Evaluation of Intratumoral Administration of Tumor Necrosis Factor-alpha in Patients with Malignant Glioma

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1 Evaluation of Intratumoral Administration of Tumor Necrosis Factor-alpha in Patients with Malignant Glioma SHINYA OSHIRO 1, HITOSHI TSUGU 1, FUMINARI KOMATSU 1, HIROKAZU OHNISHI 1, YUSHI UENO 1, SEIZABURO SAKAMOTO 1, TAKEO FUKUSHIMA 1 and GEN-ICHIRO SOMA 2 1 Department of Neurosurgery, Faculty of Medicine, Fukuoka University, Fukuoka; 2 Institute for Health Sciences, Tokushima Bunri University, Tokushima, Japan Abstract. Background: This study assessed safety and efficacy for intratumoral administration of tumor necrosis factor- (TNF-SAM2) into the post-operative tumor cavity through an Ommaya reservoir for patients with malignant glioma. Materials and Methods: Seven patients with malignant glioma, comprising 3 cases with glioblastoma multiforme (GBM), 3 cases with anaplastic astrocytoma (AA) and 1 case with malignant ependymoma (ME) were included in the study. All patients were pathologically diagnosed and initially treated with adjuvant therapy (radiation and/or ranimustine and/or systemic TNF-SAM2 infusion) following surgical resection. TNF-SAM2 was administrated into the post-operative tumor cavity through a reservoir at a concentration of 1x10 4 U/body when recurrence was detected, or as initial induction therapy concomitant with radiotherapy. Results: Partial response to this regional immunotherapy was seen in 4 out of 7 patients, and 1 patient with GBM has remained clinically stable for >184 weeks without tumor progression. With AA, 2 cases appeared to display slowed advance and longer times to tumor recurrence or regrowth. No serious adverse effects, such as brain edema, hemorrhage or seizure were observed, nor systemic toxicities. Conclusion: Local immunotherapy with TNF-SAM2 may safely contribute to therapeutic efficacy in some patients with malignant glioma. Despite recent advances in radiation therapy, chemotherapy and surgical resection, the prognosis for patients with malignant glioma remains very poor (1, 2). Glioma is often Correspondence to: Shinya Oshiro, MD, Department of Neurosurgery, Faculty of Medicine, Fukuoka University, 45-1, 7- chome, Nanakuma, Jonan-ku, Fukuoka , Japan. Tel: , Fax: , s-oshiro@fukuokau.ac.jp Key Words: Glioma, chemotherapy, immunotherapy, local injection, tumor necrosis factor-alpha (TNF-SAM2). characterized by rapid growth and invasiveness into surrounding normal brain tissue, so tumor recurrence occurs locally (3). The diffuse, infiltrative and destructive nature of such tumors makes complete resection virtually impossible using surgical treatment alone (4, 5). In view of this poor response to conventional therapies, augmentation of host local immune responses to the tumor offers the potential of improving survival (6). Some evidence supports the use of local immunotherapy for treatment of malignant glioma (7-11). Although cellular immune function may be suppressed in patients with malignant glioma, peritumoral infiltrations of lymphocytes or macrophages are present, and increased density correlates with improved prognosis (12, 13). Clinical evaluation and characteristics of 7 cases treated with local administration of tumor necrosis factor (TNF) for patients with malignant glioma are reported. Materials and Methods Patient selection. Our study group included seven patients (four men, three women) with malignant glioma and a median age of 56 years (range, years). Histological diagnoses included glioblastoma multiforme (GBM, grade IV; n=3), anaplastic astrocytoma (AA, grade III; n=3) and malignant ependymoma (ME, grade III; n=1) according to the revised WHO criteria (14). All patients were assessed and supervised by the Department of Neurosurgery at Fukuoka University Hospital, Japan, between April 1992 and November Inclusion criteria were as follows. Patients were required to have adequate liver, bone marrow, renal and cardiovascular function, granulocyte count >1,500/ml, platelet count >10x10 4 /ml, hemoglobin >10 g/ml, serum glutamic-pyruric transaminase and alkaline phosphatase <2 times normal, bilirubin <1.5 mg % and blood urea nitrogen or creatinine <1.5 times normal prior to starting therapy. Patients were considered candidates for this study within 3 weeks after primary surgical treatment; those with any immediately life-threatening operative or post-operative complications were excluded. Written informed consent was obtained from each patient. Surgery. All patients underwent extensive resection, depending on tumor location. The extent of resection was evaluated based on /2006 $

2 Table I. Characteristics of patients with intratumoral TNF-SAM2 administration. Case Age/gender Diagnosis* Location Resection Times Pre-treatment ST(W) Outcome Response 1 38/M AA GBM L. thalamus partial 2 R+MCNU+sysTNF 256 dead PR 2 55/M AA GBM L. temporal subtotal 3 R+MCNU+sysTNF 468 dead PR 3 67/M GBM L. temporal subtotal 2 R+MCNU+sysTNF 73 dead PD 4 47/F ME L. frontal total 2 R+sysTNF 224 alive NC 5 74/M GBM R. temporal total 2 R+MCNU+sysTNF 81 dead PD 6 63/F GBM L. frontal subtotal 1 R+MCNU 184 alive PR 7 48/F AA R. thalamus partial 1 R+MCNU 28 alive NC Abbreviations: Pre-treatment, previous treatment; ST, survival time; W, weeks; R, radiation; MCNU, ranimustine; systnf, systemic TNF treatment; AA, anaplastic astrocytoma; GBM, glioblastoma mutiforme; ME, malignant ependymoma; PR, partial response; PD, progressive disease; NC, no change. Diagnosis*: malignant transformation to GBM from AA was observed in both Cases 1 and 2 on second surgery. operative reports and post-operative computed tomography (CT) and/or magnetic resonance imaging (MRI) as: grossly total, subtotal (50-95%), partial (<50%), or biopsy only. Intraoperatively, the Ommaya reservoir was placed into a cavity after tumor removal to facilitate drug infusion. Adjuvant therapy. After surgical resection of the tumor, patients underwent a course of radiation therapy (standard dose ranging from Gy at 1.5 Gy/day 5 times/week), nitrosourea-based chemotherapy [ranimustine (MCNU)] and systemic immunotherapy with TNF, which was recombinant mutant human TNFalpha (TNF-SAM2) with altered N-terminal regions that was developed and provided by Soma et al. (15, 16). MCNU was administered intravenously (i.v.) at 100 mg/m 2 on Day 1, i.e., at the onset of radiation therapy, and was followed by 80x10 4 U/m 2 TNF- SAM2 i.v. from Day 3. TNF-SAM2 was prescribed weekly during the post-operative period, concurrent with radiation therapy. MCNU was then administered every 8- to 12-week cycles until tumor progression was evident, or for a total of 4 cycles over a 1- year period. Intratumoral administration of TNF-SAM2. Patients were monitored for tumor recurrence during initial or maintenance therapy. Local injection of TNF-SAM2 was started when CT or MRI detected any recurrence. More recently, local injection was performed as initial induction therapy following first surgery, concomitant with radiation therapy. This TNF-SAM2 was administered into the post-operative tumor cavity through the Ommaya reservoir. Before local administration of TNF-SAM2, the cavity was confirmed to be closed without any leakages to the subarachnoid space or ventricle. The treatment schedule consisted of several courses of intratumoral administration of TNF-SAM2 at a concentration of 1x10 4 U/body. This dosage was determined based on a phase I trial and our preclinical animal study (17, 18). The dosage was 0.01-fold lower than the dosage injected systemically. This local immunotherapy continued at 1 or 2 week intervals on an outpatient basis until tumor progression. Data collection. All medical records were reviewed and entered into a database. Common toxicities were defined using WHO criteria (18). The parameters that were monitored to determine response to therapy included neurological status and tumor size as measured on CT and MRI before and after each treatment and at 3-month intervals. Tumor size was estimated as the volume of abnormal enhanced lesion on CT and/or MRI studies. Response was classified into one of 4 categories: i) complete response (CR), complete disappearance of tumor for a period of 4 weeks; ii) partial response (PR), a reduction of 50% in tumor size for 4 weeks; iii) no change (NC), either a decrease of <50% or an increase of <25% in tumor size for 4 weeks; and iv) progressive disease (PD), an increase of 25% in tumor size. Duration of survival was defined as the period from start of treatment to death or most recent evaluation. Results Clinical outcome. Response to treatment with intratumoral administration of TNF-SAM2 is summarized in Table I. Second surgery for recurrence or regrowth was required for five out of the seven patients, and malignant transformation to GBM was observed in two out of the three AA cases during follow-up. Out of three evaluable patients with GBM diagnosed at initial surgery, two patients (Cases 3 and 5) displayed PD in response to treatment with local injection of TNF-SAM2, and finally died of tumor progression with survival times of 73 and 81 weeks, respectively. Conversely, Case 6 with GBM displayed PR to treatment, and remained in a clinically stable state for >184 weeks without tumor progression. Although two patients with AA diagnosed at initial surgery (Cases 1 and 2) displayed malignant transformation to GBM during follow-up, PR to treatment was achieved with survival times of 256 and 468 weeks, respectively. These patients exhibited longer time to tumor regrowth or recurrence. Case 4 with ME and Case 7 with AA have continued in the same state without any recurrence (NC) for >224 weeks and >28 weeks, respectively. In these responders, MRI studies revealed cyst formation as necrotic cavity instead of tumor progression. 4028

3 Oshiro et al: Intratumoral Administration of Tumor Necrosis Factor for Malignant Glioma Figure 1. Case 2 with anaplastic astrocytoma. Serial MRI obtained before treatment shows a left temporal mass lesion (A), and after subtotal removal of the tumor and adjuvant therapy (radiation and MCNU and systemic TNF-SAM2) with initial course of intratumoral TNF-SAM2 treatment (B). After discontinuation of any treatments for 2 years, tumor recurrence developed along the margin of the surgical bed (C). Toxicity of intratumoral administration. Treatment toxicity was assessed in accordance with WHO criteria (19). Systemic administration of TNF has been reported to cause a variety of systemic toxicities, including fever, chill, general fatigue and hypotension/hepatic dysfunction (20). Local injection of TNF into the tumor cavity did not result in serious adverse effects, such as brain edema, hemorrhage or seizures, or in systemic toxicities. Representative cases. Case 2, a 47-year-old man who presented with partial epilepsy (Figure 1A), underwent resection of left temporal lobe AA (subtotal removal) in June After surgery, the patient underwent multimodal therapy using radiation therapy, MCNU and systemic TNF- SAM2 treatment (Figure 1B). Although local administration of TNF-SAM2 was continued as maintenance therapy for 3 years after adjuvant therapy, he declined to maintain intratumoral treatment beyond this time. Conservative observation without treatment was, therefore, continued from this time. However, recurrence was noted along the margin of the surgical bed on MRI in July 2001 (Figure 1C). Partial removal of the recurrent tumor was performed, and histological examination demonstrated malignant transformation to GBM from AA. Resumption of local treatment with TNF-SAM2 was then conducted and maintained for >2 years. Although the residual tumor progressed gradually with cerebrospinal fluid dissemination, the neurological status remained the same for >2 years. He finally died 468 weeks (approximately 9 years) after initial surgery. Case 6, a 59-year-old woman who presented with recent memory disturbance and right-side weakness (Figure 2A), underwent subtotal resection of left frontal lobe GBM in 4029

4 Figure 2. Case 6 with glioblastoma multiforme. Serial MRI obtained before treatment shows a left frontal mass lesion (A). Just after surgery with subtotal removal of the tumor (B). After adjuvant therapy (radiation and MCNU) with several courses of intratumoral TNF administration, no marked changes in residual tumor were seen (C). Discussion December 2001 (Figure 2B). Multimodal therapy using radiation and MCNU was started as induction therapy using the same protocol as described for Case 2. Intratumoral administration of TNF-SAM2 has been given as maintenance therapy at 1-week intervals since March Neurological status remained unchanged and stable for >184 weeks (approximately 3.5 years). Follow-up MRI demonstrated cyst formation as necrotic cavity instead of tumor progression (Figure 2C). TNF was originally characterized as a substance mediating hemorrhagic necrosis in various types of tumors (21). As a result, numerous attempts have been made to utilize TNF for the treatment of cancer in both experimental animals and clinical trials. Although certain levels of immunological and tumoricidal response have been observed in experimental tumor models, clinical trials have proven unsuccessful due to considerable adverse effects without apparent therapeutic benefits (22-24). To increase the antitumor activity of TNF, an elevated concentration of TNF at the tumor site is needed without flow into the systemic circulation (25, 26). Regional administration of TNF is, thus, thought likely to be more effective in achieving local concentration. In terms of local administration, clinical trials have demonstrated that isolated limb perfusion of TNF-alpha with melphalan achieves >70% response rate (CR and PR) in patients suffering from unresectable bulk melanoma or soft-tissue sarcoma (27). Promising strategies for effective treatment of brain tumors, such as malignant glioma, have always been hampered by difficulties in drug delivery. The blood-brain barrier (BBB) usually prevents effective delivery of systemically administered drugs. In an effort to improve drug delivery within the brain and in view of the biological features of therapeutic efficacy in 4030

5 Oshiro et al: Intratumoral Administration of Tumor Necrosis Factor for Malignant Glioma TNF treatments, we evaluated intratumoral application of TNF into the post-operative tumor cavity through an Ommaya reservoir for patients with malignant glioma. No significant adverse effects, such as brain edema, hemorrhage or seizure were seen, unlike with systemic infusion. This agent, thus, appears safe for local injection into the tumor cavity. However, the present study could not establish the therapeutic efficacy of local TNF therapy, as other modalities of treatment had been performed previously or were applied simultaneously. Nevertheless, favorable clinical responses were observed in some cases with malignant glioma. Case 6 with GBM has remained clinically stable for >184 weeks without tumor progression during maintenance therapy. There were only a few reported cases with GBM in response to systemic administration of TNF (28). Despite malignant transformation to GBM during follow-up, 2 patients with AA achieved PR, and exhibited tumor recurrence after a long time, with survival times of 256 and 468 weeks, respectively. These cases probably benefited from local treatment with TNF. Selection and identification of patients with cytokineresponsive tumors is important. Variable in vivo TNF sensitivity has been observed among patients with malignant glioma, and reliable predictors of in vivo TNF response have yet to be identified. Advances in technology have enabled us to select a subpopulation of patients with malignant astrocytoma who should respond well to intratumoral TNF immunotherapy. It has recently been shown that endothelialmonocyte-activating polypeptide II (EMAPII) expression in GBM might predict clinical response to systemic or local TNF therapy and may potentially be used in identifying patients with cytokine-responsive tumors (29). In most responders to intratumoral TNF treatments, either formation of a cystic cavity or decreased gadolinium enhancement at the tumor site can be radiologically observed on serial CT or MRI. These radiological findings consist characteristics of effective treatment in glioma patients (10, 30). Whether this process was caused by intratumoral TNF administration alone or in combination with the effects of other multimodality treatments remains unclear, but cavity volume increases may be attributable to the spread of necrotic changes in tumor tissue. In conclusion, local immunotherapy with TNF may safely contribute to therapeutic efficacy in some patients with malignant glioma. Further experience with more patients is needed to conclude whether or not such combined regimens can provide therapeutic benefits and improve survival in patients with malignant glioma. 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