whole-brain irradiation vs. 6% of patients receiving partial-brain irradiation 1 year after treatment. Surma-Aho et al. (39) compared a group of 28 patients with low-grade glioma treated with radiotherapy who were still alive 7 years after treatment and 59 patients with
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low-grade glioma not treated with radiotherapy. The group that had postoperative radiotherapy performed significantly worse than the no-radiotherapy group in a cognitive test. Taphoorn et al. (40) reported the results of neurologic examinations: neuropsychological tests of attention, memory, language, and visiospatial and frontal lobe function. Three groups of about 20 patients were compared: a group of patients with low-grade tumor and localized irradiation of 45 to 63 Gy, a group of patients with low-grade tumor without radiotherapy, and a group of patients with no brain tumor. Neurologic tests after a follow-up of 3.5 years on average were the same in the two low-grade tumor groups. In contrast, Taylor et al. (41) conclude that there is no clear trend toward cognitive worsening after irradiation in a series of 701 highgrade brain tumor patients who received radiotherapy on two consecutive North Central Cancer Treatment Group randomized treatment trials. The number of patients that experienced a greater than 3-point decrease in MMSE from baseline among nonprogressors was 10.5% at 6 months, 5.5% at 12 months, 10% at 18 months, and 4 of 22 and 18.2% at 24 months. In our series, 11 patients were disease free at last follow-up, and 6 of them had a job, 4 full-time and 2 part-time, but 2 patients had severe impairment of neurocognitive function. Even for the 8 patients with quite good social adaptation results on the MMSE, the test assessed an impairment of neurocognitive function with results between 20 and 30 (4 between 20 and 24), which is rather low. Forette et al. consider that if the MMSE score is 23 or less, diagnostic tests for dementia must be performed (42). Studies of volume effects will remain more demanding for the brain than for most other organs, because of the brain’s complex structure. Data on long-term effects after fractionated partial volume irradiation using conformal techniques are rare. Santoni et al. (43) investigated temporal damage in 96 patients treated with high-dose proton or photon for chordoma of the skull base. The volumes greater than 70 cm induce a tendency toward a higher rate of temporal damage. Large amounts of data are required to quantify the dose– volume relationship for various localizations. Clinical symptoms may be the result of radiation late effects or tumor progression. The diagnosis of radionecrosis vs. tumor progression is very difficult to make. The impact of radiation doses on survival has been assessed in high-grade gliomas (44). In low-grade gliomas, an EORTC trial failed to demonstrate a relationship between radiation dose and treatment outcome (11). In our study, the doses were 54 to 64 Gy. The impact of radiation dose has not been already established for highgrade oligodendroglioma. Conformal radiotherapy delivers homogeneous doses to the tumoral tissue, while sparing unaffected parenchyma. Optimal dose is currently a matter of debate.
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CONCLUSION Despite conformal radiotherapy after biopsy or incomplete resection for oligodendroglial tumors, and despite relative high-dose radiotherapy, infield recurrences remain very fre-
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quent and associated with long-term significant neuropsychic toxicity. New perspectives, such as chromosomic studies to select patients, chemoradiotherapy schedules, or conformal and/or radiobiologically efficient radiation, are necessary.
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Confirmation of the value of postoperative irradiation and lack of potentiation of bleomycin on survival time: A prospective multicenter trial of the Scandinavian Glioblastoma Study Group. Cancer 1981;47(4):649–652. Gannett D, Wisbeck W, Silbergeld D, Berger M. The role of post operative irradiation in the treatment of oligodendroglioma. Int J Radiat Oncol Biol Phys 1994;30(3):567–573. Shaw E, Scheithauer B, O’Fallon J, Davis D. Mixed oligodendrogliomas: A survival and prognostic factor analysis. Neurosurgery 1994;34(4):577–582. Nijjar T, Simpson J, Gadalla T, Mc cartney M. Oligodendroglioma. Cancer 1993;71(12):4002–4006. Allam A, Radwi A, El Weshi A, Hassounah M. Oligodendroglioma: An analysis of prognostic factors and treatment results. Am J Clin Oncol 2000;23(2):170–175. Kleihues P, Burger PC, Scheithauer BW. Hystological typing of tumors of the central nervous system, in International Histological Classification of Tumours. Geneva World Health Organisation. 1995. Burman C, Kutcher GJ, Emami B, Goiteein M. PCV chemotherapy for recurrent oligodendrogliomas and oligoastrocytomas. Neurosurgery 1998;43:1066–1073. Henderson KH, Shaw EG. Randomized trials of radiation therapy in adult low grade gliomas. Semin Radiat Oncol 2001;11:145–150. Celli P, Nofrone I, Palma L, Cantore G, Fortuna A. Cerebral oligodendroglioma: Prognostic factors and life history. Neurosurgery 1994;35(6):1018–1025. Cairncross JG, Ueki K, Zlatescu MC, et al. Specific chromosomal losses predict chemotherapeutic response and survival in patients with anaplastic oligodendrogliomas. J Natl Cancer Inst 1998;90:1473–1479. Bauman G, Ino Y, Ueki K, et al. Allelic loss of chromosome 1p and radiotherapy plus chemotherapy in patients with oligodendrogliomas. Int J Radiat Oncol Biol Phys 2000;48:825– 830. Smith JS, Perry A, Borell TJ, et al. Alterations of chromosome arms 1p and 19 q as predictors of survival in oligodendrodriomas astrocytomas and mixed oligodendrodrogliopmas. J Clin Oncol 2000;18:636–645. Ino Y, Betensky RA, Zlatescu M, et al. Molecular subtypes of anaplastic oligodendroglioma: Implications for patient management at diagnosis. Clin Cancer Res 2001;7:839–845. Leighton C, Fisher B, Bauman G, et al. Supratentorial lowgrade glioma in adults: An analysis of prognostic factors and timing of radiation. J Clin Oncol 1997;15(4):1294–1301. Fortin D, Cairncross J, Hammond R. Oligodendroglioma: An appraisal of recent data pertaining to diagnosis and treatment. Neurosurgery 1999;45(6):1279–1291. Streffer J, Schabet M, Bamberg M, et al. A role for preirradiation PCV chemotherapy for oligodendroglial brain tumors. J Neurol 2000;247(4):297–302. Flandin I, Sunyach MP. ASTRO Meeting, 51, supp 1, nov 2001 (Abstract). Pu AT, Sandler HM, Radany EH, Blaivas M, Page MA, Ross DA. Low grade gliomas: Preliminary analysis of failure patterns among patients treated using 3D conformal external beam irradiation. Int J Radiat Oncol Biol Phys 1995;31(3):461– 466. Rudoler S, Cornj BW, Werner-Wasik M, Flanders A, Preston
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PE, Curran WJ. Patterns of tumor progression after radiotherapy for low-grade gliomas. Am J Clin Oncol 1998;21(1):23– 27. Mansur DB, Hekmatpanah J, Wollman R, Macdonald L, Nicholas K, Mundt AJ. Low grade gliomas treated with adjuvant radiation therapy in the modern imaging era. Am J Clin Oncol 2000;23(3):222–226. Crossen JR, Garwood D, Glastein E, Neuwelt EA. Neurobehavioral sequelae of cranial irradiation in adults: A review of radiation-induced encephalopathy. J Clin Oncol 1994;12:627– 642. Olson JD, Riedel E, De Angelis L. Long term outcome of low grade oligodendroglioma and mixed glioma. Neurology 2000; 54:1442–1448. Curran D, Kiebert GM, Aaronson NK. Quality of life after radiation therapy of cerebral low-grade gliomas of the adult: Results of a phase III randomized trial on dose response (EORTC Trial 22844) [Abstract]. Proc ASCO 1998;17:379a. Kleinberg L, Wallner K, Malkin MG. Good performance status of long-term disease-free survivors of intracranial gliomas. Int J Radiat Oncol Biol Phys 1993;26:129–133. Surma-aho O, Niemela¨ M, Vilkki J, Kouri M, Brander A,
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Ja¨ a¨ skela¨ inen J. Adverse long-term effects of brain radiotherapy in adult low-grade glioma patients. Neurology 2001;56: 1285–1290. Taphoorn MJB, Schiphorst AK, Snoek FJ. Cognitive functions and quality of life in patients with low-grade gliomas: The impact of radiotherapy. Ann Neurol 1994;36:48–54. Taylor BV, Buckner JC, Cascino TL, et al. Effects of radiation and chemotherapy on cognitive function in patients with highgrade glioma. J Clin Oncol 1998;16(6):2195–2201. Forette F, Seux ML, Staessen JA, et al. Prevention of dementia in randomised double-blind placebo-controlled Systolic Hypertension in Europe (Syst-Eur) trial. Lancet 1998;352(9137):1347–1351. Santoni R, Liebsch N, Finkelstein DM. Temporal lobe damage following surgery and high-dose photon and proton irradiation in 96 patients affected by chordomas and chondrosarcomas of base of the skull. Int J Radiat Oncol Biol Phys 1998;41:59– 68. Walker MD, Strike TA, Sheline GE. An analysis of dose effect relationship in radiotherapy of malignant gliomas. Int J Radiat Oncol Biol Phys 1979;5:1721–1725.
doi:10.1016/S0360-3016(03)00089-0
3D-CRT
CONFORMAL IRRADIATION FOR PURE AND MIXED OLIGODENDROGLIOMA: THE EXPERIENCE OF CENTRE LEON BERARD LYON M. P. SUNYACH, M.D.,* P. POMMIER, M.D.,* I. MARTEL LAFAY, M.D.,* J. GUYOTAT, M.D., PH.D.,† G. GINESTET,* E. JOUANNEAU, M.D.,† A. JOUVET, M.D., PH.D.,‡ M. SINDOU, M.D., PH.D.,† P. BRET, M.D.,† C. CARRIE, M.D.,* AND D. FRAPPAZ, M.D.* *Department of Radiotherapy, Centre Leon Berard, Lyon, France; Departments of †Neurosurgery and ‡Neuropathology, Hoˆpital Wertheimer, Lyon, France Purpose: To assess whether conformal radiotherapy (CRT) after incomplete surgery or biopsy for pure oligodendrogliomas and mixed gliomas results in decreased long-term sequelae without impairing local control and while reducing irradiated volume. Materials and Methods: Twenty-six consecutive patients who presented with pure (21) or mixed (5) oligodendrogliomas and who were given incomplete resections were treated according 3 different strategies: CRT alone (12), chemotherapy followed by CRT (4), and chemotherapy and delayed CRT at the time of tumor progression (10). CRT consisted of multiple noncoplanar fields. Median dose was 60 Gy. Quality of CRT was assessed using tumor and normal tissue conformal indexes. The location of recurrences was assessed with MRI and dosimetric data. Late sequelae were assessed by a questionnaire exploring professional outcome, and also by a Mini Mental State Examination test. Results: The mean overall survival was 5.2 years. Fifteen patients experienced a local relapse. All but 1 occurred in the 95% isodose. Among 11 nonevolutive patients, 6 have a full-time or part-time job. Conclusion: Despite CRT, infield recurrence was a common feature in patients with oligodendrogliomas and mixed tumors. Further research, including molecular biology typing of tumors and type of treatment, is warranted to improve survival and quality of life. © 2003 Elsevier Inc. Gliomas, Oligodendrogliomas, Conformal, Radiotherapy.
Oligodendrogliomas are rare glial tumors, although their prevalence may probably be underestimated. According to Coons et al. (1) and Daumas-Duport et al. (2), the proportion of oligodendrogliomas may represent as much as 25– 33% of glial tumors. Recognizing an oligodendroglial tumor is of utmost importance, because it is widely published that they frequently show sensitivity to chemotherapy at diagnosis (3, 4) and even at the time of recurrence (5–7). This is especially true when a 1p 19 q deletion is found by molecular biology (8). Survival of patients with oligodendrogliomas or mixed tumors is significantly higher compared with survival of patients with pure high-grade astrocytomas. In a review of RTOG 83– 02, Donahue et al. reported a median survival of patients with oligodendrogliomas or mixed tumors of 7.3 years compared with a median survival of 3.4 years for pure anaplastic astrocytomas (9). Leighton et al. reviewed the
records of patients with supratentorial low-grade fibrillary astrocytoma, oligodendroglioma, and mixed glioma treated at a regional cancer center in Canada between 1979 and 1995. Overall and progression-free survivals were longer for patients with an oligodendroglioma or mixed glioma than with astrocytoma (median 13 vs. 7.5 years, p ⫽ 0.003; median progression-free 5.6 vs. 4.4 years) (10). There is no clear demonstration in the current literature that frontline radiotherapy is always effective in improving survival in the subgroup of oligodendrogliomas. For lowgrade gliomas treated with frontline radiotherapy, randomized prospective trials by European Organization for Research and Treatment of Cancer (EORTC) (11) and by Mayo/North Central Cancer Treatment Group (12) demonstrated that low doses (range: 45–50.4 Gy) were as effective as higher doses (range: 59.4 – 64.8 Gy), but it is important to note that in these studies, oligodendrogliomas were not segregated from astrocytomas. An EORTC randomized trial
Reprint requests to: Dr. Sunyach, Radiotherapy Department, Centre Leon Berard, 28 rue Laennec, 69373, Lyon, France. E-mail: [email protected] Presented at the 3rd S. Takahashi Memorial International Work-
shop on 3-Dimensional Conformal Radiotherapy, December 8 –10, 2001, Nagoya, Japan. Received Feb 18, 2002, and in revised form Sep 28, 2002. Accepted for publication Oct 11, 2002.
INTRODUCTION
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(13) showed no overall difference in 5-year survival when comparing postoperative irradiation of 54 Gy with observation in low-grade gliomas. However, immediate vs. delayed radiation did significantly prolong the 5-year progressionfree survival (44% vs. 37%, p ⫽ 0.02). Oligodendrogliomas were not segregated from astrocytomas in this study. In contrast, it is demonstrated that radiotherapy prolongs the overall survival in high-grade gliomas. Randomized study comparing radiation with best supportive care after surgery and radiation combined to chemotherapy, to chemotherapy alone in high-grade glioma, confirmed a modest overall survival improvement with radiotherapy (14, 15). But here again, these studies included high-grade oligodendrogliomas and other high-grade gliomas. When the subgroup of oligodendrogliomas is specifically analyzed, some studies confirm the improved survival with the use of radiotherapy (16, 17), whereas others do not (18, 19). All those series are retrospective. To date, no randomized study has assessed the role of radiotherapy in treating oligodendrogliomas. Prolonged survival is possible for at least some patients treated for oligodendrogliomas. The 5-year overall survival rate ranged from 55% to 83%, and the 10-year survival rate ranged from 29% to 46% in a series of oligodendrogliomas treated with surgery and radiotherapy (16 –19). When longterm survival is achieved, neurocognitive sequelae of radiotherapy may be detected, and their consequences on quality of life may become a major handicap. Conformal radiotherapy is supposed to be a tool to decrease late toxicity, because its aim is to spare normal tissue while focusing on tumoral tissues; however, controversy exists regarding the definition of the target. The optimal protocol of radiotherapy is not well established. This may be crucial for a disease in which prolonged survival may be expected. Conformational radiotherapy has been available at Centre Leon Berard since 1995 and has been used to treat all oligodendrogliomas and Grade 2 or 3 mixed tumors. In this report, we present our experience at Centre Leon Berard with pure and mixed oligodendrogliomas using this technique.
PATIENTS AND METHODS Between January 1996 and January 2001, 26 patients (16 men and 10 women) were treated with conformal radiotherapy for oligodendrogliomas at Centre Leon Berard, Lyon. The median age was 43 years (range: 19 – 63 years). All patients had a median Karnofsky index performance status of 90 (range: 60 –100). The tumor involved frontal lobe (10 patients), temporal lobe (3 patients), parietal lobe (10 patients), occipital lobe (2 patients), and thalamus (1 patient). Initial symptoms were seizures only (8 patients), headache only (1 patient), and seizures and headache (2 patients); focal symptoms were motor deficits and/or visual impairment and/or aphasia (15 patients). The extent of the tumor was assessed before radiotherapy by enhanced computer-
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ized tomography scan (3 patients) and MRI (23 patients). Twenty-two patients presented a contrast enhancement. Pathologic diagnosis and grading were established by one expert neuropathologist (A.J.). Twenty-one patients presented with pure oligodendrogliomas and 5 with mixed tumor. Among 21 patients with pure oligodendrogliomas, 15 had a Grade 3, and 6 had a Grade 2 according to the WHO classification. Out of the 5 patients with mixed oligoastrocytomas, 2 were Grade 2, and 3 were Grade 3 according to the WHO classification (20). Treatment Eleven patients had a biopsy, and 15 had a partial removal at the time of the initial surgery. Six patients had been previously treated with serial complete removal without immediate adjuvant therapy. Twelve patients received first-line chemotherapy (procarbazine CCNU vincristine: PCV) immediately followed by conformal radiotherapy (Group 1), 10 patients were treated by conformal radiotherapy at the time of relapse after chemotherapy (Group 2), and 4 patients underwent exclusive conformal irradiation (Group 3). Radiotherapy Dose delivered was 54 – 64 Gy (median dose: 60 Gy). Radiation was given with 2 Gy per fraction, 5 fractions per week. Irradiation was delivered with an Elekta linear accelerator with multileaf collimator. X-rays of 6 to 10 MeV were used. Patients were immobilized in the supine position in a thermoplastic face mask. The immobilization on the table was obtained with a carbon mask holder, which does not disturb the dose repartition. Unenhanced planning scans were performed with 5-mm slices from the top to the lower part of the brain. For gross target volume (GTV), only tumor (T1 sequence on MRI or, for 3 patients, hypodensity on CT scanning) was taken into account; edema was excluded (T2 sequence on MRI). Target volume was not limited to the contrast enhancement. When radiotherapy was delivered after chemotherapy (Group 1: 12 patients), the irradiated volume was the postchemotherapy volume. A merged image was obtained for the last 3 patients. The technique became available at the Center in January 2000. A 0.5–1-cm safety margin was added to the GTV for a clinical target volume (CTV), except for 4 patients with evolutive disease after chemotherapy, for whom a 1.5- or 2-cm margin was chosen. A 3-mm setup margin was added to the CTV for the planning target volume (PTV). The dose to the chiasma, the optic nerve, and the brainstem was limited to 54 Gy (even if the treated volume had to be decreased at this site). Multiple isocentric, noncoplanar paired fields (median: 8 fields) were used to deliver homogenous high doses to the PTV, sparing the normal brain. Dose–volume histograms were performed for the tumor and normal brain. The tumor volume conformity index, TCI, normal tissue (brain) conformity index, NTCI, and global conformality index, GCI, were calculated as follows:
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Fig. 1. Overall survival.
95% TCI ⫽ PTV volume in the 95% isodose/PTV volume 95% NTCI ⫽ PTV volume in the 95% isodose/ 95% isodose volume 95% GCI ⫽ 95% TCI ⫻ 95% NTCI 1/ 2 Normal tissue complication probability (21) was calculated. All irradiation fields were controlled at the initiation of treatment. Two orthogonal port films were performed every week to check the position of the isocenter. Follow-up by clinical examination and MRI was performed every 3 months the first year and every 6 months afterward. At the time of analysis, target volume was reviewed with preradiotherapy MRI or scan when available. For the patients who recurred, the initial target volume and site of recurrence were reviewed with preradiotherapy MRI or scanner and MRI at the time of recurrence. The site of recurrence was compared to dosimetric data to determine whether the recurrence occurred in the 95% isodose or outside the treated volume. Control port films were reviewed for the patients who recurred to assess the quality of repositioning. A Mini Mental Test was sent through the mail to the 11 patients who were disease free at the time of analysis. They were advised to either fill out the questionnaire with a proxy or to return to Centre Leon Berard for an interview. Statistics Overall and disease-free survival rates were calculated using the Kaplan-Meier method. Survival was calculated
from the end of radiotherapy even for patients treated with frontline chemotherapy. RESULTS With a median follow-up of 65 months, the mean overall survival rate was 5.2 years. Five-year overall survival was 63.4% (Fig. 1) . Forty-seven percent of patients were alive and disease free 5 years after the end of radiotherapy (Fig. 2). At the last follow-up, 16 patients were alive (11 without disease, 5 with progressive disease), and 10 patients died from tumor progression. In Group 1, 4 out of the 12 patients (chemotherapy followed by conformal radiotherapy) relapsed. Among the 4 patients in Group 2 (exclusive radiotherapy), 2 recurred. Among the 10 patients treated with radiotherapy at the time of recurrence (Group 3), only 1 is disease free 18 months after irradiation; 9 patients recurred. Two out of 5 patients presenting with a mixed tumor recurred. Three out of 6 patients presenting with a pure Grade 2 oligodendroglioma recurred, and 10 out of 15 presenting with a Grade 3 pure oligodendroglioma relapsed. Fifteen patients presented a Karnofsky index of 90 to 100, and of these, 8 recurred, whereas 7/11 recurred when the initial Karnofsky index was less than 80. One out of 3 patients who received a dose of radiotherapy less than 60 Gy (range: 54 –56 Gy) recurred. Fourteen out of 23 patients recurred when the dose was 60 Gy or more. Analysis of site of recurrence shows that 14 patients recurred in the 95% isodose (12 in the field, and 2 at its border), and 1 patient presented 2 recurrences in the 90% and 80% isodoses. For this patient, the treated volume had to be decreased because of chiasma. Analysis of port films controlled for patients who presented recurrent disease did not show any deviation that could explain the recurrence.
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Fig. 2. Disease-free survival.
Dosimetric results CT scan performed for dosimetries were printed, so analysis of site of recurrence was available for all 26 patients. However, dosimetric analysis was performed for 15 patients, because of loss of the dosimetric data for the 11 first patients treated initially, because of modifications of the dosimetric system. Normal tissue conformity index was 0.4 – 0.94 (mean: 0.92), tumor conformity index was 0.87–1 (mean: 0.82), and global conformity index was 0.66 – 0.91 (mean: 0.86). Clinical results and dosimetric data for all patients are
reported in Table 1.The patient with normal tissue conformity index 0.4 had a very small target volume. Social adaptation and analysis of late toxicities Eleven patients are alive without disease at the last follow-up and have received no further treatment after radiotherapy. Four of them have a full-time job, and 2 have a part-time job. In contrast, 2 patients required considerable assistance (Karnofsky 60 –50), and another 3 patients did not require assistance but were unable to work (Karnofsky 80)—1 because of blindness present before irradiation and 1
Table 1. Results of dosimetrics
Patients
Dose (Gy)
Volume of isodose 95% (cc)
1 2 3 4 5
60 64 60 60 50 ⫹ 10
198 74 123 135 –
29,7 30,7 23,3 34,5 65,6
0.91 0.94 0.93 0.92 –
0.88 0.4 0.86 0.81 –
0.90 0.66 0.90 0.86 –
0.95 0.77 0.36 – 5.53
6 7 8 9 10 11 13 14 15 12
56 54 60 60 60 60 60 60 60 60
205 281 472 315 142 – 516 357 454 –
35,6 36,0 63,20 59,14 39,4 37,4 75,22 61,11 68,15 47,9
0.94 0.91 0.87 1 0.88 – 0.96 0.93 0.87 –
0.89 0.88 0.88 0.73 0.94 – 0.85 0.66 0.83 –
0.91 0.90 0.88 0.85 0.91 – 0.90 0.78 0.85 –
1.44 0.8 10.22 4.77 1.31 –2.58 13.87 6.22 9.03 3.03
V30 (5) V60 (%)
TCI 95%
NTCI 95%
GCI 95%
NTCP 95%
Evolution Recurrence isodose 95% Disease free Disease free Death evolutive disease Recurrence isodose 90% ⫹ second loc 80% Evolutive disease isodose 95% Disease free Dependent disease free Recurrence isodose 95% Evolutive disease Disease free Evolutive disease Evolutive disease Disease free Disease free
Abbreviations: TCI ⫽ tumor conformity index; NICI ⫽ normal tissue conformity index; GCI ⫽ global conformity index; NTCP ⫽ normal tissue complication probability.
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Table 2. Results for the 8 patients who performed MMSE test Age at the time of RT 50 30 19 49 26 49 39 39
years years years years years years years years
Volume of V95
Total dose
V30; V60
60 60 60 60 60 60 60 60
68%; 15% 47%; 9% 30%; 7% 23%; 11%
454 cc
39%; 4%,
142 cc
74 cc 114 cc
63%; 20%
because of seizures; the last one started working after treatment, but stopped after 4 years because of fatigue. No radionecrosis was observed during the follow-up Mini Mental Test has been proposed for the 11 patients who were disease free at the last follow-up. Two patients were unable to answer the questionnaire. One of them needed a ventricular derivation for late radiation-induced toxicity. One patient refused to perform the test. Results for the 8 patients are reported in Table 2. Patients with a long follow-up show bad performance on the Mini Mental State Examination (MMSE) test (mean: 27, range: 20 – 30). One patient treated when he was 19 years old had limited irradiated volume but tumor located in the temporal region. His result on the MMSE test shows high impairment in cognitive function. DISCUSSION We report our experience with conformal radiotherapy in the treatment of oligodendroglioma or oligoastrocytoma. Therapeutic strategies have changed dramatically during the last decade, so 20 patients received radiotherapy as adjuvant treatment, and 6 received radiotherapy as second-line treatment. Overall survival at 5 years after radiotherapy is 63%, and 5-year disease-free survival is 47%. These results are consistent with other reports in the literature. Five-year overall survival rate ranges from 55% to 83%, and 10-year survival ranges from 29% to 49% in a series of oligodendrogliomas treated with surgery and radiotherapy (16 –19, 22). Celli et al. suggested that the benefit for radiation exists, but probably not for all patients (23). They reported in a series of 137 oligodendrogliomas a significantly better survival with exclusive radiation therapy in multivariate analysis, except in the subgroup of patients with histories of seizures, who were neurologically healthy at diagnosis. Bad performance status (19), high-grade subtype (16, 18), and hemiparesis (16) have been reported as poor prognostic factors. There remains considerable heterogeneity in clinical outcomes among patients with oligodendrogliomas. Molecular markers have now been shown to have prognostic value in the case of oligodendrogliomas. Tumors with chromosome loss of 1p have better response to chemotherapy (24), better response to radiotherapy (25), and longer survival (23).
1.5 6 7 3 7 3 7 2
years years years years years years years years
NTCP
Localization
Results of MMES test
9%
Perietal Frontal Temporal Occipital Parietal Frontal Frontal Frontal
27 28 23 27 22 30 20 24
0.77 0.36 1.31 10
After radiotherapy, the median progression-free survival was 55 months for patients who harbored allelic loss of chromosome 1p vs. 6.2 months for those who did not (p ⬎ 0.001). Those with loss of 1p and 19 q have particularly favorable outcomes (26). Ino et al. suggested the presence of four relevant groups of histologically defined anaplastic oligodendrogliomas (27). Radiation protocols and timing of irradiation will have to be adapted to such prognostic factors in the future. For patients with low-grade glioma, timing of radiotherapy may not be important. Leighton et al. (28). retrospectively reported the experience of a regional cancer center in Canada between 1979 and 1995. In their experience, radiotherapy deferred until tumor progression vs. immediate radiotherapy was associated with longer survival on univariate analysis. However, patients with the worse prognostic factors were more likely to be treated with radiotherapy. EORTC randomized trial (13) showed no overall difference in 5-year survival comparing postoperative irradiation of 54 Gy with observation in low-grade gliomas. However, immediate vs. delayed radiation did significantly prolong the 5-year progression-free survival (44% vs. 37%, p ⫽ 0.02). In these studies, oligodendrogliomas were not segregated from astrocytomas. Though dramatic advances have occurred in chemotherapy (3– 6) over the past decade, radiotherapy still plays an important role in the treatment of oligodendrogliomas. But according to several authors (29, 30), radiotherapy may be delayed and administered at the time of recurrence. Our experience was reported at the ASTRO meeting in 2001 (31): 116 patients were treated in our department between 1982 and 1999 with chemotherapy or radiotherapy after complete surgery or biopsy for oligodendroglioma or mixed tumor. Delay before further treatment is significantly longer after radiotherapy: 52 months after exclusive radiotherapy, 23 months after exclusive chemotherapy, and 37 months after chemotherapy followed by radiotherapy (p ⫽ 0.0001), but no significant difference was found for overall survival. This suggests that disease-free survival is shorter when radiotherapy is not delivered as first-line treatment, but that deleterious effects of radiotherapy may be postponed without decreasing survival rate. The target volume is an important parameter that impacts on treatment outcome. Decreasing the irradiated volume may induce an increase of local recurrence, because of the
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infiltrative nature of primary brain tumor. Pu et al. (32) reported a series of 46 low-grade gliomas treated with conformal radiotherapy. The GTV was defined as T2 volume if MRI was available or area of enhancement or if absent low attenuation on CT. CTV was equal to GTV, plus a 1–3 cm margin. After 45 to 50 Gy, margins were reduced to 0 –2 cm. All 11 recurrences occurred in the boost region. Rudoler et al. (33) reviewed 30 patients with low-grade gliomas treated this partial brain fields encompassing tumor plus edema and a more than 2-cm margin. Fifty-three patients recurred. All recurrences were located in fields. Mansur et al. (34) reported results of 28 patients treated with limited-field irradiation encompassing the tumor bed and a 2-cm margin; 46% of patients relapsed. All recurrences were in the initial treated volume. In our series, 15 patients among the 26 presented a local evolution. Fourteen recurrences were localized within the 95% isodose, but 2 patients presented a recurrence in the limit of fields. Another patient presented a recurrence in the 80% and 90% isodose, but for this patient, the chiasmatic region was protected, and relapse occurred at this site. Thus, limiting the GTV to the tumor as defined on the T1 sequence of MRI does not seem to downgrade the rate of local control. The question of target volume after chemotherapy is a matter of debate. Among the 11 patients treated with chemotherapy followed by conformational radiotherapy delivered to the postchemotherapy volume, there were 4 relapses, all of which occurred in the 95% isodose. Considering residual volume as target volume did not seem to increase the failure rate. In the present study, high conformal irradiation, assessed with conformal indexes for PTV and normal tissues, was achieved. Median tumor conformity index was 0.82. Late neurocognitive defects in patients who have received radiation therapy to the central nervous system are well documented (35). Clinical syndrome of white matter injury may occur as a consequence of therapeutic irradiation. White matter injury includes nonspecific symptoms: personality changes, deficits in intelligence, or dementia. In contrast, brain necrosis symptoms include motor or sensitive deficits. In the series reported by Olson et al. (36), radiation necrosis, diagnosed in 9 patients (15%), occurred in a median time of 52 months after radiotherapy for lowgrade gliomas. Delayed cognitive impairment due to radiotherapy was noted in 13 patients, and 6 required ventriculoperitoneal derivation. Curran et al. (37) reported the results of quality of life in the EORTC trial comparing low vs. high dose of radiotherapy in low-grade glioma. Patients receiving higher doses reported lower levels of functioning. Kleinberg et al. (38) measured the employment history and memory function 1 year after treatment of 30 gliomas surviving more than 1 year. Memory deficits occurred in 43% of patients receiving whole-brain irradiation vs. 6% of patients receiving partial-brain irradiation 1 year after treatment. Surma-Aho et al. (39) compared a group of 28 patients with low-grade glioma treated with radiotherapy who were still alive 7 years after treatment and 59 patients with
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low-grade glioma not treated with radiotherapy. The group that had postoperative radiotherapy performed significantly worse than the no-radiotherapy group in a cognitive test. Taphoorn et al. (40) reported the results of neurologic examinations: neuropsychological tests of attention, memory, language, and visiospatial and frontal lobe function. Three groups of about 20 patients were compared: a group of patients with low-grade tumor and localized irradiation of 45 to 63 Gy, a group of patients with low-grade tumor without radiotherapy, and a group of patients with no brain tumor. Neurologic tests after a follow-up of 3.5 years on average were the same in the two low-grade tumor groups. In contrast, Taylor et al. (41) conclude that there is no clear trend toward cognitive worsening after irradiation in a series of 701 highgrade brain tumor patients who received radiotherapy on two consecutive North Central Cancer Treatment Group randomized treatment trials. The number of patients that experienced a greater than 3-point decrease in MMSE from baseline among nonprogressors was 10.5% at 6 months, 5.5% at 12 months, 10% at 18 months, and 4 of 22 and 18.2% at 24 months. In our series, 11 patients were disease free at last follow-up, and 6 of them had a job, 4 full-time and 2 part-time, but 2 patients had severe impairment of neurocognitive function. Even for the 8 patients with quite good social adaptation results on the MMSE, the test assessed an impairment of neurocognitive function with results between 20 and 30 (4 between 20 and 24), which is rather low. Forette et al. consider that if the MMSE score is 23 or less, diagnostic tests for dementia must be performed (42). Studies of volume effects will remain more demanding for the brain than for most other organs, because of the brain’s complex structure. Data on long-term effects after fractionated partial volume irradiation using conformal techniques are rare. Santoni et al. (43) investigated temporal damage in 96 patients treated with high-dose proton or photon for chordoma of the skull base. The volumes greater than 70 cm induce a tendency toward a higher rate of temporal damage. Large amounts of data are required to quantify the dose– volume relationship for various localizations. Clinical symptoms may be the result of radiation late effects or tumor progression. The diagnosis of radionecrosis vs. tumor progression is very difficult to make. The impact of radiation doses on survival has been assessed in high-grade gliomas (44). In low-grade gliomas, an EORTC trial failed to demonstrate a relationship between radiation dose and treatment outcome (11). In our study, the doses were 54 to 64 Gy. The impact of radiation dose has not been already established for highgrade oligodendroglioma. Conformal radiotherapy delivers homogeneous doses to the tumoral tissue, while sparing unaffected parenchyma. Optimal dose is currently a matter of debate.
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CONCLUSION Despite conformal radiotherapy after biopsy or incomplete resection for oligodendroglial tumors, and despite relative high-dose radiotherapy, infield recurrences remain very fre-
Volume 56, Number 1, 2003
quent and associated with long-term significant neuropsychic toxicity. New perspectives, such as chromosomic studies to select patients, chemoradiotherapy schedules, or conformal and/or radiobiologically efficient radiation, are necessary.
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