ANTICANCER RESEARCH 25: 3715-3724 (2005)

Efficacy and Feasibility of Procarbazine, Ranimustine and Vincristine Chemotherapy, and the Role of Surgical Resection in Anaplastic Oligodendroglioma

MASAAKI YAMAMOTO1, MITSUTOSHI IWAASA1, MASANI NONAKA1, HITOSHI TSUGU1, KAZUKI NABESHIMA2 and TAKEO FUKUSHIMA1

Departments of 1Neurosurgery and 2Pathology, Fukuoka University School of Medicine, Fukuoka 814-0180, Japan

Abstract. The safety, tolerance and preliminary efficacy of a and the response rate was high. Thus, wide resection with a chemotherapy regimen consisting of procarbazine (PCB), risk of major neurological morbidity due to nearby functionally ranimustine (MCNU) and vincristine (VCR) were assessed for critical areas can be avoided. However, since the relapse rate patients with newly diagnosed supratentorial anaplastic was high, a second-line chemotherapy should be developed for oligodendroglioma. Materials and Methods: Between October anaplastic oligodendroglioma to improve the long-term control 1999 and September 2003, 5 patients were enrolled. The initial of the disease. regimens were prescribed as adjuvant therapy in conjunction with radiotherapy following standard surgical treatment. All Oligodendroglioma is a rare, although increasingly more patients received a chemotherapy comprising ranimustine (100 common, primary brain tumor (1), which represents 4 to mg/m2) intravenously on Day 1, procarbazine (60 mg/m2) on 15% of primary glial tumors (2-6). Significant attention has Days 8 to 21, and vincristine (1.4 mg/m2, maximum total 2 been focused on oligodendrogliomas because of their mg) on Days 8 and 29. The cycles were repeated every 8 weeks unique chemosensitivity compared with astrocytomas (7, 8). until tumor progression was evident, or for a total of 6 cycles Many patients with new or recurrent anaplastic over a 1-year period. The primary end-points were safety and oligodendroglioma have responded well to PCV tolerability, while the secondary end-point was overall survival. (procarbazine, lomustine and vincristine) chemotherapy (1, Results: Five consecutive eligible patients were treated. Of the 9, 10). Oligodendrogliomas have a high incidence of alleic 4 evaluable patients, 3 partially responded to the treatment loss of 1p and 19q chromosomal arms (11), which is (PR), while 1 had a complete response (CR): all patients are associated with chemosensitivity (12, 13). While most newly still alive. However, 3 of the 5 patients showed relapse, with a diagnosed patients with oligodendrogliomas frequently time to tumor progression (TTP) of 50, 143 and 241 weeks, respond well to PCV, with some responses being durable respectively. Two of these patients received combined treatment (14), most show disease progression after the initial with carboplatin, etoposide and recombinant human mutant treatment (15, 16). The median survival may be greater than tumor necrosis factor-alpha at the first relapse. This regimen 10 years in well-differentiated oligodendroglioma, whereas appeared to be safe and neither neurological toxicity, severe or patients with anaplastic oligodendrogliomas have a median life-threatening hematological toxicity, nor fatal toxicity (WHO survival time of less than 5 years (4, 17-19) and ultimately Grade 4) were experienced. Conclusion: These results suggest die of their disease (20). that a chemotherapy regimen consisting of PCB, MCNU and Many neurosurgeons recommend that gliomas should be VCR in this patient population seems to be safe and tolerable, resected as extensively as possible, which is associated with longer survival, especially in patients with glioblastoma (21, 22). The extent of resection of the tumor has been considered a favorable prognostic factor even in Correspondence to: Masaaki Yamamoto, MD, Ph.D., Department oligodendroglioma (23). However, it is still difficult to resect of Neurosurgery, Fukuoka University School of Medicine, 45-1, 7- gliomas completely because of their diffuse, infiltrative and chome, Nanakuma, Jonan-ku, Fukuoka 814 - 0180, Japan. Tel: 81- destructive nature (24), especially if they are near 92 - 801 - 1011 (extension 3441), Fax: 81-92 - 865 - 9901, e-mail: [email protected] functionally critical areas. In this study, we reviewed our results of anaplastic Key Words: Anaplastic oligodendroglioma, procarbazine, ranimustine, oligodendroglioma treated by surgical removal and vincristine. radiation therapy concomitant with a chemotherapy

0250-7005/2005 $2.00+.40 3715 ANTICANCER RESEARCH 25: 3715-3724 (2005) regimen consisting of PCB, MCNU and VCR, a modified Table I. Patient characteristics and treatment. PCV regimen using drugs available in Japan, and Case Sex Age Surgery PCV Response TTP Survival D/A determined the efficacy and role of this initial treatment for No. (Year) (Wks) (Wks) anaplastic oligodendroglioma. 1 M 33 total 2 - 50 265 A Materials and Methods 2 F 42 partial 6 PR 241 253 A Patient selection. Five patients met the following inclusion criteria for enrollment onto the study. The patients were adults (>18 years 3 M 39 partial 6 CR - 204 A and <70 years old) with malignant oligodendroglioma. The histological diagnosis was anaplastic oligodendroglioma (grade III) 4 M 35 partial 6 PR 143 208 A (human brain tumors were classified according to the revised WHO criteria for tumors of the central nervous system ) (25); no previous 5 M 49 partial 6 PR - 67 A treatment with chemotherapy or immunotherapy; Karnofsky TTP, time to progression; D/A, dead or alive. performance status (KPS) >60%; and life expectancy >8 weeks. The patients were required to have adequate liver, bone marrow, renal and cardiovascular function, granulocyte count >1,500/ml, platelet count >10x104/ml, hemoglobin >10 g/ml, SGTP and alkaline phosphatase <2 times normal, bilirubin <1.5 mg% and BN or creatinine <1.5 times normal prior to starting therapy. They were reduction of 50% or more in tumor size for at least 4 weeks; NC, candidates for this study within 3 weeks after the primary surgical no change, defined as either a decrease of less than 50% or an treatment, while patients with any immediately life-threatening increase of less than 25% in tumor size for at least 4 weeks; and PD, operative or postoperative complications were excluded. Written progressive disease, defined as an increase of 25% or more in tumor informed consent was obtained from each patient. size. The duration of survival was defined as the period from the start of treatment to death or the most recent evaluation. Surgery. All of the patients underwent extensive resection, depending upon the tumor location. Tumors near functionally Results critical areas were left in subtotal or partial removal when it was determined that further removal of the tumor could cause major neurological morbidity. Intraoperative pathological diagnosis was Patient characteristics. Five consecutive eligible patients (4 made by either frozen section or squash smear. The extent of the men and 1 woman) were treated with a chemotherapy resection was evaluated by postoperative magnetic resonance regimen consisting of PCB, MCNU and VCR between imaging (MRI): i.e., grossly total; subtotal (50% to 99%); partial September 1998 and August 2003. Their characteristics are (<50%); or biopsy only. summarized in Table I. All the patients were more than 18 Radiation therapy. Radiation therapy, given prior to chemotherapy, years old and had pathologically-confirmed anaplastic was provided at 60 Gy, administered 1.5 Gy per day, 5 times a oligodendroglioma. The oldest patient was 49 years old and week. In all cases, postsurgical CT or MR imaging was used to the youngest was 33 years old. Their mean age was 39.6 years. delineate the irradiation field and volumes. Clinical outcome. The 5 patients received this regimen for up Chemotherapy. MCNU was administered intravenously at 100 mg/m2 on Day 1 followed by 1.4 mg/m2 VCR intravenously on Day to 6 cycles (Table I). Of 4 evaluable patients, 3 partially 8 and Day 29. Between Days 8 and 21, PCB was administered responded to the treatment (PR), and 1 showed a complete orally at 60 mg/m2, usually in conjunction with antiemetic response (CR). Three patients subsequently relapsed with a medications, as modified from a previous report (8). time to tumor progression (TTP) of 50, 241 and 143 weeks, Chemotherapy was given with this regimen each 8-week cycle until respectively. Case 1 underwent surgical resection of the tumor tumor progression was evident, or for a total of 6 cycles over a 1- at the time of tumor recurrence. All of the patients are still year period. Evaluations consisted of a hemogram and liver alive (range 67 – 265 weeks) and the median overall survival function studies obtained on Days 1, 8 and 22. has not been reached. Data collection and statistical analyses. All medical records were reviewed and entered into a database. Common toxicities were Toxicity of treatment. Treatment toxicity was assessed in defined using the WHO criteria (26). The parameters that were accordance with the WHO criteria (26). All the patients monitored to determine the response to therapy included experienced toxicity as the result of radiation therapy, in the neurological status and tumor size, as measured on MRI before and form of alopecia and mild skin reactions to radiation. One after each treatment and at 3-month intervals. The tumor size was estimated as the volume of abnormal enhanced lesion on MRI patient (Case 1) stopped this chemotherapy regimen due to studies. The response was classified into 1 of 4 categories: CR, a skin reaction to PCB and MCNU of Grade 3 severity. complete response, defined as complete disappearance of the tumor Transient elevation of serum transaminases (ALT, AST) for a period of at least 4 weeks; PR, partial response, defined as a occurred in 2 patients (< grade 2). Neither neurological

3716 Yamamoto et al: Procarbazine, Ranimustine and Vincristine Chemotherapy in Anaplastic Oligodendroglioma

Figure 1. Case 2. T1-weighted MRI showing a heterogeneously enhanced lesion at the right frontal lobe that invaded the contralateral frontal lobe via the corpus callosum.

toxicity, severe or life-threatening hematological toxicity, nor fatal toxicity (WHO Grade 4) was experienced. None of the patients experienced delayed treatment due to treatment-related toxicities.

Representative cases. Case 2, a 42-year-old female, presented with dizziness. T1-weighted MRI showed a partially enhanced mass lesion at the right frontal lobe, which involved the contralateral frontal lobe via the corpus callosum (Figure 1). She was initially treated with surgery (partial resection) and diagnosed with anaplastic oligodendroglioma in January 2000 (Figure 2). There was remnant tumor on postoperative MRI (Figure 3, A and B). After 6 courses of PCB, MCNU and VCR, MR images in May 2001 showed a decrease in tumor volume of more than 50% (Figure 3, C and D). Follow-up MRI in August 2004, 241 weeks from the beginning of her initial treatment, showed a well-enhanced mass lesion at the right frontal lobe Figure 2. Case 2, primary lesion. The tumor shows a proliferation of anaplastic oligodendroglial cells with nuclear atypia and high mitotic (Figure 4, A, B and C). The T/N ratio of this lesion on TI- activity. Original magnification, x 200. SPECT was more than 4.0, which was interpreted as tumor recurrence. The patient underwent another operation with partial resection, and histopathological examination of the surgical specimen revealed recurrent anaplastic oligodendroglioma (Figure 5). She subsequently received and frozen section revealed anaplastic oligodendroglioma, adjuvant chemotherapy with carboplatin and etoposide. which confirmed the postoperative histopathological Case 5 was a 49-year-old male who presented with recent examination of a surgical specimen (Figure 7 B). He memory disturbance and personality change. MRI in July underwent resection of a right frontal tumor (partial 2003 showed a right frontal mass lesion with extension into removal), and the remnant tumor was evident on the contralateral frontal lobe (Figure 6). Intraoperative postoperative MRI in July 2003 (Figure 8, A and B). After histopathological diagnosis with squash smear (Figure 7 A) 6 courses of PCB, MCNU and VCR, MR images in

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Figure 3. Serial MR images obtained before chemotherapy (A, B), and after the 6 courses of procarbazine (PCB), ranimustine (MCNU) and vincristine (VCR), showing a decrease in tumor volume of more than 50% (C, D) in Case 2.

September 2004 showed a decrease in tumor volume of but we still do not know if there are better or less toxic more than 50% (Figure 8, C and D), and this patient has regimens, or whether PCV therapy can provide a curative remained clinically stable for more than 6 months. response in patients with anaplastic oligodendrogliomas. In this study, a clear benefit was observed in the response Discussion rate with a chemotherapy regimen consisting of PCB, MCNU and VCR concurrent with radiotherapy. Of the 4 evaluable There are still many unanswered questions regarding the patients, 3 (75.0%) partially responded to treatment and 1 best treatment for patients with oligodendroglioma, (25.0%) had a complete response: all of the patients are still although the biochemical basis of oligodendroglioma alive. Although this chemotherapy often induced mild chemosensitivity has been clarified over the past decade (12, hematological toxicity and skin rashes, these were transient 15, 27, 28). Currently, PCV plays an important role (29-31), and quickly responded to medication. Grade 4 hematological

3718 Yamamoto et al: Procarbazine, Ranimustine and Vincristine Chemotherapy in Anaplastic Oligodendroglioma

Figure 4. MR images showing a regrowth of residual tumor at the right frontal parenchyma (A, B and C). TI-SPECT showing a hot-spot at the right frontal lobe with a T/N ratio of more than 4.0 (D) in Case 2.

Figure 5. Case 2, recurrent tumor. The tumor shows increased cellularity, nuclear atypia and high mitotic activity. Original magnification, x 100.

3719 ANTICANCER RESEARCH 25: 3715-3724 (2005)

Figure 6. Case 5. T2-weighted MRI demonstrating a high-intensity mass lesion spreading into the contralateral frontal lobe (A, B), which was enhanced heterogeneously by Gd-T1-weighted MRI (C, D).

toxicities were not experienced in this study. None of the contralateral frontal lobe via the corpus callosum, so that patients experienced a treatment delay due to toxicities. total removal of the tumor was virtually impossible, even There is still some controversy regarding the extent of using new technologies such as a surgical navigation system. surgical resection to be performed for malignant gliomas. Our results suggest that surgical resection of the tumor can Many neurosurgeons recommend that gliomas should be be limited to subtotal or partial removal in oligodendroglial resected as extensively as possible, which is associated with tumors when the tumor is located near a critical area and if longer survival, especially in patients with glioblastoma (21, it is thought that surgical removal of the tumor could cause 22). The extent of resection of the tumor has been major neurological morbidity. Adjuvant therapy with PCV considered a favorable prognostic factor even in anaplastic chemotherapy is effective for remnant malignant oligodendroglioma (23, 32). However, it is sometimes oligodendroglioma (14). It is also important to accurately impossible to resect gliomas completely without major select and identify patients with oligodendroglial tumors neurological morbidity when they are near functionally during the operation who will respond well to adjuvant critical areas. In 3 of our cases, the tumor invaded the chemotherapy with PCV. A simple intraoperative diagnostic

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Figure 7. Case 5. A) Smear cytology shows tumor cells that spread readily with little cellular cohesion and no gliofibrillary matrix. The cells have rounded but larger and hyperchromatic nuclei. Binucleation is also seen. B) Histology shows tumor cells with pronounced nuclear atypia and mitotic figures. Original magnification, x 200 (A, B).

Figure 8. Serial MR images obtained before chemotherapy with evident remnant tumor (A, B), and after 6 courses of procarbazine (PCB), ranimustine (MCNU) and vincristine (VCR), showing a decrease in tumor volume of more than 50% (C, D) in Case 5.

3721 ANTICANCER RESEARCH 25: 3715-3724 (2005) marker should be developed for malignant glioma to detect 6 Ellis TL, Stieber VW and Austin RC: Oligodendroglioma. Curr oligodendroglial components, since it is time-consuming to Treat Options Oncol 4: 479-490, 2003. detect LOH in 1p and 19q in tumor tissues (33). 7 Cairncross JG, Macdonald DR and Ramsay DA: Aggressive However, the results of this study showed that the long- oligodendroglioma: a chemosensitive tumor. Neurosurgery 31: 78-82, 1992. term relapse rate was high. In 2 of 4 cases, the tumor 8 Glass J, Hochberg FH, Gruber ML, Louis DN, Smith D and subsequently recurred after 1-year of chemotherapy with Rattner B: The treatment of oligodendrogliomas and mixed PCB, MCNU and VCR. Furthermore, the second-line oligodendroglioma-astrocytomas with PCV chemotherapy. J chemotherapy with carboplatin and etoposide failed to Neurosurg 76: 741-745, 1992. provide a durable response in one case. Little is known about 9 Cairncross G, Macdonald D, Ludwin S, Lee D, Cascino T, what agents may be effective as salvage therapy for tumor Buckner J, Fulton D, Dropcho E, Stewart D, Schold C Jr et al: progression in patients who have been previously treated with Chemotherapy for anaplastic oligodendroglioma. National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol PCV or other chemotherapy (34). Further treatment with 12: 2013-2021, 1994. PCV after the prior administration of PCV seemed to be 10 Kim L, Hochberg FH, Thornton AF, Harsh GRT, Patel H, ineffective (35). A variety of multimodal salvage therapies for Finkelstein D and Louis DN: Procarbazine, lomustine and tumor progression in patients who have been previously vincristine (PCV) chemotherapy for grade III and grade IV treated with PCV or other chemotherapy have been oligoastrocytomas. 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