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Japanese Journal of Clinical Oncology Pages 31-36

Comparison of Accelerated Hyperfractionated Radiotherapy and Conventional Radiotherapy for Supratentorial Malignant Glioma
Introduction
   Subjects and Methods
   Patients
   Radiation Therapy
   Adjuvant Therapy
   Statistical Analysis
Results
   Survival and Relapse-free Survival
   Prognostic Factors
   Late Toxicity
Discussion
References

Comparison of Accelerated Hyperfractionated Radiotherapy and Conventional Radiotherapy for Supratentorial Malignant Glioma

Comparison of Accelerated Hyperfractionated Radiotherapy and Conventional Radiotherapy for Supratentorial Malignant Glioma Yuta Shibamoto1,2, Yasumasa Nishimura2, Kazushige Tsutsui3, Keisuke Sasai2, Masaji Takahashi1,2 and Mitsuyuki Abe2

1Department of Oncology, Chest Disease Research Institute and 2Department of Radiology, Faculty of Medicine, Kyoto University, Kyoto, and 3Department of Radiology, Wakayama Red Cross Hospital, Wakayama, Japan

Between 1988 and 1993, 71 patients with glioblastoma or anaplastic astrocytoma were treated either with accelerated hyperfractionation radiotherapy (1.5 Gy twice daily to a total dose of 69 Gy, n = 35) or with conventional fractionation radiotherapy (1.8 Gy daily to 64.8 Gy, n = 36). Two patients in each group did not complete radiotherapy, leaving 67 evaluable. All patients received the chemotherapeutic regime ACNU intraarterially (50 mg/m2) or intravenously (100 mg/m2) prior to and after radiotherapy. Between 1990 and 1992, 19 patients also received intravenous interferon-[beta] (3 x 106 U, three times weekly) during radiotherapy. The median survival time was 14.5 months for the accelerated hyperfractionation group and 14 months for the conventional fractionation group. The median time to progression was 12 months for the accelerated hyperfractionation group and 9.5 months for the conventional fractionation group. There was no significant difference in either survival (P = 0.89) or progression-free survival (P = 0.25) between the accelerated hyperfractionation and conventional fractionation groups. Interferon therapy was associated with poorer survival. Brain necrosis developed in four out of 10 patients receiving accelerated hyperfractionation radiotherapy plus interferon-[beta], but in none of nine patients receiving conventional fractionation radiotherapy plus interferon (P = 0.033). In conclusion, our study failed to demonstrate any possible benefit of accelerated hyperfractionation radiotherapy for malignant glioma. The incidence of brain necrosis may be increased by combining accelerated hyperfractionation radiotherapy and interferon-[beta].

Key Words: brain neoplasm - radiation therapy - malignant glioma - accelerated hyperfractionation - interferon

Introduction

Malignant glioma is usually treated by surgery and postoperative radiation therapy (RT); 60 Gy with conventional fractionation (CF) is considered the standard RT regimen (1). Although survival time is prolonged by such treatment, the median survival time (MST) after operation is usually only 10-13 months for glioblastoma and 18-30 months for anaplastic astrocytoma (1-3). The 5-year survival rate is <5% for glioblastoma and 15-30% for anaplastic astrocytoma. According to the Brain Tumor Registry of Japan (4), the 2- and 5-year survival rates were 38.0% and 19.7% respectively for 2768 patients with malignant glioma receiving radiation therapy between 1978 and 1987.

In an attempt to improve the dismal prognosis for patients with malignant glioma, various strategies have been tried. Adjuvant chemotherapy using nitrosoureas is one such strategy, and ACNU (nimustine) has been shown to modestly prolong survival of patients with malignant glioma (4,5). With respect to the radiation method, the multiple fractions per day (MFD) regimen has been investigated by many groups. Hyperfractionation (HF) aims at increasing tumor control by increasing the total radiation dose through using a small dose per fraction (6). A recent study by the Radiation Therapy Oncology Group has shown that dose escalation up to 81.6 Gy is feasible by using 1.2 Gy twice daily, although the best survival was obtained in patients treated with 72 Gy (7). Accelerated fractionation (AF) is indicated for rapidly growing tumors (with a short potential doubling time) to prevent repopulation of tumor cells during the course of RT (6). Cell kinetic studies have indicated that many malignant gliomas have a short potential doubling time (8,9) and thus they are considered to be suitable for AF. Accelerated hyperfractionation (AHF) aims at taking advantage of both HF and AF by applying higher total doses over a shorter treatment period, but this method has not been extensively investigated for brain tumors. The present study was therefore undertaken to compare the efficacy of AHF-RT with that of CF-RT in patients with malignant glioma.

Subjects and Methods

Patients

This study was initially designed as a randomized one, but during the course of the study, interferon therapy was additionally given to some patients, so the randomized nature of the study was lost. Nevertheless, all patients were randomly assigned to receive either AHF-RT or CF-RT. Between 1988 and 1993, 71 patients with histologically confirmed supratentorial malignant glioma, aged between 16 and 78, and adequate cardiac, hepatic, renal and bone marrow function, entered this study at Kyoto University and affiliated hospitals. Patients with recurrent tumors or another concurrent malignancy were excluded. Four patients (two each in the AHF and CF groups) did not complete the planned treatment and were excluded from further analysis. The remaining 67 patients included 42 males and 25 females aged from 16 to 78 years (median age: 57 years). All patients underwent surgery shortly before RT. There were 48 patients with glioblastoma (GB) and 19 with anaplastic astrocytoma (AA). The distinction between GB and AA was the presence or absence of necrosis (2). The clinical characteristics of each group are shown in Table 1; all of the factors assessed were balanced (P > 0.05).

Radiation Therapy

RT was given with 6 or 10 MV X-rays delivered by a linear accelerator from Monday to Friday in all patients. The AHF regimen consisted of two daily fractions of 1.5 Gy given 5-6 h apart to a total dose of 69 Gy, and the CF regimen consisted of a daily fraction of 1.8 Gy given to a total dose of 64.8 Gy. The CF regimen was based on our previous experience with the optimal dose for malignant glioma (3) and the AHF regimen (69 Gy) was considered equivalent to the other regimen in terms of late toxicity; assuming full recovery between the two fractions, the `equivalent dose'(10) (= D * N-0.377 * T-0.058, where D is the total dose in cGy, N is the number of fractions, and T is the total number of days) was 1340 for both regimens. In both groups, the radiation field covered thc tumor plus a 3-3.5 cm margin and included all the high intensity areas on T2-weighted images of magnetic resonance imaging (MRI). After 54 Gy in the AHF regimen and 50.4 Gy in the CF regimen, the field was reduced to cover the tumor plus a 1-1.5 cm margin. The dose was specified at the center of the mid-plane for parallel opposed fields and at the intersection of the central axes for two rectangular or multiple fields.

Table 1. Clinical characteristics of the subjects
  Total Glioblastoma Anaplastic astrocytoma
  AHF CF P AHF CF P AHF CF P
Sex
Male 19 23 0.39 12 15 0.38 7 8 0.91
Female 14 11   12 9   2 2  
Age
Mean 52 53 0.88 57 56 0.85 41 46 0.53
+/-SD +/-16 +/-17   +/-13 +/-16   +/-18 +/-17  
PS
0 1 19 15 0.27 14 10 0.25 5 5 0.81
2-4 14 19   10 14   4 5  
Site
Frontal 10 13 0.19 6 9 0.096 4 4 0.93
Parietal 9 6   7 3   2 3  
Temporal 9 14   6 11   3 3  
Occipital 5 1   5 1   0 0  
Surgery
Extensive 16 14 0.55 10 10 1.0 6 4 0.25
Non-extensive 17 20   14 14   3 6  
Interferon-[beta]
(+) 10 9 0.73 6 5 0.73 4 4 0.84
(-) 23 25   18 19   5 6  
ACNU
Intraarterial 22 27 0.24 15 19 0.20 7 8 0.91
Intravenous 11 7   9 5   2 2  
Extensive surgery indicates removal of more than 80% of the tumor; AHF, accelerated hyperfractionation; CF, conventional fractionation; PS, performance status (World Health Organization)

Adjuvant Therapy

All patients received ACNU either intraarterially (50 mg/m2) or intravenously (100 mg/m2) on the day before starting RT and also within a few days after completing RT. These doses of ACNU were assumed to be of equivalent efficacy. All patients treated between May 1990 and March 1992 were also given intravenous human fibroblast interferon-[beta] (3 * 106 U, three times weekly) during the RT course, according to a protocol of the neurosurgeons group.

Statistical Analysis

Differences in patient characteristics and the incidence of toxicity were examined by the [chi]2 test or Welch's t-test. Survival and relapse-free survival rates were calculated from the date of operation by the Kaplan-Meier method and differences in survival were examined by the log-rank test. No patients were lost to follow-up. The influence of various potential prognostic factors was further examined by multivariate analysis using the Cox proportional hazards model. All these statistical analyses were carried out using a computer program (Halbau 4; Gendaisuugakusha, Kyoto, Japan).

Results

Survival and Relapse-free Survival

There have been a total of 57 deaths, with 51 due to disease progression, four due to complications of brain necrosis (pneumonia etc.), and two due to intercurrent disease. Disease progression occurred in 56 patients, being within the RT field in 51, at the margin of the RT field in one, and through meningeal dissemination in four. Figs 1 and 2 show overall survival and progression-free survival curves for the two groups. The MST was 14.5 months for the AHF group and 14 months for the CF group, and the 2-year survival rate was 33% vs 26% (P = 0.89). The median time to progression (MTP) was 12 months for the AHF group and 9.5 months for the CF group, and the 2-year progression-free survival was 28% vs 10% (P = 0.25). Thus there were no significant differcnces between the two groups.


Figure 1. Survival of all patients. --: accelerated hyperfractionation (n = 33); - - -: conventional fractionation (n = 34). P = 0.89. Ticks represent individual living patients.


Figure 2. Progression-free survival of all patients.-: accelerated hyperfractionation (n = 33); - - -: conventional fractionation (n = 34). P = 0.25. Ticks represent individual patients alive or dead without disease progression

Since the prognosis of GB patients is known to be worse than that of AA patients, survival data were also calculated separately for GB and AA. Survival data for the GB patients are shown in Table 1; there was no significant difference in either survival or progression-free survival between the AHF and CF groups. The MST was 43.5 months for the nine AA patients receiving AHF-RT and 28 months for the 10 AA patients receiving CF-RT, but the 4-year survival rate was 28% vs 34% (P = 0.86). The MTP was 34.5 months for the AA patients treated with AHF and 18 months for the AA patients treated with CF, but the 3-year progression-free survival was 0% vs 25% (P = 0.75). Again, there were no significant differences.

Nineteen patients (11 GB and eight AA patients) received interferon-[beta] in addition to the other therapy. On multivariate analysis, the survival and progression-free survival rates of the 11 GB patients were worse than those of the 37 GB patients without interferon (Tables 2 and 2). In addition, on univariate analysis the survival of the eight AA patients receiving interferon was worse than that of the 11 AA patients without interferon (MST: 15 months vs 49.5 months; 2-year survival rate: 25% vs 81%; P = 0.011), although the progression-free survival was not different (MTP: 18 months vs 14 months; 2-year progression-free survival: 29% vs34%; P = 0.66).

Since interferon-[beta] had some influence on prognosis, patients receiving interferon were then excluded to compare the prognosis of the AHF and CF groups. However, there were again no differences in either survival or progression-free survival between the two groups (P = 0.92 and 0.33 respectively).

Table 2. Survival and progression-free survival of glioblastoma patients according to various potential prognostic factors
Survival Progression-free survival
Variable n MST 2 yr (%) P MTP 2 yr (%) P
Sex
Male 27 12 12 0.051 8.5 9.1 0.78
Female 21 14.5 29   9.5 14  
Age
<60 25 13 32 0.16 8.5 17 0.32
>= 60 23 12.5 4.8   9.5 5.2  
PS
0, 1 24 15 30 0.017 10 18 0.11
2-4 24 12 8.3   7 5  
Site
Frontal 15 14 27 0.42 11.5 15 0.15
Other 33 12.5 15   7.5 11  
Surgery
Extensive 20 14.5 25 0.18 10 20 0.26
Non-extensive 28 12.5 14   8.5 4.5  
Radiation
AHF 24 13 24 0.47 9.5 20 0.17
CF 24 12.5 14   7 4.2  
Interferon-[beta]
(+) 11 10.5 18 0.40 0 0.0005  
(-) 37 13 20   10 15  
ACNU
Intraarterial 34 13 24 0.31 9.5 12 0.41
Intravenous 14 13 7.1   7 14  
Extensive surgery indicates the removal of more than 80% of the tumor; MST, median survival time in months; MTP, median time to progression in months; PS, performance status according to World Health Organization; AHF, accelerated hyperfractionation; CF, conventional fractionation.

Prognostic Factors

Tables 2 and 2 summarize the influence of various potential prognostic factors on the outcome of treatment in the GB patients. Prognostic factors for AA were not examined because the number of patients was too small. In univariate analysis, a good performance status was associated with better survival and the use of interferon was associated with a worse progression-free survival rate. In multivariate analysis, female gender, good performance status, and no interferon therapy proved to be significantly associated with better survival. The latter two factors were also associated with better progression-free survival.

Late Toxicity

Necrosis developed in the surrounding normal brain in seven patients (six in the AHF group and one in the CF group, P = 0.041; five of 49 patients receiving intraarterial ACNU and two of 18 patients receiving intravenous ACNU, P = 0.91) at 2-16 months after RT. Necrosis was confirmed by reoperation in two patients and by autopsy in two, while the remaining three patients had contrast-enhanced lesions on CT/MRI that were considered to be necrosis on the basis of the response to corticosteroids and non-expansion during follow-up for at least 5 months. Brain necrosis developed in four out of 10 patients receiving AHF-RT and interferon, but in none of nine patients receiving CF-RT and interferon (P = 0.033). In contrast, the incidence of brain necrosis did not differ between the AHF and CF patients who did not receive interferon (2/23 vs 1/25, P = 0.50). Two patients undergoing resection of the necrotic tissue survived another 2 and 11 months respectively.

Discussion

The results of previous studies on the efficacy of MFD regimens for malignant glioma have been conflicting. A randomized study conducted by Shin et al. (12) indicated an advantage of HF-RT (61.41 Gy as 0.89 Gy thrice daily) over CF-RT (58 Gy in 30 daily fractions). However, several randomized studies (7,13-15) have not necessarily indicated any advantage of HF regimens over CF regimens. Regarding AF-RT, several studies (l3,16-l8) have also shown no clear benefit of using short treatment times. Bignardi and Bertoni (l9) compared 60 Gy given as 1.5 Gy twice daily and 60 Gy with CF in a nonrandomized fashion. Although their study did not take advantage of HF to deliver higher doses, the prognosis was significantly worse in the MFD group.

Table 3. Multivariate analysis of prognostic factors for glioblastoma patients
  P value
  Survival Progression-free survival
Variable Full model Best-fit model Full model Best-fit model
Sex (male/female) 0.0027 0.0039 0.40 -
Age (<60/ >= 60) 0.41 - 0.69 -
Performance status
(0-1/2-4)		 0.0027

 0.00093

 0.071

 0.035
Site (frontal/parietal
/temporal/occipital)		 0.60

 -

 0.54

 -
Surgery (extensive/
non-extensive)		 0.57

 -

 0.84

 -
Radiation
(AHF/CF)		 0.28

 -

 0.11

 -
Interferon-[beta]
(+/-)		 0.026

 0.013

 0.0027

 0.00087
ACNU (intraarterial/
intravenous)		 0.13

 -

 0.39

 -
The best-fit model was determined by the lowest Akaike Information Criterion (11); AHF, accelerated hyperfractionation; CF, conventional fractionation.

In the present study, we aimed at utilizing the advantages of both HF and AF, i.e., higher radiation doses and a shorter treatment period, but failed to demonstrate any benefit. The dose of 69 Gy in the AHF arm was assumed to be equivalent to 64.8 Gy delivered by CF in terms of late toxicity. Improvement of the prognosis of malignant glioma can be expected after increasing the total radiation dose (20), but it seems that the difference in total dose between the AHF and CF groups (4.2 Gy) might have been too small to obtain a statistical increment of prognosis in this study population (n = 67). Furthermore, the biologically effective dose (BED) (21) for the AHF regimen is 2.9 Gy higher than that for the CF regimen when assuming an [alpha]/[beta]ratio of 10 Gy, full recovery between the two daily fractions, and no repopulation during RT, but when an [alpha]/[beta] of 3 Gy is assumed, BEDs for the two regimens become similar. Both of these [alpha]/[beta] ratios have been reported for malignant glioma cells (22,23).

The total treatment period was about 2.7 weeks shorter in the AHF group than in the CF group, which should be beneficial for rapidly growing tumors. Previous studies on cell kinetics (8,9) have suggested that a considerable proportion of malignant gliomas have a short potential doubling time (<5 days), but recent studies do not necessarily support this conclusion. In a study using bromodeoxyuridine labeling and flow cytometry (24), the mean potential doubling time of nine malignant gliomas was found to be 12 days. Also, our study using the cytochalasin B assay (25) showed that the mean potential doubling time of four malignant gliomas was 11 days (26). Patients with malignant glioma have a grave prognosis, but this may be more closely related to the fact that the tumor expands within the limited confines of the central nervous system, and the proliferative activity of malignant glioma may not be so high compared with some other malignant tumors. Therefore, shortening the overall treatment time may not have a great impact on the efficacy of RT.

This study confirmed the importance of performance status (for both survival and progression-free survival) and sex (for survival only) as prognostic factors for glioblastoma. Regarding the other known prognostic factors such as age (young > old), extent of surgery (extensive > non-extensive), and tumor site (frontal > other) (27,28), similar trends could be seen, but they did not prove to be significant. This could be due to the sample size used in the present study.

Interferon therapy has been reported by several Japanese investigators to be useful for malignant glioma (29,30), although negative results have been reported in Western countries (3l). In a Japanese multi-institutional study (29), patients with malignant glioma treated with a combination of radiation, ACNU, and interferon-[beta] had a higher response rate than those treated with radiation and ACNU. In contrast, our results indicated that interferon therapy was associated with worse survival and progression-free survival. The poorer survival rate in our patients receiving interferon can be partly accounted for by adverse reactions, since three of the four patients who received interferon and developed brain necrosis subsequently died of complications resulting from this necrosis. However, we have no definite explanation for the worse progression-free survival of the patients receiving interferon. In this study, administration of 3 * 106 U of interferon-[beta] thrice weekly often caused high fever and made the patients sicker, which might have adversely affected the effect of RT. The risk of combining interferon-[beta] with AHF-RT also became evident. A similar adverse effect on normal brain tissue has been reported when interferon-[alpha] is used in conjunction with RT (32,33). It is not clear why brain necrosis developed more often in the patients receiving AHF-RT and interferon, but the AHF regimen might be potentially more toxic than the CF regimen and the toxicity might have been enhanced by adding interferon-[beta]. A more careful evaluation is clearly necessary with regard to the role of interferon therapy in malignant glioma.

In conclusion, this study failed to demonstrate any possible advantage of the AHF regimen for malignant glioma. This may be partly due to the small patient number, but in the light of the results of other studies using various MFD schedules, it seems unlikely that the prognosis of malignant glioma would be greatly improved by modifying the fractionation of radiation. Further attempts to improve the prognosis by combining radiation with other treatment modalities are necessary.

References

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Received May 15, 1996; accepted July 3, 1996
For reprints and all correspondence: Yuta Shibamoto, Department of Oncology, Chest Disease Research Institute, Kyoto University, Sakyo-ku, Kyoto 606-01, Japan
Abbreviations: RT, radiation therapy; CF, conventional fractionation; MST, median survival time; MFD, multiple fractions per day; HF, hyperfractionation; AF, accelerated fractionation; AHF, accelerated hyperfractionation; GB, glioblastoma; AA, anaplastic astrocytoma; MRI, magnetic resonance imaging; MTP, median time to progression; BED, biologically effective dose

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