Japanese Journal of Clinical Oncology 31:246-250 (2001)
© 2001 Foundation for Promotion of Cancer Research
Radiotherapy Combined with Nimustine Hydrochloride and Etoposide for Malignant Gliomas: Results of a Pilot Study
1Neurosurgery Division, National Cancer Center Hospital and 2Pathology Division, National Cancer Center Research Institute, Tokyo, Japan
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Background: The aim of this study was to examine the effectiveness of radio-chemotherapy using nimustine hydrochloride (ACNU) and etoposide (VP-16) for malignant gliomas.
Methods: From 1985 through 1998, 33 consecutive patients with supratentorial malignant gliomas were treated by a single protocol. The mean age was 45.8 years (range 12–76 years). The median Karnofsky performance score was 80 (range 60–100). There were 14 anaplastic astrocytomas (AA) and 19 glioblastomas (GBM). Following surgery, 60 Gy of radiotherapy combined with an adjuvant chemotherapy using ACNU (80 mg/m2 i.v. days 1 and 36) and etoposide (80 mg/m2 i.v. days 2, 3, 37 and 38) was administered. On completion of the initial radio-chemotherapy, a single cycle of the same chemotherapy was repeated every 6–8 weeks until tumor progression or for 2 years at the maximum.
Results: All 33 patients tolerated treatment. We observed complete response in five cases (15%), partial response in nine (27%), no change in 11 (33%) and progressive disease in eight (24%). The response rate (>50% reduction) was therefore 42.4%. Median progression-free survival (PFS) for all 33 patients was 8.4 months: 7.8 months for GBMs and 13.5 months for AAs. There was no significant difference in PFS between GBM and AA patients (p = 0.14). The median survival time of all 33 patients was 21.1 months: 16.2 months for GBMs and 49.9 months for AAs. The difference in survival between AA and GBM was statistically significant (p = 0.0019). Myelosuppression appeared in 11 patients: grade 2 hematological toxicity in 10 cases (30%) and grade 3 in one case (3%). We did not observe any gastrointestinal toxicity. Multivariate analysis showed that age and initial histological grade had independent prognostic significance.
Conclusion: RT with ACNU and etoposide are feasible and well tolerated and the treatment results were comparable to the best results reported in the literature.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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The prognosis of patients with malignant gliomas has not improved significantly over the past three decades. One of the reasons is that these tumors generally show marked resistance to conventional radio-chemotherapy, which achieves only around 1 year median survival at best (1). Three major factors are known to contribute to the chemo-resistance of malignant gliomas: (1) the blood–brain barrier (BBB) hindering the drug delivery to the tumor cells, (2) unique cell-cycle kinetics with most tumor cells staying at the G0 stage and (3) intra-tumoral heterogeneity leading to rapid development of drug resistance (2–5). Currently used chemotherapy protocols are designed with the aim of overcoming those negative factors by combining several reagents with different modes of action and other characteristics. Since 1985, we have adopted combination chemotherapy using nimustine hydrochloride (ACNU) and etoposide (VP-16). Etoposide is a cell cycle-specific agent that blocks tumor cell proliferation at the G2 phase by damaging DNA by interacting with topoisomerase II (6). In various animal tumors, etoposide has shown synergistic effect with carmustine, cisplatin, carboplatin and vincristine (7). By combining etoposide with ACNU, one of the most popular cell cycle non-specific alkylating reagents used for malignant gliomas, we expected that there might be a synergistic effect which would improve the treatment response of malignant gliomas (8–10). In this study, we retrospectively analyzed our 13-year experience of ACNU–etoposide combination chemotherapy administered as an adjuvant therapy with radiation and also as a maintenance chemotherapy.
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PATIENTS AND METHODS |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Thirty-three consecutive patients with supratentorial malignant glioma treated at the National Cancer Center Hospital from 1985 to 1998 were reviewed retrospectively. Histological diagnosis was made by a staff pathologist (Y.N.) and the tumors were classified according to the World Health Organization classification (11). All patients had Karnofsky performance status (KPS) >60 on admission, and normal hematological, hepatic and renal function. Patients first underwent surgical removal of the tumor, followed by radio-chemotherapy which was started within 2 weeks after the surgery. A radiation dose of 60 Gy in 30 sessions was prescribed using a 6 MV photon beam collimated by a multi-leaf collimator which was equipped with a linear accelerator (NELac 1012A, NEC, Tokyo, Japan). CT was taken to feed three-dimensional treatment data to a treatment planning machine (FOCUS, Computerized Medical Systems, Maryland Height, MO). Clinical target volume I (CTV-I) was determined in the tumor region and its surrounding edema on the treatment planning machine with reference to MR images taken before and after surgical resection. Clinical target volume II (CTV-II) was also determined in the tumor area with a 1 cm margin on the treatment machine. Planning treatment volumes I and II (PTV-I and II) were determined within the area including the 1 cm margin outside the CTV-I and CTV-II, respectively, using a three-dimensional treatment plan which included conformal radiotherapy. For adjuvant chemotherapy, ACNU (80 mg/m2, i.v.) was administered on days 1 and 36 and VP-16 (80 mg/m2, i.v.) was administered on days 2, 3, 37 and 38. After completion of the initial radio-chemotherapy, the same chemotherapy (ACNU on day 1 and VP-16 on days 2 and 3) was repeated every 6–8 weeks for 2 years or until the tumors progressed despite the therapy. All patients received at least two cycles of chemotherapy. Most of the patients received betamethasone after surgery, which was tapered off in all cases. Complete blood counts including white blood cell differential and platelet counts were performed every 2 weeks during the chemotherapy. The toxicity of the therapy was monitored using the National Cancer Institute (NCI) Common Toxicity Criteria.
All patients were evaluated for treatment response after each cycle of chemotherapy by comparing the volume of contrast enhancing mass on CT or MRI each time with that of the first post-operative CT or MRI. Complete response (CR) was defined as complete disappearance of the enhancing lesion, partial response (PR) as >50% reduction in tumor size, no change (NC) as <50% reduction or <25% increase in tumor size and progressive disease (PD) as >25% increase in tumor size or development of any new lesion. Tumors were considered to have responded to the therapy if they showed CR or PR at any time point. Post-operative tumor volume (Vpost-op) was defined as residual tumor volume immediately after surgery and post-treatment volume (Vpost-tx) was defined as the tumor volume after the completion of chemoradiotherapy. The progression-free survival (PFS) was defined as the time from the initial operation to the development of progressive disease on CT scan or to the last follow-up. Cox proportional hazards model analysis was used to determine factors predictive of survival time. The PFS and survival time were calculated by the Kaplan–Meier method. Differences in survival were assessed by the log-rank test. For categorical variables, a two-tailed Fisher’s exact test was used. Initial histological grade, age (<50 vs >50 years), KPS (<80 vs >80), gender, Vpost-op (<5 vs >5 ml) and Vpost-tx (<5 vs >5 ml) were assessed for prognostic significance for survival on univariate analysis in patients with malignant gliomas.
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RESULTS |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Patients’ Characteristics
There were 19 men and 14 women with ages ranging from 12 to 76 years (mean, 45.8 years). Follow-up periods ranged from 8 to 87 months (median, 18.4 months). Histological diagnosis of the tumor was anaplastic astrocytoma (AA) in 14 (42%) and glioblastoma (GBM) in 19 (58%). All 33 patients were fully evaluable for PFS, survival time and toxicity. The median preoperative Karnofsky performance score was 80 (60–100, mean 77.5). The initial tumor volume measured as contrast-enhanced mass ranged from 8.1 to 113.0 ml (mean 44.3 ml). Four patients had biopsy only, 14 had partial resection (<95% removal) and 15 had subtotal resection (>95% removal). There was no surgery-related morbidity or mortality. Vpost-op ranged from 0.4 to 52.2 ml (mean, 12.3 ml; median, 7.4 ml) and Vpost-tx ranged from 0 to 32.7 ml (mean, 10.0 ml; median, 6.5 ml) (Table 1).
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Tumor recurrence was confirmed in 29 patients, while four remained progression-free at the last follow-up. The median cycle of the maintenance chemotherapy was 2 (0–10, mean 3.9). Treatment for recurrence varied among patients: 10 patients underwent reoperation and received chemotherapy of whom three received additional irradiation and 14 patients received chemotherapy of whom two received immunotherapy using immunomodulating cytokines and immune effector cells such as lymphokine-activated killer cells (LAK cells).
Response to treatment was CR in five cases (15%), PR in nine (27%), NC in 11 (33%) and PD in eight (24%). The overall response rate was therefore 42.4% (CR and PR).
Median progression-free survival (PFS) was 8.4 months for all 33 patients, 13.5 months for AA and 7.8 months for GBM. One-year PFS was 57% for AA and 21% for GBM and 3-year PFS was 36% for AA and 7% for GBM. The difference in PFS between AA and GBM patients was not statistically significant, although there was a tendency for worse PFS in GBMs (p = 0.14, Figure 1). On the other hand, the difference in PFS between responders and non-responders was statistically significant (p = 0.01). A significant association was found between Vpost-op <5ml and Vpost-tx <5ml (p = 0.0366, Fisher’s exact test). When PFS was compared by Vpost-op or by Vpost-tx, Vpost-op did not significantly affect PFS (p = 0.6), whereas patients with <5 ml Vpost-tx (n = 17) had significantly better PFS than patients with >5 ml Vpost-tx (n = 16, p = 0.0256, log-rank test, Figure 2). Tumor regrowth occurred in four (28%) of the 14 patients with <5 ml Vpost-op. Tumors continued to shrink with the maintenance chemotherapy in six (32%) of the 19 patients with >5 ml Vpost-op.
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5 ml in volume and those with tumors >5 ml. p = 0.0256.The median survival for all 33 patients was 21.1 months; 16.2 months for GBM and 49.9 months for AA. The difference between AA and GBM was statistically significant (p = 0.0019, Figure 3). Median survival for the treatment responders (n = 14) was 36.2 months, whereas it was 17.8 months for the non-responders (n = 19, p = 0.0525, log-rank test). Of the five complete responders (1GBM, 4AA), four were still alive at the last follow-up (median 46.4 months) and one died 36.2 months after the initial surgery.
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Factor Analysis
Among the factors examined, initial histological grade, KPS > 80, Vpost-tx <5 ml and age <50 years were significant prognostic factors. On the other hand, Vpost-op <5 ml was not a statistically significant prognostic factor. In multivariate analysis, histological grade and age were the independent survival predictors (Table 2).
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Complications
The toxicity observed in this series is summarized in Table 3. The only major complication caused by this treatment was myelosuppression (white blood cells <2000/mm3 or platelets <50 000/mm3), which was observed in 11 patients: grade 2 in 10 (30%) and grade 3 in one (3%). Grade 3 memory loss and grade 2 mood alteration occurred in three patients (9%), who survived more than 30 months. These CNS complications were due partly to radio-chemotherapy. We did not observe any gastrointestinal toxicity.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Our experience presented here showed that the combined chemotherapy with ACNU and etoposide, used both for adjuvant therapy with radiotherapy and for maintenance chemotherapy, provided good results in PFS and actuarial survivals, 8.4 and 21.1 months, respectively. These results are equivalent to the best results reported in the literature using other reagents (12–15). The treatment was relatively well tolerated with a small number of major complications. We also confirmed that the age and histological grade at the initial treatment were important prognostic factors, as previously reported.
An interesting observation was that V post-tx, the minimum tumor volume after the completion of maintenance chemotherapy, was associated with PFS, whereas Vpost-op, the tumor volume immediately following the initial surgery, was not. One of the reasons for this dissociation was that there was a significant variation among individual tumors in the responsiveness to the post-operative treatment. For instance, of 19 patients with a tumor with >5 ml Vpost-op, tumors continue to shrink with the maintenance chemotherapy in six (32%), whereas tumors progressed almost immediately in four (29%) of 14 patients with a tumor with <5 ml Vpost-op. Therefore, response to the chemo-radiotherapy was likely to be an important factor affecting the time to progression. On the other hand, there was a strong association between Vpost-op and Vpost-tx, confirming that surgical resection is an important measure to realize a reduction in the minimum Vpost-tx, which in turn should lead to longer PFS. Therefore, our study is also in line with the notion that maximum surgical resection is preferable for patients with malignant gliomas. However, the overall survival was not statistically better for patients with <5 ml Vpost-tx, indicating that deterioration following recurrence still remained rapid and fatal.
In our study, patients with AA generally had significantly better survival benefit from treatment than those with GBM, which agrees with many other studies showing that the tumor grade is the most important prognostic factor in gliomas. Although the molecular mechanism for such differences is not yet clear, it is well known that GBMs generally harbor much more genetic alterations than lower grade gliomas, which would provide a possible explanation for this difference (16).
Although we did not observe it in this series, secondary acute non-lymphocytic leukemia has recently been described in patients receiving etoposide (17,18). There seems to be specific clinical features for this etoposide-induced secondary leukemia: (1) the median latent period is shorter at 12–18 months compared with 48–72 months for secondary leukemia induced by other drugs, (2) bone marrow shows a predominance of monocytic or myelomonocytic features and (3) abnormalities of chromosome 11 are common. Because of its mode of action, etoposide has a high risk of chromosomal damage and the effect is known to be cumulative. Therefore, careful monitoring for the total dosage of etoposide is required in this chemotherapy regimen.
In summary, although our treatment protocol with ACNU, etoposide and radiotherapy could not clearly show superiority over other regimens in this relatively small study, it is a promising approach for treating malignant gliomas both in theory and in preliminary results. A prospective randomized study would be necessary to demonstrate the possible benefit more conclusively.
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FOOTNOTES |
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+ For reprints and all correspondence: Minoru Tanaka, Neurosurgery Division, National Cancer Center Hospital, 1–1, Tsukiji 5-chome, Chuo-ku, Tokyo 104-0045, Japan. E-mail: mntanaka-nsu@umin.ac.jp
Abbreviations: ACNU, nimustine hydrochloride; VP-16, etoposide; AA, anaplastic astrocytomas; GBM, glioblastomas; RT, radiotherapy; KPS, Karnofsky performance status; NCI, National Cancer Institute; CR, complete response; PR, partial response; NC, no change; PD, progressive disease; Vpost-op, post-operative tumor volume; Vpost-tx, post-treatment volume; PFS, progression-free survival
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Received October 12, 2000; accepted February 26, 2001.
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