Journal of Neuro-Oncology 13: 261-264, 1992. © 1992KluwerAcademic Publishers. Printedin the Netherlands. Clinical Study

Pre-radiation chemotherapy in glioma patients with poor prognostic factors Kjell Watne, 10le Nome, 1 Bjarne Hager 2 and Henry Hirschberg 3 The Departments of i Oncology and 2Radiology, The Norwegian Radium Hospital, Oslo, Norway and 3Department of Neurosurgery, The National Hospital, Oslo, Norway

Key words: glioblastoma multiforme, pre-radiation chemotherapy, vincristine, CCNU, procarbazine Summary

Nineteen patients in an age group from 56-67 years (mean age 62,5 years) with histologically verified glioblastoma multiforme were treated with chemotherapy consisting of two cycles of oral CCNU, intravenous vincristine and oral procarbazine prior to radiation therapy. Ten of the patients had stable disease, monitored by CT scan and neurological examination, and received whole brain radiation. The median survival was 12 months. Nine patients who had progressive disease during chemotherapy did not receive radiation treatment and were put on palliative treatment with dexamethasone. This group had a median survival of 3 months. The median survival in all of the 19 patients who entered the study was 9 months which was comparable to the survival of 56 patients with glioblastoma multiforme who, in a retrospective study, received post-operative radiotherapy. The most important factor predicting survival was steroid-dependency after surgery.

Introduction

The malignant glioma carries an extremely poor prognosis particularly in older patients and in patients with a poor performance status [1-4]. Median survival of patients over 60 years is generally reported as less than six months with few, if any, long-term survivors [5-7]. Despite current therapy survival is predictably limited and local control of the tumor difficult if not impossible to achieve. A limited number of the patients will certainly benefit from radiation treatment, but the problem of selection has been difficult [5, 7-9]. In a recent study at the Norwegian Radium Hospital (NRH) 79 patients with malignant glioma received post-operative intra-carotid chemotherapy (BCNU) followed by radiation [10]. One of the findings from this study was that there might be a parallelism between sensitivity to chemotherapy and sensitivity to radiation. Most patients who responded to chemotherapy also apparently had a

response to radiation. In contrast none of the patients who had progressive disease during initial chemotherapy, had a beneficial effect of subsequent radiation [10]. These results prompted us to commence a study in glioma patients with poor prognostic factors (age over 55 years and/or poor performance status) employing a simplified treatment protocol. The patients received 2 cycles of combined chemotherapy consisting of oral procarbazine and CCNU and intra-venous vincristine (PCV). If the patients had stable disease after chemotherapy, radiation was initiated. In patients who had progressive disease during chemotherapy palliative treatment with dexamethasone was started and no radiation was given. The initial results of this trial are reported here.

Materials and methods

Nineteen patients harboring glioblastoma multi-

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Fig. 1. Survival of the 10 patients who received 2 cycles of PCV followed by radiation ( .) compared to the survival of the 9 patients who progressed during chemotherapy ( - - - ) .

forme were referred to the program following craniotomy with tumour resection. In all patients a CT scan was performed 2 days after craniotomy in order to have a baseline CT in the further evaluation of the patients. The mean age was 62,5 years (56-67 years). There were 8 females and 11 males. Thirteen of the patients had an ECOG performance status of 0-2, whereas 6 patients had an ECOG status of 3-4. Eleven of the patients were steroid dependent after operation, whereas 8 patients were off steroid medication. Chemotherapy started 2 weeks after operation. Vincristine 2 mg was administered by a peripheral vein and 160 mg CCNU was administered orally on day 1. Procarbazine 50 mg 3 times daily was administered orally day 2-8. Dexamethasone 4mg 4 times daily was started on day 1 and then scaled down and discontinued after 10 days. A second

course of chemotherapy was administered after 6 weeks. Blood counts were performed before each cycle of chemotherapy. No cases of bone marrow depression were seen after chemotherapy. A neurological examination was performed before each cycle of chemotherapy. The performance status using ECOG scale (0 = fully active, 1 = ambulatory, light work, 2 = in bed less than 50% of the time, self care, 3 = in bed more than 50% of the time, limited self-care, 4 = completely bed-ridden, no self-care) were noted. If the patient's clinical status deteriorated during chemotherapy, palliative treatment with dexamethasone was initiated. In the patients who experienced clinical improvement or stabilisation associated with a tapering down of dexamethasone treatment, CT scan with and without contrast were performed to confirm the regression or stabilisation of the tumor. Radiation therapy was then instituted. The radiotherapy technique employed two opposed portals encompassing the whole brain to a midline dose of 5400cGy in 30 fractions. Both fields were treated daily and treatment was given on a 5-day week schedule. In order to compare our results with historical controls, all medical records of patients with brain tumors treated between 1983 and 1990 were reviewed. In this period 56 patients older than 55 years and harboring glioblastoma multiforme had received post-operative radiotherapy. In all patients a craniotomy with a radical tumour resection was performed and all patients received post-operative radiotherapy employing two opposed portals encompassing the whole brain to a midlinc dose of 5000 cGy in 25 fractions. Both fields were treated

Table 1. Survival in months in both treatment groups related to the most important prognostic factors. Control group**

PCV group*

ECOG Steroid depend.

0-2 3-4 +

No of patients

Survival (months)

No of patients

Survival (months)

13 6 8 11

10 6 10 5

38 18 42 14

10 5 11 5

p = 0.1 p = 0.003

* Two cycles of chemotherapy (procarbazine, CCNU, vincristine) before radiation. ** Radiation only.

p = 0.04 p = 0.003

263 daily on a 5-day per week schedule. This group is later referred to as the control group. The mean age was 63 years (56-76 years). Eighteen of the patients were females, whereas 38 were males. Forty-two of the patients were not steroid dependent, whereas the remaining 14 patients were steroid dependent. Eighteen of the patients had an ECOG performance status of 3-4 whereas 38 patients had an ECOG performance status of 0-2. The main characteristics are shown in Table 1.

Results

In the PCV group the median survival of all 19 patients was 9 months. The survival of the 10 patients who had stable disease confirmed by CT scan and who received radiation was 12 months which was significantly better than the survival of 3 months observed in patients who had progressive disease during chemotherapy (Fig. 1). There was no difference in the extent of tumour resection in the two treatment groups. Only one of the 11 patients who were steroid dependent responded to treatment. The median survival of 10 months in the patients who were not steroid dependent was significantly better than the survival of only 5 months in the patients who were steroid dependent (Table 1). The patients who had a good performance status had a slightly, although not significantly better survival (Table 1). In the control group the median survival was 9 months. As in the PCV group, the patients who were steroid dependent had a significantly poorer survival compared to the patients who were not steroid dependent (Table 1). The patients with poor performance status had a significantly poorer survival compared to those with initial good performance status (Table 1).

standard 6 week course of post-operative radiotherapy is disproportionately long, given their poor prognosis for survival [11-13]. There is therefore a need to improve the survival-treatment time ratio by decreasing the standard treatment time and also a need to find a way to select out those patients who will benefit from radiation. In this study the median survival was 9 months both in the pre-radiation chemotherapy group and in the control group who received adjuvant radiotherapy. The most important difference between the two patient populations is that the patients included in the current PCV trial could return home one week after operation. The chemotherapy could then be given ambulatory by the local hospital, allowing the patient to stay at home for 3 months during which time the patient's performance status is at the highest level. The patients who had stable disease could thereafter be given radiotherapy. The median survival of 12 months in this patient group is better than the survival of 9 months in the control group. It could be argued that the patients who had progressive disease during chemotherapy and who thereafter received palliative treatment with steroids, could have benefitted of early radiation. Our earlier results with 79 patients with malignant gliomas have shown however, that a correlation exists between sensitivity to chemotherapy and radio-responsiveness [10]. In both the PCV- and control group steroid dependency had a marked impact on survival and the combination of chemotherapy and radiation did not improve the poor outcome in these patients. Admitting the imperfections of a non-randomized study and of a small number of patients our data suggest that glioma patients with poor prognostic factors (older age and/or poor performance status) should first be treated with pre-radiation PCV chemotherapy, thus allowing the selection of the patients who will benefit most by further radiation therapy.

Discussion References

The malignant glioma carries an extremely poor prognosis particularly in the older patients and in patients with a poor performance status and the

1. Walker MD, Alexander E, Hunt WE, MacCartyCS, Mahaley MS, MealeyJ, Norell HA, Owens G, RansohoffJ,

264

2.

3.

4. 5. 6.

7.

Wilson CB, Gehan EA, Strike TA: Evaluation of BCNU and/or radiotherapy in the treatment of anaplastic gliomas. J Neurosurg 94: 333-343, 1978 Chang CH, Schoenfeld D, Horton J, Salazar O, PerezTamayo R, Kramer S: Comparison of postoperative radiotherapy and combined postoperative radiotherapy and chemotherapy in the multidisciplinarymanagement of gliomas. Cancer 52: 997-1007, 1983 Cooper JS, Borok TL, Ransohoff J, George A, Lin J, Newall J: Results of combined modality therapy. JAMA 248:62-65 Hochberg FH, Pruitt A: Assumptions in the radiotherapy of glioblastoma. Neurology 30: 90%911, 1980 Newall J, Ransohoff J, Kaplan B: Glioblastoma in the older patient. J Neuro-Oncol 6: 325-327, 1988 Hatlevoll R, Lindegaard KF, Hagen S, Kristiansen K, Nesbakken R, Torvik A, Ganz JC, Mella O, Rosengren B, Ringkj0b R, Arnasson O, Lindgren S, Lipecki M, Notter G, Littbrand B, S~iterborg N-E, Benediktsson G, Johansson L, Sp/innare B, Brun A, Berthelsen A, Busch H, Gr6nbacke E, Ryg~rd J, Haase JP, Lambrethsen E, Midholm S, Sehested P, Heikkinen M, Nystr6m S, Taskinen P, M~intyl~i M, Elgen K, Aaskoven O, De Garris ST, Jensen RH, Matheson AI: Combined modality treatment of operated astrocytomas grade 3 and 4. A prospective and randomized study of misonidazole and radiotherapy with two different radiation schedules and subsequent CCNU chemotherapy. Stage II of a prospective multicenter trial of the Scandinavian Glioblastoma Study Group. Cancer 56: 41-47, 1985 Gehan HA, Walker MD: Prognostic factors for patients

8.

9.

10.

11.

12.

13.

with brain tumors. In: Modern Concepts In Brain Tumor Therapy: Laboratory and Clinical Investigations. National Cancer Institute Monograph, No. 46, DHEW publication No. NIH 77-1236. Washington DC: Government Printing Office, 189-195, 1977 EORTC Brain Tumor Group. Effect of CCNU on survival rate of objective remission and duration of free interval in patients with malignant brain glioma - Final evaluation. Eur J Cancer 14: 851-856, 1978 Onoyama Y, Abe M, Yabumoto E, Sakamoto T, Nishidai T, Suyama S: Radiation therapy in the treatment of glioblastoma. Am J Roentgenol 126: 481-492, 1976 Watne K, Nome O, Hager B, Hirschberg H: Combined intra-arterial chemotherapy and irradiation of malignant gliomas. Acta Oncol 30: 001, 1991 Byar DP, Green SB, Strike TA: Prognostic factors for malignant glioma. In: Walker MD (ed) Oncology of the nervous system. Martinus Nijhoff, Boston 379-395, 1983 Nelson JS, Tsudaka Y, Schoenfeld D, Fulling K, Lamarche J, Peress N: Necrosis as a prognostic criterion in malignant supratentorial astrocytic gliomas. Cancer 52: 550-554, 1983 Garrett MJ, Hughes HJ, Freedman LS: A comparison of radiotherapy alone with radiotherapy and CCNU in cerebral glioma. Clin Oncol 4: 71-76, 1978

Address for offprints: Kjell Watne, Dept. of Medical Oncology, The Norwegian Radium Hospital, Oslo, Norway