KISEP J Korean Neurosurg Soc 35 : 127-135, 2004

Clinical Article Clinical Study : Phase II Study of Continuous ACNU (nimustine) and CDDP () Infusion Followed by Conventional Radiotherapy in Patients with High Grade Astrocytomas

Seung-Joon Lee, M.D.,1,4 Sang Hyung Lee, M.D.,1,4 Hee-Won Jung, M.D.,1,4 Chae-Yong Kim, M.D.,1,4 Dae Seog Heo, M.D.,2 Il Han Kim, M.D.3 Departments of Neurosurgery,1 Internal Medicine,2 and Radiation Oncology,3 Seoul National University College of Medicine, Seoul, Korea Neuroscience Institute4 of Medical Research Center, Seoul National University, Seoul, Korea

Objective : This study is aimed at evaluating the efficacy and the toxicity of a 72-hour continuous intravenous infusion of ACNU and CDDP before radiotherapy in adult patients with newly diagnosed anaplastic astrocytoma and glioblastoma. Methods : Forty-three adult patients with a postoperative Karnofsky performance status greater than 60 were entered into this protocol without any prior treatment. Two cycles of preradiation were performed at 6-week intervals. Conventional radiotherapy was begun 6 weeks later. Magnetic resonance (MR) imaging studies were conducted pre- and postoperatively, and follow-up MR images at the beginning of each treatment and every three months after radiotherapy completion. Response rate, survival rate, prognostic factors and complications were evaluated. Results : Among 43 patients mentioned above, twenty-one patients completed two cycles of chemotherapy. One patient showed complete remission, ten partial response, seven stable disease and three progressive disease. The median survival time was 15.9 months. Overall response rate was 22.3%. Twenty-seven showed pancytopenia, including two bleeding tendencies, one intracerebral hemorrhage resulting to death, and another two infections. Considering the prognostic factors, only a mutated p53 level of under 20%(% of tumor cells containing mutated p53) was correlated with survival prolongation. Prognostic factor of age under 45 was the only significant factor of extending the time to progression. Conclusion : This treatment protocol shows favorable results of preradiation chemotherapy using ACNU and CDDP.

KEY WORDS : ACNU Anaplastic astrocytoma CDDP Chemotherapy Glioblastoma Radiotherapy.

Introduction local versus systemic-have been examined to achieve remission, to maintain a progression-free state, or to prolong lifetime. In n spite of the recently developed treatment modalities, 1997, Grossman et al. performed on a phase II study of the I high grade astrocytoma, including anaplastic astrocytoma continuous infusion of (BCNU) and cisplatin and glioblastoma, are known as the most dedifferentiated followed by cranial irradiation in adults with newly diagnosed gliomas, showing diffuse infiltration, rapid progression and high grade astrocytoma and reported a median survival of 13 repeated recurrence. Many adjuvant treatment modalities months8). have been employed, but no treatment option has survived Because ACNU was more widely used compound, scrutiny, except postsurgical conventional radiotherapy (CRT). and verified as an effective one, the authors planned a prosp- Since conventional radiotherapy have been performed as an ective Phase II study of the two-cycle continuous infusion adjuvant therapy, many combinations of treatment modalities- using nimustine hydrochloride(ACNU), instead of BCNU, and cisplatin followed by CRT in patients with newly diagnosed Received：June 17, 2003 Accepted：August 28, 2003 Address for reprints：Sang Hyung Lee, M.D., Department anaplastic astrocytoma or glioblastoma to evaluate response of Neurosurgery, Neuroscience Institute of Medical Research, rate, to estimate median survival time and time to progression, Seoul National University College of Medicine, Boramae Hospital, and to identify the prognostic factors influencing survival and Sindaebang 2-dong, Dongjak-gu, Seoul 156-707, Korea Tel：02) 840-2481 , Fax：02) 831-2826 progression. Futhermore, we designed more prolonged treatment E-mail： [email protected] intervals by six weeks to monitor the toxicity of the protocol.

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Materials and Methods The second chemotherapy was adjusted in case of continued myelosuppression, that is, dosage of chemotherapeutic agent he clinical protocol was approved by the Institutional was reduced by 25% if the white blood cell(WBC) count was T Review Board of The Clinical Research Institute of the 3,000 /μL ~ 4,000 /μL or the platelet count 75,000 /μL ~ 100,000 author's hospital. Informed consent was obtained from all / L. If the WBC was under 3,000 /μL or the platelet count patients enrolled. under 75,000 /μL, the protocol was suspended for one week. If absolute neutrophil counts decreased under 1,500 the Criteria for patient enrollment second cycle was not performed, and CRT was performed Patients were enrolled if they met the following conditions : immediately. 1) they were between 18 and 70 years of age with a histologically Treatments were resumed when the hematologic profiles confirmed supratentorial anaplastic astrocytoma or glioblastoma ; met the prechemotherapy criteria. Chemotherapy was ceased 2) they had Karnofsky performance scale(KPS) of greater and CRT was initiated if MR performed before the second than 60 when being exposed to chemotherapy ; 3) they had a chemotherapy cycle revealed an increase in the contrast- normal hematologic (WBC count > 4,000 /μL and platelet enhancing tumor volume of more than 25% of the previous count > 100,000 /μL), renal (creatinine clearance > 50 ml/min), value, or if the neurologic status had worsened even though and hepatic (total bilirubin level < 2.0 mg/dL) profiles; and 4) the corticosteroid dose had been increased. they had not received any prior treatment. All patients with CSF seeding or a histological diagnosis of gliomatosis cerebri Conventional radiotherapy (CRT) were excluded. CRT was performed at a total dose of 60Gy, at 1.8Gy per day for five days a week. The field of irradiation was the area Treatment of contrast enhancement on the preCRT MR image including Chemotherapy the area of surrounding edema, and with a margin of 3cm. All patients had been hospitalized and operated either by According to this research protocol, radiation therapy was stereotactic biopsy or by tumor removal at the author's institute. initiated 6 weeks after the last chemotherapy. CRT was Oral intake was not limited during the chemotherapy. A total immediate engaged when progression was identified within of two cycles intravenous continuous infusion of ACNU(40 two cycles of chemotherapy. Even though postoperative or mg/m2/day) and cisplatin(40 mg/m2/day) for 72 hours were postchemotherapy MR revealed no residual enhancement; planned. Copious hydration including normal saline with CRT succeeded in all patients enrolled in this protocol, with potassium chloride was given before and following the adm- appropriate treatment dose adjustments, as determined by a inistration of chemotherapeutic agents. Antacid, such as rani- radiation oncologist. tidine, was injected intravenously every 8 hours. Diphenylhy- danto in or valproic acid was used as an anticonvulsant, orally Supportive care measures or intravenously. ACNU was prepared as described by Frequent blood samplings to monitor hematology and Grossman et al.8). Mannitol(20%) was used generously, if chemistry profiles were performed. Transfusions of platelet necessary, during the chemotherapy. and packed red blood cells were performed to maintain the Concurrent, continuous infusion of ACNU and cisplatin criteria above. Anticonvulsants were also closely monitored were administered via different venous routes. Chemothera- to maintain the appropriate level at the upper end of the pies were performed with 6-week intervals if the hematologic therapeutic range. Corticosteroids were administered if there parameters met the criteria mentioned at the start of the next were symptoms of increased intracranial pressure. Magn- schedule. Before the beginning of the chemotherapy, a magnetic esium and potassium were routinely supplied to prevent resonance imaging(MRI) study was performed to check the cisplatin-induced peripheral neuropathy. No limitation of disease progression, and more importantly, to serve as a means supportive cares or existed during this this for evaluating response. protocol period. The second chemotherapy was performed in the patients who did not have hematologic abnormalities and did not Measurement of responses and survival show progressive disease on follow-up MRI immediately Neurological examination, hematology and chemistry prior to commencement. The protocol was postponed for 10 profiles, and brain MRIs were obtained before initiating each weeks in the case of myelosuppression or hepatic dysfunction. chemotherapy treatment, before radiation therapy and at

128 J Korean Neurosurg Soc 35 SJ Lee, et al. three-month intervals after CRT. Responses to the chemotherapy considered to be non-assessable for response determination, were also assessed by comparing the contrastenhanced MR but assessable for toxicity and survival. Stable disease(SD) is images and neurological examinations. In addition, the imaging used to mean that the clinical status and enhancing volumes study was repeated whenever patients' neurological status did not satisfy the above criteria. Additional therapies including were deteriorated. The patients whose postoperative MRI did reoperation, Gamma Knife Surgery or palliative chemotherapy not show any measurable enhancement were not included in were available for patients with recurrence undergoing the the evaluation of response to the chemotherapeutic agent. presented protocol. The following response criteria were adopted to evaluate the efficacy of chemotherapy7). Complete response(CR) was Statistical analysis defined as the disappearance of all contrast-enhancing tumor One of the aims of this study was to determine the response in a patient with a stable or improving neurological examination, rate of two cycles of ACNU and cisplatin. The other was to without corticosteroids for more than 1 month. Partial response estimate the median survival and time to progression, and the (PR) required a reduction in the contrast-enhancing tumor third was to analyze covariates to identify prognostic factors. volume of more than 50% with a stable or improving neurological The 43 patients were divided into three groups. The first examination for more than 1 month. group was composed of those that completed the treatment Steroid medication was allowed for this group. Progressive course, the second was of those that completed one cycle of disease(PD) was defined as a greater than 25% increase in the chemotherapy accompanied by CRT, and the third group volume of contrast-enhancement on MR images or progressive contained those that received CRT without chemotherapy. neurological abnormalities. Patients who needed an increased The Kaplan-Meier method was employed to assess time to corticosteroid dose were considered as non-responders, and progression(TTP) and overall survival. TTP and overall survival those without residual measurable disease after surgery were were evaluated from the first day of chemotherapy to the date of progression, to the day of death Table 1. Characteristics of all 43 patients enrolled. Patient enrollment began in May 1999 and ended in January 2002(33 months). Three patients of anaplastic astrocytoma and 40 patients of glioblastoma were or to the last day of follow-up included. Nine patients with non-measurable disease in gadolinium-enhanced MR images immediate confirmed by medical records, postoperatively, and four patients that received postoperative CRT, because of their poor postoperative telephone investigations etc. performance status, were excluded from the response analysis. Fifteen patients received gross or near total removal, 15 subtotal removal, and 13 stereotactic biopsy. Twenty-seven patients(62.8%) were successfully Comparisons of group survival received two cycles of chemotherapy and radiation therapy. Twelve patients(27.9%) received one cycle of analyses were performed by using chemotherapy followed by CRT the log-rank test. A p-value < 0.05 Patients' factors Data Age was considered statistically sig- median 46.3 nificant, and p-value between 0.05 range 19 ~ 65 and 0.1 was considered to "show a Gender trend". For covariate analysis of male 26 female 17 survival and progression-free Prior surgery duration, the Cox Regression GTR+NTR 15 method was adopted. All statistical STR 15 analyses were performed using a Stereotactic biopsy 13 commercial program from Stati- Karnofsky Performance Scale (postoperative) no more than 70 6 stical Program Social Science 80 3 (SPSS) (version 10.0). 90 23 100 11 Results mean 88.6 Treatment groups two chemotherapy cycle 27 Patient characteristics one chemotherapy cycle 12 Patient enrollment began in May radiotherapy only 4 1999 and ended in January 2002 Pathology (33 months). A total of 43 patients anaplastic astrocytoma 3 glioblastoma 40 with newly diagnosed anaplastic GTR : gross total removal, NTR : near total removal, STR : subtotal removal astrocytoma and glioblastoma were

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Table 2. Responses to treatment protocols. Responses to the chemotherapy were assessed by comparing stereotactic biopsy or 3 weeks the contrast-enhanced MR images and neurological examinations. Complete response(CR) was defined as a from debulking surgery. Mean disappearance of all contrast-enhancing tumor in a patient with a stable or improving neurological examination. Partial response(PR) required a reduction in the contrast-enhancing tumor volume of more than postoperative Karnofsky perfor- 50% with a stable or improving neurological examination. Progressive disease(PD) was defined as a greater mance scale was 88.6(Table 1). than 25% increase in the volume of contrast-enhancement on MR images or progressive neurological abnormalities. Stable disease(SD) is used to mean that the clinical status and enhancing volumes did not Twenty-seven patients(62.8%) satisfy the above criteria. After the first chemotherapy(n=30), no CR was achieved. PR was achieved in were successfully received two 5(16.7%), SD in 14(46.7%), PD occurred 11(36.7%). After the second chemotherapy(n=21), one patients cycles of chemotherapy and radia- achieved CR(4.8%), 10 PR(47.6%), and 7 SD(33.3%). After the completion of CRT(n=18), one achieved CR(5.6%), 3 PR(16.7%), 8 SD(44.4%), and 6 had PD(33.3%), which resulted in an overall response rate of tion therapy. Twelve patients 22.3%(5.6% + 16.7% = 22.3%) (27.9%) received one cycle of che- CR PR SD PD unknown motherapy foll-owed by CRT. The after the first 9* (23.0 %) major reasons that patients did not chemotherapy (n=30) 0 5 (16.7 %) 14 (46.7 %) 11 (36.7 %) (n=39) complete two cycles of chemo- after the second therapy were disease progression chemotherapy (n=21) 1 (4.8 %) 10 (47.6 %) 7 (33.3 %) 3 (14.3 %) 0 and medical complications due to after radiotherapy the chemotherapeutic agents. (n=18) 1 (5.6 %) 3 (16.7 %) 8 (44.4 %) 6 (33.3 %) 0 Twenty-one patients(52.5%) exp- CR : complete response, PR : partial response, SD : stable disease, PD : progressive disease. * : unmeasurable because no tumor visible on the prechemotherapy MRI. overall response rate : CR + PR after radiotherapy erienced cytopenia after the first cycle of chemotherapy (n=40), six Table 3. Univariate analysis of prognostic factors(log-rank test). Analyses of probable factors, i.e., gender, age, resection, KPS, Ki-67 and p53 were performed on the data from 43 analyzable patients with respect to patients(22.2%) suffered it after time to progression and overall survival using the statistical methods described above. By univariate analysis the second cycle (n=27). for survival, a level of mutated p53 under 20% was the only statistically significant variable(p=0.009). Time to progression and an age under 45 were the only statistically significant variables(p<0.05). GTR and a p53 mutation level of under 20% just showed trends(p=0.051, and 0.055, respectively) Response for survival analysis for time to progression After the first chemotherapy (p-value) (p-value) (n=30), no CR was achieved. PR gender 0.740 0.396 was achieved in 5(16.7%), SD in age under 45 0.092 0.038 14(46.7%), PD occurred 11(36.7%). GTR 0.290 0.051 After the second chemotherapy KPS over 90 0.082 0.369 Ki-67 under 5% 0.760 0.299 (n=21), one patients achieved p53 mutation under 20% 0.009 0.055 CR(4.8%), 10 PR(47.6%), and 7 GTR : gross total removal including near total removal. KPS : Karnofsky Performance Scale. Ki-67 : proliferation SD(33.3%). Three patients(14.3%) index. p53 : percentage of tumor cells with a p53 mutaion had evidence of PD during the chemotherapy course on this enrolled onto this protocol. Three patients with anaplastic protocol. After the completion of CRT(n=18), one achieved astrocytoma and 40 patients of glioblastoma were included. CR(5.6%), 3 PR(16.7%), 8 SD(44.4%), and 6 had All of these patients were included in the survival and toxicity PD(33.3%), which resulted in an overall response rate of analysis. However, only 21 patients with residual measurable 22.3% (Table 2). disease after surgery, who fulfilled the designed chemotherapy One patient died due to an intracerebral hemorrhage with course, were eligible for response analysis. Nine patients with cytopenia after the second chemotherapy, the other did not non-measurable disease in gadolinium-enhanced MR images receive CRT, and a third was lost. Of the nine patients with immediate postoperatively were excluded from the response no residual measurable disease after surgery, five patients analysis. Four patients that received postoperative CRT suffered tumor recurrence after combined chemotherapy because of their poor postoperative performance status, were and radiotherapy. also excluded from the response analysis. Patient ages ranged from 19 to 65 years(mean, 46.3 years, 26 males and 17 Survival females). Surgical treatment before chemotherapy included The Kaplan-Meier survival curve for all patients enrolled debulking in 30 patients(69.8%) : 15 received gross or near into this research protocol is presented in Figure 1. Twenty- total removal, 15 subtotal removal, and 13 stereotactic biopsy. two patients died during the follow-up period, 14 patients Most patients began therapy on this protocol 2 weeks after remained alive to the last follow-up, and 7 were lost to

130 J Korean Neurosurg Soc 35 SJ Lee, et al.

Covariate analysis of prognostic factors 1.0 Covariate analyses of probable factors, i.e., gender, age, resection, KPS, Ki-67 and p53 were performed on the data from 43 analyzable patients with respect to time to progression and overall survival using the statistical methods described above. By univariate analysis for survival, a mutated p53 in level of under 20%(% of tumor cells containing mutated p53) .5 was the only statistically significant variable(p=0.009). Age under 45 and a KPS over 90 were not statistically meaningful, Cumulative Survival but show a trend(p=0.09, and 0.08 respectively). By univariate analysis, time to progression and an age under 45 were the only statistically significant variables(p<0.05). GTR and a 0.0 p53 mutation level of under 20% just showed trends(p=0.051, 0 12 24 36 48 Survival (Months) and 0.055, respectively) (Table 3). Four variables, which were identified as meaningful by univariate analysis were subject Fig. 1. Overall survival of all the patients enrolled by the Kaplan- to multivariate analyses using the Cox Regression method1,25). Meier method. Median overall survival is 15.9 months(95% CI 7.1~24.7 months) and the one-year survival is 80%. Twenty-two In terms of survival analysis, only a p53 mutation level of patients died during the follow-up period, 14 patients remained under 20% showed statistically significance(p<0.05). For time alive to the last follow-up, and 7 were lost to follow-up. to progression(TTP), an age of under 45 was significan(p<0.05). GTR showed a trend only (p=0.054) (Table 4). 1.0

Toxicity The toxicities associated with this regimen were significant. Myelosuppression was particularly common and was expe- rienced at least once in 27 of 39 patients who were exposed to

.5 chemotherapy. One patient died from intracerebral and intrav- entricular hemorrhage during cytopenia. In addition, one patient visited the emergency room for control of epistaxis during the treatment period. Acute renal failure occurred in one patient, who recovered with minor renal dysfunction. Two patients showed recurrent or severe infections. One of 0.0 012243648 these had a recurrent urinary tract infection, which eventually resulted in sepsis, but finally recovered. The other suffered Progress Free Duration (Months) pneumonia. Vesicant reaction occurred in one patient. No Fig. 2. Time to progression for the patients enrolled by the Kaplan- unexpected clinical or radiological adverse events was noted Meier method. Median time to progression is 5.7 months(95% CI 4.7~6.7 months). during the course of the cranial irradiation in the study subjects. Gastrointestinal complaints such as nausea and follow-up. The median overall survival of all 43 patients was vomiting were frequently observed in many patients but all 15.9 months(95% CI 7.1~24.7 months). Their 1-year survival were transient(Table 5). rate was 80%, and the 2-year survival rate was 42%(Fig. 1). The median time to tumor progression for 34 patients was 5.7 Discussion months(95% CI 4.7~6.7 months) (Fig. 2). Survival comparisons by the log-rank test also showed no correlation Comparison of responses between the degree-of-resection, i.e., GTR(gross total High grade astrocytoma remains a dreadful disease despite removal, including near total removal), STR(subtotal the recent developments in drug and the other treatment removal) and Bx(stereotactic biosy). The relevant p-values modalities that have improved surgical techniques and were 0.52(GTR vs STR), 0.38(STR vs Bx) and 0.11(Bx vs radiation treatment. Only 10% of patients with glioblastoma GTR), respectively. and 44% of those with anaplastic astrocytoma manage to

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Table 4. Multivariate analysis of prognostic factors*(Cox regression methods). Four variables, which were tried. Moreover, many reports have identified as meaningful by univariate analysis(Table 3.) were subject to multivariate analyses using the Cox been published about nitrosourea, Regression method. In terms of survival analysis, only a p53 mutation level of under 20% showed statistically significance(p<0.05). For time to progression(TTP), an age of under 45 was significant(p<0.05). GTR showed platin analogues, and various a trend only(p=0.054). routes for administration. From for survival analysis for time to progression then on, nitrosourea compounds (p-value) (p-value) have been considered as the sigle GTR 0.37 0.054 effective agent in case of malignant KPS over 90 0.21 0.92 glioma15, 27). age under 45 0.15 0.041 p53 mutation over 20% 0.039 0.16 Grossman et al. peformed a * : multivariate analysis by Cox regression test(backward, proportional). GTR : gross total removal including near phase II study of preradiation total removal. KPS : Karnofsky Performance Scale. p53 : percentage of tumor cells with a p53 mutation adjuvant chemotherapy(chem- oradiotherapy) with BCNU(lipid- Table 5. Various complications of the chemotherapy in the presented protocol. Myelosuppression was particularly common and was experienced at least once in 27 of 39 patients who were exposed to soluble, nonionized, and BBB chemotherapy. Twenty-one patients(53.9%) experienced cytopenia after the first cycle of chemotherapy permeable nitrosourea), combined (n=39), six patients(22.2%) suffered it after the second cycle(n=27). One patient died from intracerebral and with water-soluble CDDP(cis- intraventricular hemorrhage during cytopenia. Acute renal failure occurred in one patient, who recovered with minor renal dysfunction. Two patients showed recurrent or severe infections of a pneumonia and a recurrent diamminedichloroplatinum II) urinary tract infection, which eventually resulted in sepsis, but finally recovered. Vesicant reaction occurred in administered as a continuous one patient intravenous infusion8). Various complications occurrence (%) Radiotherapy as a local treatment Cytopenia* after the first chemotherapy (n=39) 21 (53.9 %) and chemotherapy as a systemic after the second chemotherapy (n=27) 66 (22.2 %) treatment can be combined in not occurred 12 (30.8 %) many ways, but Grossman et al. Bleeding tendency emphasized that their study ICH with IVH 1 (expired) demonstrated it was possible to severe epistaxis 1 perform chemotherapy before Infection radiation without adversely recurrent UTI resulting in sepsis 1 (recovered) influencing survival in patients pneumonia 1 8) Acute Renal Failure 1 with high grade astrocytoma . Vesicant reaction 1 Thus, we designed the present * : Hematologic status that did not meet the criteria of WBC count > 4,000/uL, and of platelet count > study along the lines described by 100,000/uL. ICH : intracerebral hemorrhage. IVH : intraventricular hemorrhage. UTI : urinary tract infection. Figure Legends Grossman et al., though the nitro- sourea compound was changed survive for more than 2 years from diagnosis6). Because of the because reports on a phase II study of ACNU(1-(4-amino-2- paucity of promising drugs for malignant glioma and the abu- methyl-5-pyrimidinyl)methyl-3-(2-chloroethyl)-3-nitrosourea ndance of various toxicities from the use of chemotherapeutic hydrochlo ride; Nimustine) showed a synergistic effect by ag-ents, the development of a trea-tment protocol for high synchronization of the cell kinetics.(synchronized grade astrocytomas remains a key issue for neurosurgeons radiochemotherapy)17,29). In addition, to adequately monitor and neuro-oncologists. However, definite progress has been toxicities, the treatment intervals were prolonged and made in the treatment of this disease over the past two chemotherapeutic dose adjustments were permitted in the decades. Since adjuvant chemotherapy using nitrosourea, like present study. The report by Grossman et al. indicated a BCNU(ca-rmustine), has been added to adj-uvant radio- median survival of 12.9 months, and 1- and 2-year survival therapy, postsurgical radiotherapy combined with some kind rates of 62% and 19%, respectively; calculated from the day of chemotherapeutic or rad-iosensitizing agent has been inv- of diagnosis8). In the present study we obtained a median estigated as a means of developing a standard treatment survival of 15.9 months, and 1- and 2-year survivals of 80% protocol for high grade gliomas31). Many other combinations and 42%. In addition, the present protocol was calculated of PCV(Proca-rbazine CCNU() )18), 5- from the first day of chemotherapy. Comparing the present FH() plus HU(hydroxyurea)14), and the report with that of Grossman et al. and with other reports concomitant use of various radiosensitizers has also been dealing with ACNU, the treatment protocol adopted by the

132 J Korean Neurosurg Soc 35 SJ Lee, et al. present study was superior in terms of median survival and nitrosourea24). On the other hand, more toxic central nervous overall survival rate. However, our results do not surpass toxicities occurred such as ipsilateral visual loss, severe those of Matstani et al17), who used postradiation chemo- central neurotoxicity, toxic encephalopathy, seizure, therapy with ACNU plus VCR. These workers achieved a hemiparesis, and an impaired mental status along with median survival of 23.6 months(101.1 weeks) and a 2-year significantly shorter survival12,13,24). More positively, BCNU survival of 45.9%17). These results are significantly better than plus a 72-hour continuous infusion of 5-FU was reported to those achieved with other ACNU combinations or other produce better results than many other bolus regimens16). combinations without ACNU17). However, a recent meta- Moreover, the continuous infusion of water-soluble analysis revealed that combination chemotherapy for high chemotherapeutic agents such as CDDP, may result in a more grade astrocytoma show no better, and perhaps poorer uniform drug distribution within brain tumors15). survival than single drug therapy, such as BCNU, in randomized controlled trials11). Analyses of prognostic factors Regarding the time to progression, our results were Nowadays, molecular biology has become more and more disappointing, the median time to progression of 5.7 months important, and many reports have dealt with the prognostic was no better than the other ACNU combination protocol17). factors of age, gender, KPS, degree of resection. Only a small The response rate was also less than expected, and produced number of reports dealing with p53 or Ki-67 proliferation results similar to those of Matstani et al.17) However, as index are to be found4,9,10,26,28,32). In the present study, a p53 mentioned by Grossman it is difficult to measure the response mutation level of < 20% was found to be a statistically rates in case of primary brain tumor, because the region of significant predictor of survival(p<0.05), and an age of under contrast enhancement reflects the region of blood-brain 45 was found to be significantly correlated with the prolonged barrier dysfunction, rather than the true tumor volume. time to progression(p<0.05). Gross total removal(GTR) Moreover, factors such as radiotherapy or glucocorticoids lacked significance, but it showed a trend(p=0.054). A could influence the results. number of reports support these results4,9,10,26). Despite its The reason of the discouraging time to progression and the potentiality, the Ki-67 proliferation index was not statistically response rate may be due to intervals of six weeks rather than significant, which is in agreement with a previous report5). In 4 weeks or less between . As Grossman a recent study, Ki-67 and p53 protein showed decreased stated, the major risk of this protocol seems inevitable given expressions in relapsed tumors after radiochemotherapy the 6 to 10 weeks delay before the administration of the versus the tumors before radiochemotherapy4,31). Although second chemotherapy or radiaotherapy8). In addition, it may various reports contradict the findings of the present study be due to preradiation chemotherapy rather than traditional about the relevance of the apoptotic determinator p5319,28) and postradiation chemotherapy, but, the respective weighting of the proliferation index Ki-6721), they should be considered remain controversial6,15). The prolonged intervals between not only as prognostic factors but in terms of decisions each treatment may be important because residual tumor at concerning adjuvant treatment. the primary site was reported to re-grow after radiation Prognostic factors including age under 45, gender, KPS therapy in most cases2,22). Therefore, Matstani et al. advocated over 90, GTR, Ki-67 under 5%, and p53 under 20% were that it is necessary to control the postoperative tumor analyzed as described previously1). At first, the four more remnants as much as possible by radiation therapy17). likely variables of age under 45, KPS over 90, GTR, and a Nevertheless, recent preradiation chemotherapy for malignant p53 mutation of under 20% were chosen by univariate log gliomas has provided encouraging results in a phase II trial rank testing to select a smaller set of baseline variables for conducted by Grossman et al8). Cox modeling, because Cox regression methods may become Whereas, the intravenous continuous administration has unstable if too many baseline variables are used. Multivariate been verified by many reports available. To be effective, a analyses was then performed by Cox regression25). chemotherapy must reach neoplastic cells in tumoricidal concentrations15). At first, intra-arterial(IA) administration Prospectives was thought to be of benefit theoretically, by avoiding first The majority of high grade astrocytomas start to re-grow at pass clearance, and by reducing the effective dose of the primary site after the completion of CRT2,22). Therefore, it chemotherapeutic agents and by decreasing the systemic side is recommended to control postoperative tumor remnants by effects, especially with respect to the use of lipophilic radiation therapy17). Although multidrug regimen18),

VOLUME 35 February, 2004 133 ACNU and CDDP Infusion concurrent use of radiosensitizers, RT dose intensification and 7. Gilbert MR, Lunsford LD, Kondziolka D : A phase II trial of 11) continuous infusion chemotherapy, external beam radiotherapy and CRT scheme alterations have not been found to be local boost radiotherapy. Proc Am Soc Clin Oncol 13 : 179, 1994 significant3,17,20,23). In addition, the order between CRT and 8. Grossman SA, Wharam M, Sheidler V, Kleinberg L, Zeltzman M, Yue N, et al : Phase II study of continuous infusion carmustine and chemotherapy, and the intervals between treatments remain at Cisplatin followed by cranial irradiation in adults with newly issue. Further studies should be performed using meta- diagnosed high-grade astrocytoma. J Clin Oncol 15 : 2596-2603, analysis to compare the regimen here desribed with the 1997 9. Gwak HS, Hwang SK, Kim JE, Paek SH, Park SH, Kim DG, et al : different treatment protocols. Protocol establishment for high Prognostic factors in long-term survivors with glioblastoma. J grade astrocytoma is discouraging because of heterogeneity, Korean Neurosurg Soc 31 : 3-10, 2002 30) 10. Haas-Kogan DA, Yount G, Haas M, Levi D, Kogan SS, Hu L, et al : and the various drug-sensitivities and resistances of tumors . p53-dependent G1 arrest and p53-independent apoptosis influence The development of new technologies, such as RT- the radiobiologic response of glioblastoma. Int J Radiat Oncol Biol PCR(reverse transcriptase-polymerase chain reaction), for Phys 36 : 95-103, 1996 11. Huncharek M, Muscat J, Geschwind JF : Multi-drug versus single determining drug-resistance has enabled adjuvant therapy to agent chemotherapy for high grade astrocytoma; results of a meta- be individualized30). In particulary, ACNU should be selected analysis. Anticancer Res 18 : 4693-4697, 1998 6 12. 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