- Email: [email protected]
Misonidazole and irradiation in the treatment of high-grade astrocytomas: Further report of the Vienna study group
Int J Rad~rron Oncology Bid Phys Vol Pnntcd m the lJ.S A. All rights resewed
IO.
PP
1713-1717 Copvnght
036@3016/84 $03 00 + .oO 5 1984 Pergamon Pws Lid
??Session VI
MISONIDAZOLE AND IRRADIATION IN THE TREATMENT ASTROCYTOMAS: FURTHER REPORT OF THE VIENNA BRIGITTE STADLER,
OF HIGH-GRADE STUDY GROUP
M.D., KARL HEINZ MARCHER, M.D., H. DIETER KOGELNIK, M.D.* AND TIBOR SZEPESI, M.D.
University Clinic for Radiotherapy
and Radiobiology of Vienna, Alserstrasse 4, A-1090 Vienna, Austria
A randomized study investigating the value of misonidazole in patients irradiated for grade III andIV supratentorial astrocytomas was started in June1977. With a minimum follow-up time of 6 months, 45 patients who completed therapy are available for analysis. All patients received the same radiation treatment (66.5 Gy in 31 fractions over 7.5 weeks, Geld size reduction after 45 Gy). In the first, second and eighth week, a 4 Gy tumor dose was given on Monday and Thursday. Misonidaxole was given 4 hours before irradiation to 18 randomized patients on those 6 treatment days (2.1-2.7 g/m* per treatment day). Daily tumor doses of 1.7 Gy were administered Monday through Friday from the third until the seventh week. Medhm survival for patients treated with misonidazole is 13.8 months; for those treated by irradiation alone it was 9.8 months. The corresponding 1 year survival rates are 64 and 25%, respectively. Survival plots indicate some advantage for the patients treated with misonidazole, however statistically there is no significant difference observed (p > 0.08). There are no significant differences in Karnofsky performance status, sex and in histological grade or in age distribution between the groups. However, the type of surgery (complete or subtotal) influenced survival markedly: patients with complete surgery lived significantly longer (p < 0.0009). Neurotoxic side effects of misonidazole were minhnal. High-grade astrocytomas,
Radiotherapy,
Misonidazole.
INTRODUCI-ION
did not show any advantage.’ Therefore, chemical agents, which are able to replace oxygen in hypoxic tumor cells, were investigated in numerous in vitro and in vivo experiments. After pharmacokinetic and toxicologic experience was gained, many clinical studies were initiated to evaluate the effectiveness of radiosensitizers on local tumor control in man.2*6*‘3.16 The University Clinic for Radiotherapy and Radiobiology of Vienna started, on completion of pharmacokinetic and toxicologic studies “.I9 a prospective randomized trial in high-grade astrocytomas, exploring the radiosensitizing properties of misonidazole, currently the most efficient electron-affinic hypoxic cell sensitizer under investigation.
Although the prognosis of high-grade astrocytomas is still extremely grave, the importance of postoperative irradiation in the management of this disease has become firmly established over the past two decades. Median survival following surgical resection alone and best conventional care ranges between 14 and 22 weeks.‘4.28 A randomized study by the Brain Tumor Study Group (BTSG) indicated that patients receiving postoperative whole-brain irradiation with 50 to 60 Gy had a median survival increase by 150%,28 whereas the addition of CCNU failed to improve survival.’ The high failure rate in patients with high-grade astrocytomas is related to the inability to control disease locally. The tumor destroys by local brain infiltration and kills patients without dissemination to distant organs in at least 95% of patients.21 The failure to cure patients with high-grade astrocytomas may originate in the radioresistance of the hypoxic tumor cell population. Clinical experience to overcome radioresistance by breathing oxygen under raised pressure
METHODS AND MATERIALS Forty-five patients with a minimum follow-up time of 6 months were available for analysis up to October 1983. Forty-one patients have a minimum follow-up of more than two years. All patients had histologically confirmed grade III and IV supratentorial astrocytomas. Treatment
* Current address: Institute for Radiotherapy, Landeskrankenanstalten Salzburg, Miillner Hauptstrasse 48 A-5020 SaIzburg, Austria. Presented at the Conference on Chemical Modifiers of Cancer Treatment, Banff, Canada, 26 Nov. to I Dec. 1983.
Acknowledgements-The authors are indebted to HoffmannLa Roche Wien GmbH for contributing the misonidazole used in this study. Accepted for publication 4 May 1984.
1713
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September 1984. Volume 10, Number 9
Radiation Oncology 0 Biology 0 Physics
working-day week) of 1.7 Gy were administered. The whole brain was treated until 45 Gy TD had been given (parallel opposing portals, field size - 16 cm X 12 cm). The field size was then reduced (- 10 cm X 10 cm) to cover the tumor area with a small margin of safety. Misonidazole was given orally 4 to 5 hours before irradiation on those six treatment days when fractional radiation doses of 4 Gy TD were used. The cumulative dose of misonidazole was 27 g (4.5 g per treatment day). corresponding to 12.6 to 16.4 g/m2 of surface area (mean 14.2 g/m’, 2.1-2.7 g/m2 per treatment day). Before the administration of misonidazole, chlorpromazine and thiethylpcrazine were given. In conjunction with the high fractional doses of4 Gy during the first. second and eighth week, steroids and diuretics were used. Only patients at risk of developing epileptic seizures received antiepileptic medications. Differences of means were tested for statistical significance by Breslow and Mantel-Cox tests with an agreed significance level of p = 0.05.
begun within 4 weeks of surgery. Patients who had received prior radiotherapy to the head and neck or chemotherapy were excluded in addition to those patients referred after surgery for a recurrence. Patients with a Kamofsky performance status of less than 20 were not elegible for the study. Most of the patients had a Kamofsky performance status of more than 50. Patients with adrenal steroid incompatibility and significant co-existing diseases were excluded. The patients were hospitalized for most of the treatment time. Pre- and postoperative computed tomography scans and/or brain scans were performed. All patients had routine neurologic and ophthalmologic, and occasional otologic examinations. Repeated examinations of the CBC. sedimentation rate, urinalysis, electrolytes, and hepatic and renal parameters were performed. Serum concentrations of misonidazole were determined in the early phase of the study. By randomization by a computer program, patients received one of two treatment schedules: irradiation alone or irradiation and misonidazole. Radiotherapy was identical in both treatment groups. A tumor dose (TD) of 66.5 Gy was given in 31 fractions over 7% weeks using 43 MeV photons. In the first, second and eighth week 4 Gy TD were given on Mondays and Thursdays. From the third until the seventh week, daily tumor doses (5 was
5
70 -
: 2 h
60 -
s
50
RESULTS Figure I shows the survival curves for both treatment groups. Statistically, there is no significant difference between patients treated with and without misonida7ole (p
XRT ?? MISONIDAZOLE
-
g g
40 -
8 !T 30Y F u
20 -
$ 2
-
lo1 0 c,
3-77
12 I
15I
I*---%
G---27 V-T-
30
I
--
MONTHS Fig.
1. Kaplan-Meier
survival plots for patients receiving irradiation
alone (XRT)
or irradiation
plus misonidazole
High-grade astrocy%?mastreated with misonidazole and irradiation 0 B.
-_.__
T----
3
--
171
et ol
tration. In combination with steroids.” neurologic side effects such as peripheral neuropathies and tinnitus were minimal despite the use of relatively high cumulative g/m’). Three doses of misonidazole of 27 g (12.6-16.4 out of 18 patients ( 17%) experienced mild stocking-like paraesthesias on the lower extremities at the end of the second treatment week, which lasted a few weeks. In 5 of 18 patients (28%) a transient tinnitus occurred at the same time.
> 0.08). The mean survival time of the misonidazole group ( 13.8 months) is not significantly longer than that of the group having received irradiation alone (9.8 months). The corresponding 1 year survival rates are 64 and 2590, respectively. In our study there was an even distribution of patients with radical or subtotal surgery in both treatment arms (55 and 56% radical and subtotal operations, respectively). Patients with complete surgery lived significantly longer (p < 0.0009), median survival 13.8 vs. 6.7 months (Fig. 2). There were no significant differences in Kamofsky performance status, sex and in histological grade distribution between the groups. The mean age of the patients is 52 years in the sensitizer group; for patients treated by irradiation alone it is 56 years. The age distribution also shows no statistically significant difference (p > 0.3). Mean serum levels 4 hours after administration of 4.5 g (2.1-2.7 g/m2) misonidazole were usually in the range of 90-160 mg/1.‘7.‘9 With these serum levels significant sensitizer enhancement ratios may be expected.‘.8 There was no adverse influence of misonidazole on renal or hepatic parameters. All other hematologic examinations also remained within normal limits. The drug was well tolerated with the use of antinausea medications 30 minutes before misonidazole adminis-
SUBTOTAL
ST4DLER
DISCUSSION The most important factors influencing prognosis of high-grade astrocytomas are the type of surgery performed, histopathologic grade, the age at time of operation and the initial performance status. In our study there is a clear indication of shorter survival in patients who had subtotal removal of the tumor as compared to patients with ‘complete’ surgery (p < 0.0009), (Fig. 2). Other authors found similar differences in survival in their investigations.4,‘,“” Patients with grade III tumors have a significantly better survival than patients having grade IV lesions.24 In our small series there was an even distribution of histological grades between the treatment groups and no dependence
I __ _
----
6
---
9
12
15
18
21
I
24
,
I
27
30
MONTHS Fig. 2. Kaplan-Meier
survival plots for patients with complete
or subtotal surgery.
1716
Radiation Oncology 0 Biology 0 Physics
of survival on histological grade could be found. Also, the initial Kamofsky performance status as well as the age distribution of patients were equal between our treatment groups. An important factor for survival are radiotherapeutic parameters, especially tumor dose and treatment volume. Many authors emphasized the value of large treatment fields for adequate coverage of the tumors. They found a significant longer survival in patients with larger treatment volumes than in those treated with limited fields.20.25 In contradiction to these findings, Maire,” suggested, in a retrospective analysis of computerized tomographic scans, restricting the irradiated volume to the tumor site and to presumptive extension pathways. This is because more than 95% of the patients show recurrence within the original tumor site, and radiation damages in normal brain tissue could impair the quality of life. Nevertheless, neuropathologists describe a plane tumor extension on the brain surface in some high-malignant astrocytomas.26 Patients receiving higher radiation doses show a longer surviva1.24*25,28 The dose used in our study corresponds with the recommendations of Kramer and Salazar et a1.20.25We employed doses equivalent to 1890 ret, which equals about 70 Gy in 7 weeks. A shrinking field technique, which is now generally recommended, was applied. In a previous publication, the preliminary results of our study had shown a statistically significant better survival for patients receiving misonidazole.‘* In the current analysis, the significance of the survival advantage for the
September 1984, Volume 10, Number 9
misonidazole group was lost (Fig. 7), although the mean survival time for these patients of 13.8 months is still much longer than that for the patient group that received irradiation alone (9.8 months). However, because of the relatively small number of patients in either arm, a statistical analysis may weaken the chance of getting a positive result. So far, the preliminary and final results of all studies investigating misonidazole as a radiosensitizer for highgrade astrocytomas are rather disappointing,5.‘0.“.‘2.22.23 and do not indicate a real gain in survival In some of these studies, additional chemotherapy was also included as part of the treatment.“*** Although intercomparison of all the mentioned studies might be difficult because of the marked variations in the treatment protocols, the overall negative results seem to indicate that misonidazole is not the desired radiosensitizer for high-grade astrocytomas. Still, final results of ongoing trials have to be reported before firm conclusions about the value of misonidazole can be made. In particular, the outcome of an ongoing EORTC-study using misonidazole and multiple daily radiation fractions will be of great interest; in the pilot study, encouraging results had been reported.’ With the development of new radiation sensitizers with improved therapeutic ratios, it should be possible in the near future to indicate clearly whether poorly reoxygenating hypoxic tumor cells are the major cause of the current inability to improve survival of high-grade astrocytomas.
REFERENCES G.E., Dawson, K., Stratford, I.J.: Electron-affinic radiation sensitizers for hypoxic cells: Prospects and limitations with present and future drugs. In Progress in RadioOncology (Proc. Int. Symp. Baden. Austria, 1978). Karcher, K.H., Kogelnik, H.D.. Meyer, H.J. (Eds.). Stuttgart, Georg Thieme Verlag, and New York. Thieme--Stratton Inc. 1980, pp. 84-95. 2. Adams, G.E., Fowler, J.F., Wardman, P. (Eds.): Hypoxic cell radiosensititen in radiobiology and radiotherapy. Brif. J. Cancer 37(Suppl. 3): 1978. 3. Ang, K.K., van der Schueren, E.. Notter, G., Hotiot, J.C., Chenal, C., Fauchon, F.. Raps, J., van Peperzeel, H., Coffin, J.C., Vessiere, M., van Glabbeke, M.V.: Split course multiple fractionated radiotherapy schedule combined with misonidazole for the management of grade 111and IV ghomas: A pilot feasibility study of the radiotherapy group of the EORTC. Int. J. Radial. Oncol. Biol. Phys. 8: 1657- 1664, I. Adams,
1982. 4. Bleehen, N.M.: The Cambridge
Glioma Trial of misonidazole and radiation therapy with associated phatmacokinetic studies. Cancer Clin. Trials 3: 267-273, 1980. 5. Bleehen, N.M.: MRC study of misonidazole and radiotherapy for high grade astrocytomas (Abstr.) Proceedings II. Meeting of ESTRO, Bordeaux, France, 2 1, 1983. 6. Brady, L.W. (Ed.): Radiation Sensitizers. Their Use in the Clinical Management ofcancer. New York, Masson, 1980. 7. Chang, C.H.: Hyperbaric oxygen and radiation therapy in the management ofghoblastoma. Nat!. Cancer Inst. Monogr. 46: 163-169,
1977.
8. Dische, S.: Hypoxic cell sensitizers. In Proceedings of 2nd International Symposium on Biological Bases and Clinical Implications of Tumor Resistance. Rome 1980. NY, Mas-
son, (In press). 9. EORTC Brain Tumor Group: Effect of CCNU on survival
rate of objective remission and duration of free interval in patients with malignant brain ghoma-Final evaluation. Eur. J. Cancer 14: 851-856, 1978. 10. Gonzalez-Gonzalez, D.: Randomized
double blind study
in patients operated for malignant brain ghoma, using radiotherapy in combination with either misonidazole or placebo (Abstr.). Proceedings 1. Meeting of ESTRO, London, UK. 32, 1982. I I. Hagen, S: A randomized study of radiotherapy, misonidazole and CCNU in operated patients with astrocytomas Grade III/IV (Abstr.) Proceedings II. Meeting of ESTRO, Bordeaux, France, 41, 1983. 12. Horiot, J.C., Van den Bogaert, W., Ang, K.K., Chaplain, G., Van der Schueren, E., Nabid. A., Vessiere, M.: EORTC experience with misonidazole combined with multiple daily fractionated (MDF) radiotherapy (Abstr.), ESTRO, 29. 1982. 13. Int. J. Radiation Oncology Biol. Phys. 8: 323-815, 1982. Proceedings of the Key Biscayne Conference. 14. Jellinger, K., Kothbauer, P., Volt, D., Vollmer, R., Weisz, R.: Combination chemotherapy (COMP Protocol) and radiotherapy in anaplastic supratentorial gliomas. Acfa Neurochir. 51: I-13, 1979. 15. Jentzsch, K., Kiircher, K.H., Kogelnik, H.D., Maida, E.,
High-grade astroqtomas treated withmisonidazole and irradiation ??B. STADLER Mamoli, B., Wessely, P., Zaunbauer, F., Nitsche. V.: Initial clinical experience with the radiosensitizing nitroimidazole Ro 07-0582.Strahlentherapie 153: 825-83 1, 1977. 16. Karcher, K.H., Kogelnik, H.D., Reinattz, G.: Progress in Radio-Oncology. II. New York, Raven Press, 1982. 17. Kogelnik, H.D.: Clinical experience with misonidazoleHigh-dose fractions versus daily low doses. Cancer Clin. Trials 3: 179- 186, 1980. 18. Kogelnik, H.D., Karcher, K.H., Szepesi, T., Schratter-Sehn, A.U.: High-dose irradiation and misonidazole in the treatment of malignant ghomas: A preliminary report. Progress in Radio-oncology II: 189-195. 198 1. 19. Kogelnik, H.D., Meyer, H.J., Jentzsch, K.: Hypoxic cell sensitizers in radiobiology and radiotherapy (Proc. 8th L. H. Gray Conf., Cambridge, UK, 1977). Br. J. Cancer 37(Suppl. III): 281-285, 1978. 20. Kramer, S.: Tumor extent as a determining factor in radiotherapy of glioblastomas. Ada Radio/ Ther. Phys. Biol. 8: 111-117, 1969. malignant 21. Maire, J.Ph.: The spread of supratentorial gliomas: A follow up study with computerized tomography after treatment (Abstr.). Proceedings II. Meeting of the ESTRO, Bordeaux, France, 35, 1983. 22. Nelson, D.F., Schoenfeld, D.. Weinstein, A.S., Nelson, J.S., Wasserman, T., Goodman, R., Carabell, S.: A randomized comparison of misonidazole sensitized radiotherapy plus BCNU and radiotherapy plus BCNU for treatment of ma-
et al.
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Iignant ghoma after surgery. Preliminary m&s of an RTOG study. Int. J. Radial. Oncoi. Biol. Phys. 9: 1143-l 151, 1983. 23. Sack, H., CaIcanis, A., Godehardt, E., Weidtman, V., Ziilch, KS., Ammon, J., Barnberg, M., He&t, M.. Keim, KIeibeI F.. Makoski, H-Br., Potthoff, P.L., Schlegal, G., Schnepper, E.: Die postoperative Strahlenbehandlung von Astrozytomen Grad 3 und 4 mit dem Strahlensensibilisator Misonidazol. Srrahlentherapie 158: 466-469, 1982. 24. Salazar, O.M., Rubin, P., Feldstein, M.L., Pizzutielio, R.: High dose radiation therapy in the treatment of malignant gliomas: Final report. Inr. J. Radiat. Oncol. Biol. Phys. 5: 1733-1740,
1979.
25. Salazar. O.M., Rubin, P., McDonald, J.V., Feldstein, M.L.: Patterns of failure in intracranial astrocytomas after irradiation: Analysis of dose and field factors. Am. J. Roentgenol. 126: 279-292,
1976.
26. Stockdorph. 0.: Bemerkungen zur Klassifikation und ‘Grading’-Einteilung (Abstr.). Die Chemotherapie der Gliome. Mainz l/2, 1983. 27. Uttasun, R.C., Tanasichuk, H., Fulton, D., Agboola, 0.. Turner, A.R., Koziol, D., Raleigh, J.: High dose misonidazole with dexamethasone rescue: A possible approach to circumvent neurotoxicity. Int. J. Radiat. Oncol. Biol. Phys. 8: 365-369,
1982.
28. Walker, M.D., Alexander, E., Jr., Hunt, W.E.: Evaluation of BCNU and/or radiotherapy in the treatment of ghomas. A Cooperative Clinical Trial. J. Neurosurg. 49: 333-343, 1978.
IO.
PP
1713-1717 Copvnght
036@3016/84 $03 00 + .oO 5 1984 Pergamon Pws Lid
??Session VI
MISONIDAZOLE AND IRRADIATION IN THE TREATMENT ASTROCYTOMAS: FURTHER REPORT OF THE VIENNA BRIGITTE STADLER,
OF HIGH-GRADE STUDY GROUP
M.D., KARL HEINZ MARCHER, M.D., H. DIETER KOGELNIK, M.D.* AND TIBOR SZEPESI, M.D.
University Clinic for Radiotherapy
and Radiobiology of Vienna, Alserstrasse 4, A-1090 Vienna, Austria
A randomized study investigating the value of misonidazole in patients irradiated for grade III andIV supratentorial astrocytomas was started in June1977. With a minimum follow-up time of 6 months, 45 patients who completed therapy are available for analysis. All patients received the same radiation treatment (66.5 Gy in 31 fractions over 7.5 weeks, Geld size reduction after 45 Gy). In the first, second and eighth week, a 4 Gy tumor dose was given on Monday and Thursday. Misonidaxole was given 4 hours before irradiation to 18 randomized patients on those 6 treatment days (2.1-2.7 g/m* per treatment day). Daily tumor doses of 1.7 Gy were administered Monday through Friday from the third until the seventh week. Medhm survival for patients treated with misonidazole is 13.8 months; for those treated by irradiation alone it was 9.8 months. The corresponding 1 year survival rates are 64 and 25%, respectively. Survival plots indicate some advantage for the patients treated with misonidazole, however statistically there is no significant difference observed (p > 0.08). There are no significant differences in Karnofsky performance status, sex and in histological grade or in age distribution between the groups. However, the type of surgery (complete or subtotal) influenced survival markedly: patients with complete surgery lived significantly longer (p < 0.0009). Neurotoxic side effects of misonidazole were minhnal. High-grade astrocytomas,
Radiotherapy,
Misonidazole.
INTRODUCI-ION
did not show any advantage.’ Therefore, chemical agents, which are able to replace oxygen in hypoxic tumor cells, were investigated in numerous in vitro and in vivo experiments. After pharmacokinetic and toxicologic experience was gained, many clinical studies were initiated to evaluate the effectiveness of radiosensitizers on local tumor control in man.2*6*‘3.16 The University Clinic for Radiotherapy and Radiobiology of Vienna started, on completion of pharmacokinetic and toxicologic studies “.I9 a prospective randomized trial in high-grade astrocytomas, exploring the radiosensitizing properties of misonidazole, currently the most efficient electron-affinic hypoxic cell sensitizer under investigation.
Although the prognosis of high-grade astrocytomas is still extremely grave, the importance of postoperative irradiation in the management of this disease has become firmly established over the past two decades. Median survival following surgical resection alone and best conventional care ranges between 14 and 22 weeks.‘4.28 A randomized study by the Brain Tumor Study Group (BTSG) indicated that patients receiving postoperative whole-brain irradiation with 50 to 60 Gy had a median survival increase by 150%,28 whereas the addition of CCNU failed to improve survival.’ The high failure rate in patients with high-grade astrocytomas is related to the inability to control disease locally. The tumor destroys by local brain infiltration and kills patients without dissemination to distant organs in at least 95% of patients.21 The failure to cure patients with high-grade astrocytomas may originate in the radioresistance of the hypoxic tumor cell population. Clinical experience to overcome radioresistance by breathing oxygen under raised pressure
METHODS AND MATERIALS Forty-five patients with a minimum follow-up time of 6 months were available for analysis up to October 1983. Forty-one patients have a minimum follow-up of more than two years. All patients had histologically confirmed grade III and IV supratentorial astrocytomas. Treatment
* Current address: Institute for Radiotherapy, Landeskrankenanstalten Salzburg, Miillner Hauptstrasse 48 A-5020 SaIzburg, Austria. Presented at the Conference on Chemical Modifiers of Cancer Treatment, Banff, Canada, 26 Nov. to I Dec. 1983.
Acknowledgements-The authors are indebted to HoffmannLa Roche Wien GmbH for contributing the misonidazole used in this study. Accepted for publication 4 May 1984.
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September 1984. Volume 10, Number 9
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working-day week) of 1.7 Gy were administered. The whole brain was treated until 45 Gy TD had been given (parallel opposing portals, field size - 16 cm X 12 cm). The field size was then reduced (- 10 cm X 10 cm) to cover the tumor area with a small margin of safety. Misonidazole was given orally 4 to 5 hours before irradiation on those six treatment days when fractional radiation doses of 4 Gy TD were used. The cumulative dose of misonidazole was 27 g (4.5 g per treatment day). corresponding to 12.6 to 16.4 g/m2 of surface area (mean 14.2 g/m’, 2.1-2.7 g/m2 per treatment day). Before the administration of misonidazole, chlorpromazine and thiethylpcrazine were given. In conjunction with the high fractional doses of4 Gy during the first. second and eighth week, steroids and diuretics were used. Only patients at risk of developing epileptic seizures received antiepileptic medications. Differences of means were tested for statistical significance by Breslow and Mantel-Cox tests with an agreed significance level of p = 0.05.
begun within 4 weeks of surgery. Patients who had received prior radiotherapy to the head and neck or chemotherapy were excluded in addition to those patients referred after surgery for a recurrence. Patients with a Kamofsky performance status of less than 20 were not elegible for the study. Most of the patients had a Kamofsky performance status of more than 50. Patients with adrenal steroid incompatibility and significant co-existing diseases were excluded. The patients were hospitalized for most of the treatment time. Pre- and postoperative computed tomography scans and/or brain scans were performed. All patients had routine neurologic and ophthalmologic, and occasional otologic examinations. Repeated examinations of the CBC. sedimentation rate, urinalysis, electrolytes, and hepatic and renal parameters were performed. Serum concentrations of misonidazole were determined in the early phase of the study. By randomization by a computer program, patients received one of two treatment schedules: irradiation alone or irradiation and misonidazole. Radiotherapy was identical in both treatment groups. A tumor dose (TD) of 66.5 Gy was given in 31 fractions over 7% weeks using 43 MeV photons. In the first, second and eighth week 4 Gy TD were given on Mondays and Thursdays. From the third until the seventh week, daily tumor doses (5 was
5
70 -
: 2 h
60 -
s
50
RESULTS Figure I shows the survival curves for both treatment groups. Statistically, there is no significant difference between patients treated with and without misonida7ole (p
XRT ?? MISONIDAZOLE
-
g g
40 -
8 !T 30Y F u
20 -
$ 2
-
lo1 0 c,
3-77
12 I
15I
I*---%
G---27 V-T-
30
I
--
MONTHS Fig.
1. Kaplan-Meier
survival plots for patients receiving irradiation
alone (XRT)
or irradiation
plus misonidazole
High-grade astrocy%?mastreated with misonidazole and irradiation 0 B.
-_.__
T----
3
--
171
et ol
tration. In combination with steroids.” neurologic side effects such as peripheral neuropathies and tinnitus were minimal despite the use of relatively high cumulative g/m’). Three doses of misonidazole of 27 g (12.6-16.4 out of 18 patients ( 17%) experienced mild stocking-like paraesthesias on the lower extremities at the end of the second treatment week, which lasted a few weeks. In 5 of 18 patients (28%) a transient tinnitus occurred at the same time.
> 0.08). The mean survival time of the misonidazole group ( 13.8 months) is not significantly longer than that of the group having received irradiation alone (9.8 months). The corresponding 1 year survival rates are 64 and 2590, respectively. In our study there was an even distribution of patients with radical or subtotal surgery in both treatment arms (55 and 56% radical and subtotal operations, respectively). Patients with complete surgery lived significantly longer (p < 0.0009), median survival 13.8 vs. 6.7 months (Fig. 2). There were no significant differences in Kamofsky performance status, sex and in histological grade distribution between the groups. The mean age of the patients is 52 years in the sensitizer group; for patients treated by irradiation alone it is 56 years. The age distribution also shows no statistically significant difference (p > 0.3). Mean serum levels 4 hours after administration of 4.5 g (2.1-2.7 g/m2) misonidazole were usually in the range of 90-160 mg/1.‘7.‘9 With these serum levels significant sensitizer enhancement ratios may be expected.‘.8 There was no adverse influence of misonidazole on renal or hepatic parameters. All other hematologic examinations also remained within normal limits. The drug was well tolerated with the use of antinausea medications 30 minutes before misonidazole adminis-
SUBTOTAL
ST4DLER
DISCUSSION The most important factors influencing prognosis of high-grade astrocytomas are the type of surgery performed, histopathologic grade, the age at time of operation and the initial performance status. In our study there is a clear indication of shorter survival in patients who had subtotal removal of the tumor as compared to patients with ‘complete’ surgery (p < 0.0009), (Fig. 2). Other authors found similar differences in survival in their investigations.4,‘,“” Patients with grade III tumors have a significantly better survival than patients having grade IV lesions.24 In our small series there was an even distribution of histological grades between the treatment groups and no dependence
I __ _
----
6
---
9
12
15
18
21
I
24
,
I
27
30
MONTHS Fig. 2. Kaplan-Meier
survival plots for patients with complete
or subtotal surgery.
1716
Radiation Oncology 0 Biology 0 Physics
of survival on histological grade could be found. Also, the initial Kamofsky performance status as well as the age distribution of patients were equal between our treatment groups. An important factor for survival are radiotherapeutic parameters, especially tumor dose and treatment volume. Many authors emphasized the value of large treatment fields for adequate coverage of the tumors. They found a significant longer survival in patients with larger treatment volumes than in those treated with limited fields.20.25 In contradiction to these findings, Maire,” suggested, in a retrospective analysis of computerized tomographic scans, restricting the irradiated volume to the tumor site and to presumptive extension pathways. This is because more than 95% of the patients show recurrence within the original tumor site, and radiation damages in normal brain tissue could impair the quality of life. Nevertheless, neuropathologists describe a plane tumor extension on the brain surface in some high-malignant astrocytomas.26 Patients receiving higher radiation doses show a longer surviva1.24*25,28 The dose used in our study corresponds with the recommendations of Kramer and Salazar et a1.20.25We employed doses equivalent to 1890 ret, which equals about 70 Gy in 7 weeks. A shrinking field technique, which is now generally recommended, was applied. In a previous publication, the preliminary results of our study had shown a statistically significant better survival for patients receiving misonidazole.‘* In the current analysis, the significance of the survival advantage for the
September 1984, Volume 10, Number 9
misonidazole group was lost (Fig. 7), although the mean survival time for these patients of 13.8 months is still much longer than that for the patient group that received irradiation alone (9.8 months). However, because of the relatively small number of patients in either arm, a statistical analysis may weaken the chance of getting a positive result. So far, the preliminary and final results of all studies investigating misonidazole as a radiosensitizer for highgrade astrocytomas are rather disappointing,5.‘0.“.‘2.22.23 and do not indicate a real gain in survival In some of these studies, additional chemotherapy was also included as part of the treatment.“*** Although intercomparison of all the mentioned studies might be difficult because of the marked variations in the treatment protocols, the overall negative results seem to indicate that misonidazole is not the desired radiosensitizer for high-grade astrocytomas. Still, final results of ongoing trials have to be reported before firm conclusions about the value of misonidazole can be made. In particular, the outcome of an ongoing EORTC-study using misonidazole and multiple daily radiation fractions will be of great interest; in the pilot study, encouraging results had been reported.’ With the development of new radiation sensitizers with improved therapeutic ratios, it should be possible in the near future to indicate clearly whether poorly reoxygenating hypoxic tumor cells are the major cause of the current inability to improve survival of high-grade astrocytomas.
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