KISEP J Korean Neurosurg Soc 35 : 127-135, 2004 Clinical Article Clinical Study : Phase II Study of Continuous ACNU (nimustine) and CDDP (cisplatin) 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 chemotherapy 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 carmustine (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 nitrosourea 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. VOLUME 35 February, 2004 127 ACNU and CDDP Infusion 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 medication 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