J Neurosurg 69:826-829, 1988 Systemic gamma-interferon therapy for recurrent gliomas M. STEPHEN MAHALEY, JR., M.D., PH.D., LINDA BERTSCH, R.N., SHARON CUSH, R.N., AND G. YANCEY GILLESPIE, PH.D. Divisions of Neurological Surgery, University of Alabama, Birmingham, Alabama, and University of North Carolina, Chapel Hill, North Carolina u," Recombinant gamma-interferon (2 mg/sq m) was administered intravenously twice weekly in 8-week courses to 14 patients with recurrent gliomas. Computerized tomography (CT) evidence of response was seen in only one patient, and stabilization for 12 to 86 weeks was recorded in three. This was a disappointing result, particularly in a series of patients with relatively small initial tumor volumes (less than 50 cu mm on enhanced CT) and Karnofsky functional ratings of 70 or higher. In addition, several instances of toxicity potentially attributable to gamma-interferon were observed. KEY W O R D S recurrent glioma 9 brain neoplasm AMMA-INTERFERONhas been reported to activate the specific cytotoxicity o f lymphocytes against glioma cells in the presence of interleukin-2, 3 to inhibit in vitro growth of glioma cell lines, 25 and to increase the h u m a n leukocyte antigen (HLA) D R surface antigens and cytoplasmic HLA-DR-specific ribonucleic acid (RNA) of glioma cells in vitro. 26'27 Smith and his coworkers administered postoperative intraventricular gamma-interferon to three patients, beginning 2 m o n t h s after radiotherapy; one of their patients experienced a gradual reduction in t u m o r size over 9 months, as observed on computerized t o m o g r a p h y (CT) scans (unpublished data). We have previously reported the clinical efficacy of alpha-interferon in the treatment o f patients with recurrent gliomas, 12 and are now reporting our less favorable clinical experience with gamma-interferon. G Clinical Material and Methods This study was designed to evaluate the toxicity and possible efficacy of r e c o m b i n a n t gamma-interferon ( I m m u n e r o n ) administered systemically to adult patients with recurrent progressive gliomas. To enhance the possibility of efficacy, based u p o n previous experience with alpha-interferon,~2 only patients with enhancing C T t u m o r volumes o f less than 50 cu c m were treated. Each patient had a K a r n o f s k y rating of 70 or higher. Fifteen patients were admitted into the study. One patient (Case 105) received only two injections of gamma-interferon because o f hypotension. The char826 9 glioma 9 interferon 9 toxicity 9 acteristics o f the patients are shown in Table 1. The dose schedule for gamma-interferon was 2 mg/sq m twice weekly (Monday and Thursday or Tuesday and Friday) for 8 weeks. Unless progression of disease was documented, this schedule was repeated twice, followed by maintenance treatment with 2 mg/sq m once weekly until progression. Patients were hospitalized for the 1st week of t r e a t m e n t and were treated as outpatients thereafter. Baseline evaluations prior to beginning treatment included contrast-enhanced C T scanning, neurological examination, Karnofsky functional rating, complete blood count with differential, platelet count, electrolyte evaluation, liver a n d renal profile, serum glucose level, urinalysis, electrocardiography, and chest x-ray film. Each patient was followed serially with contrast-enhanced C T scanning, Karnofsky rating, and neurological examination monthly as well as repeat blood and urine studies throughout the treatment period. Efficacy o f treatment was determined by comparing the enhancing t u m o r volumes on serial CT scans. The CT scans were determined to indicate response when there was 25% or greater reduction in the enhancing t u m o r volume c o m p a r e d to the baseline CT scan in the absence o f any increase in steroid administration. Stable CT scans were those in which the enhancing t u m o r volume had less than a 25% increase or decrease in size compared to baseline. Progression of disease on CT scans was determined when the enhancing t u m o r volu m e increased 25% or m o r e compared to baseline in J. Neurosurg. / Volume 69/December, 1988 Systemic gamma-interferon for recurrent gliomas TABLE 1 Clinical summary in 15 patients treated with gamma-interferon Case Age (yrs), Karnofsky No. Sex Score* 101 102 103 24, M 45, F 34, F 90 100 90 104 105 58, M 48, M 90 80 106 107 54, F 26, F 108 Type of Tumor Tumor Vol (cu cm) Prior Therapy Date of Surgery RT (Gy)t Chemotherapy~ glioblastoma glioblastoma anaplastic astrocytoma glioblastoma glioblastoma 26 4 12.5 5/85 6/85 2/81, 8/85 60.2 WB 59.5 WB + LF 55 WB 16 43 8/84, 9/85 1/85 56 WB 60.2 WB I00 90 glioblastoma glioblastoma 42 18 42, F 90 9 109 33, M 100 oligodendroglioma glioblastoma 5/85, 12/85 60 WB + LF 2/85, 5/85, 60 LF, brachy12/85 therapy 1/86 64 WB 110 111 15, M 57, F 90 100 112 113 64, F 56, M 90 100 114 115 65, M 63, F 90 90 26.25 12/84 Time to Survival Wks of Failure Time Treatment (wks) (wks) 7 6 82 7 6 86 118 17 118+ 7 1 7 4 59 4 8 4 8 4 24 18 12 12 102+ BCNU + active immunotherapy 4 4 43 CCNU, AZQ + PCZ PCNU BCNU + active immunotherapy 60.2 WB BCNU ependymoma anaplastic astrocytoma glioblastoma glioblastoma 10 17 12/83, 8/85 50.4 WB 6/84 54.8 WB BCNU 4.5 8.5 4 8.5 6 31.5 31 9.75 6/85, 5/86 3/84 43 WB, 17.2 LF 43 WB, 17.2 LF BCNU, PCZ BCNU + active immunotherapy 7 8 7 8 13 72+ astrocytoma glioblastoma 3 47.5 7/86 10/85 60 LF 43 WB, 17.2 LF 52 12 12 71+ 18 * Karnofsky functional rating at start of interferon therapy. t RT = radiation therapy; WB = RT dose to whole brain; LF = RT dose to limited field. CCNU = l-(2-chloroethyl)-3-cyclohexyl-l-nitrosourea; AZQ = aziridinylbenzoquinone; PCZ = procarbazine; PCNU = 1-(2-chloroethyl)-3(2,6-dioxo-3-piperidyl)- l-nitrosourea; BCNU = 1,3-bis(2-chloroethyl)- 1-nitrosourea. the absence of a reduction in steroid administration. T i m e to t r e a t m e n t f a i l u r e a n d l e n g t h o f s u r v i v a l w e r e a l s o c o m p u t e d f r o m t h e t i m e g a m m a - i n t e r f e r o n was i n i t i a t e d . Serial n e u r o l o g i c a l e x a m i n a t i o n s a n d K a r n o f s k y r a t i n g s w e r e r e c o r d e d a n d c o n s i d e r e d in t h e o v e r a l l evaluation of each patient. Results T e n o f t h e 15 p a t i e n t s h a d g l i o b l a s t o m a s , t w o h a d anaplastic astrocytomas, one had an ependymoma, one had an astrocytoma, and one had an oligodendroglioma ( T a b l e 1). T h e m e a n p a t i e n t age w a s 4 5 . 6 years, m e a n K a r n o f s k y r a t i n g w a s 93, a n d t h e m e a n t u m o r v o l u m e w a s 21 c u c m . T h e m e d i a n t i m e t o t r e a t m e n t failure o f t h e 14 p a t i e n t s w h o h a d d o c u m e n t e d p r o g r e s s i o n was 7 w e e k s ( m e a n 12.7 weeks). T h e m e d i a n s u r v i v a l t i m e f o r all 15 p a t i e n t s w a s 24 w e e k s . B a s e d u p o n t h e C T s c a n at 8 w e e k s a f t e r b e g i n n i n g t r e a t m e n t , 11 p a t i e n t s e x h i b i t e d t u m o r p r o g r e s s i o n , t h r e e ( C a s e s 103, 114, a n d l l 5 ) h a d r e m a i n e d stable f o r 86, 7 1 + , a n d 12 weeks, r e s p e c t i v e l y , a n d o n e ( C a s e 108) r e s p o n d e d , b u t for o n l y 12 weeks. T h e s e results a r e s u m m a r i z e d in T a b l e 2. A s o f D e c e m b e r 3 l, 1987, f o u r p a t i e n t s a r e alive b u t n o n e is b e i n g t r e a t e d w i t h i n t e r f e r o n at t h i s t i m e . T h e m o s t s e r i o u s t o x i c i t y ( T a b l e 3) d e f i n i t e l y attribu t a b l e t o g a m m a - i n t e r f e r o n w a s h y p o t e n s i o n in o n e p a t i e n t . T h i s p a t i e n t ( C a s e 105) d e v e l o p e d a systolic b l o o d p r e s s u r e o f 70 m m H g w i t h i n 1 h o u r a f t e r c o r n - J. Neurosurg. / Volume 6 9 / D e c e m b e r , 1988 TABLE 2 Summary o f results o f systemic therapy with gamma-interferon Factor* total cases histopathology, GBM/other mean age (yrs) age range (yrs) mean Karnofsky score Karnofsky score range mean tumor volume (cu cm) tumor volume range (cu cm) median time to failure (wks)t mean time to failure (wks)t median survival time (wks) CT results at 8 weeks responders stable disease disease progression No. 15 10/5 45.6 15-65 93 90-100 21.0 3-48 7 12.7 24 1 3 11 * GBM = glioblastoma; CT = computerized tomography. t Includes only 14 patients, since one patient (Case 105) received only two doses due to hypotension toxicity (see text). p l e t i o n o f t h e first i n f u s i o n , w h i c h w a s c o n f i r m e d b y a second infusion later that week. This patient was not treated further with interferon and died of tumor progression within 4 weeks. All other toxicities were well tolerated and transient, with one exception. That pat i e n t ( C a s e 1 10) s h o w e d C T e v i d e n c e o f t u m o r p r o g r e s sion after 4 weeks of treatment, but remained neuro82"/ M. S. Mahaley, Jr., et al. TABLE 3 Toxicities o f systemic gamma-interferon in 15 brain-tumor patients No. o f Cases of Toxicity Symptoms* chills fever nausea/vomiting headache confusion lethargy seizure myalgia elevated liver enzymes hypotension diaphoresis renal failure Mild Moderate Severe 8 4 7 4 3 2 1 1 6 1 1 3 10 1 3 2 2 2 1 1 1 1 1"~ 1:~ * In addition, one patient each had mild anorexia, tinnitus, epigastric discomfort, fatigue, diarrhea, and thrombophlebitis. t This patient received only two doses of interferon. The exact cause of this event (with fatality) is still uncertain. logically stable. Although all blood studies were normal during his prior treatment, 4 days following the last gamma-interferon infusion he b e c a m e ill with a sore throat, chills, and a fever o f 103*F. H e was admitted to another hospital, where a neurological examination, admission blood and chest x-ray studies, and bacterial cultures were unremarkable. He was treated with intravenous fluids, cefamandole, promethazine, and acetam i n o p h e n in addition to his usual dose of dexamethasone and carbamazepine. One week after admission, the patient's condition deteriorated with evidence of acute renal failure (uric acid 13 mg/dl, creatinine 13.4 mg/dl, blood urea nitrogen 116 mg/dl, potassium 6.9 mEq/liter) and epistaxis, despite no vascular hypertension, a normal blood platelet level, and no coagulopathy. He died 1 day later. Although no autopsy was performed, the cause o f death was considered to be acute renal failure of uncertain origin. Discussion In recent years, a n u m b e r o f biological response modifiers have emerged as potentially useful agents in the clinical m a n a g e m e n t o f patients with cancer. The lymphokines include interferons which originally were subdivided into those designated as virally induced, such as leukocyte-derived interferon (alpha) and fibroblast-derived interferon (beta), and the i m m u n e interferon (gamma). At the present time there are recombinant deoxyribonucleic acid (DNA)-derived forms of these interferons which continue to be actively studied, both experimentally and clinically as regards their inhibitory activity u p o n cancer cell growth as well as their stimulatory activity for the i m m u n e system. Beta-interferon was the first l y m p h o k i n e to be studied clinically in patients with gliomas. It has been shown to inhibit replication o f h u m a n glioma cells in v i t r o l O , l 1.13,29,30 and implanted in nude m i c e . 19"2~ In 828 addition, in vitro exposure of h u m a n glioma cells to liposome-entrapped h u m a n beta-interferon resulted in increased cytotoxicity compared to free interferon. 9 The first clinical treatments with h u m a n beta-interferon for recurrent gliomas were conducted in J a p a n 14"xs'~7"21-25 using intravenous as well as intrathecal or intratumoral routes of administration. Responses were found in 12 of 54 patients treated intravenously by Sano, et aL (unpublished data), and in eight o f 20 patients treated intrathecally or intratumorally by Nagai and AraiJ 4 Smaller groups o f patients have subsequently been treated by Bogdahn, et al., 2 Duff, et aL, 5 Yung, et at., 32 and Fetell, et al.,6 with less impressive responses. Yoshida, et aL, 3~ reported treating nine cases o f recently diagnosed brain tumors with radiotherapy, A C N U (( l4-amino-2-methyl- 5-pyrimidinyl)-methyl-3-(2-chloroethyl)-3-nitrosourea), and beta-interferon. Although their response criteria are unclear, the authors claim four complete responses and one partial response. H u m a n alpha-interferon has been evaluated clinically. 1'7"8'12'14'16'1s'24 This form of interferon also retards growth of h u m a n glioma cells in vitro 22 and in nude mice. 4 In the largest clinical series, we reported CT evidence o f response in seven o f 17 patients with recurrent gliomas who received 900 x 105 U/sq m intravenously or intramuscularly over 8 weeks. 12 G a m m a - i n t e r f e r o n has been shown in vitro to increase the H L A - D R antigens on cell surfaces and to activate lymphocytes to produce specific cytotoxicity in the presence of interleukin-2. 3'26"27Until now, the only clinical use o f gamma-interferon in glioma patients appears to be that of Smith, et al., who observed a reduction in t u m o r size on postoperative CT scans during radiotherapy and intraventricular interferon administration in one of three patients so treated (unpublished data). O u r results with recombinant g a m m a interferon are disappointing, with only one patient, an individual with an oligodendroglioma, showing CT evidence of response. Evidence of treatment failure was usually seen by the time of completion o f an 8-week course of therapy, and the median survival time for the 15 patients was 24 weeks. Most of the toxicities observed were anticipated, including vascular hypotension which, although transient, was severe enough to abandon further interferon therapy in one patient. The precise cause o f renal failure with death o f one patient after 4 weeks o f treatment is unclear, since no evidence of renal toxicity to any extent whatsoever was found in any other treated patient. Unless gamma-interferon is shown to have efficacy when used in combination with other interferons 26 or with chemotherapeutic agents, it would likely be prudent to concentrate preclinical and clinical studies on alpha- or beta-interferon. References 1. Bo~thius J, Blomgren H, Collins VP, et al: The effect of systemic human interferon-alpha administration to patients with glioblastoma multiforme. Aeta Neurochir 68: J. Neurosurg. / Volume 6 9 / D e c e m b e r , 1988 Systemic gamma-interferon for recurrent gliomas 239-251, 1983 2. Bogdahn U, Fleischer B, Hilfenhaus J, et al: Interferonbeta in patients with low-grade astrocytomas. A Phase I study. J Neuroaneol 3:125-130, 1985 3. Bogdahn U, Fleischer B, Rupniak HTR, et al: Interferon in specific T-cell mediated cytotoxicity in human gliomas. Antiviral Res 4:84, 1984 (Abstract) 4. Bradley NJ, Darling JL, Oktar N, el al: The failure of human leukocyte interferon to influence the growth of human glioma cell populations: in vitro and in vivo studies. Br J Cancer 48:819-825, 1983 5. Duff TA, Borden E, Bay J, et al: Phase II trial of interferon-c/ for treatment of recurrent glioblastoma multiforme. J Neurosurg 64:408-413, 1986 6. Fetell MR, Housepian EM, Oster MW, et al: Intratumoral administration of c/-interferon in glioblastoma: Phase I study. Neurology 37 (Suppl 1):334, 1987 (Abstract) 7. Hamada H, Asakura T, Maeda Y, et at: [A study on the direct antitumoral effect of interferon-a on human glioma.] Gan To Kogaku Ryoho 13:464-471, 1986 (Jpn) 8. Hirakawa K, Ueda S, Nakagawa Y, et al: Effect of human leukocyte interferon on malignant brain tumors. Cancer 51:1976-1981, 1983 9. Kato K, Yoshida J, Kageyama N, et al: Liposome-entrapped human interferon-c/, its pharmacokinetics and antitumor activity against malignant glioma. J Interferon Res 6 (Suppl I): 131, 1986 (Abstract) 10. Korosue K, Takeshita I, Mannoji H, et at: Interferon effects on multiplication, cytoplasmic protein and GFAP content, and morphology in human glioma cells. J Neurooncol 1:69-76, 1983 11. Lundblad D, Lundgren E: Block of a glioma cell line in S by interferon. Int J Cancer 27:749-754, 1981 12. Mahaley MS Jr, Urso MB, Whaley RA, et al: Immunobiology of primary intracranial tumors. Part 10: Therapeutic efficacy of interferon in the treatment of recurrent gliomas. J Neurosurg 63:719-725, 1985 13. Miyao Y, Shimizu K, Okamoto Y, et al: [Antitumor efficacy of recombinant interferon-C/on human glioma.] Gan To Kagaku Ryoho 14:490-494, 1987 (Jpn) 14. Nagai M, Arai T: Clinical effect of interferon in malignant brain tumours. Neurosurg Rev 7:55-64, 1984 15. Nagai M, Arai T: [Interferon therapy for malignant brain tumors: present and future.] No Shinkei Geka 10: 463-476, 1982 (Jpn) 16. Nagai M, Arai T, Kohno S, et al: [Current status of interferon therapy on malignant brain tumor.] Gun No Rinshu 29:608-615, 1983 (Jpn) 17. Nagai M, Arai T, Kohno S, et al: Local application of interferon to malignant brain tumors. Texas Rep Biol Med 41:693-698, 1982 18. Nakagawa Y, Hirakawa K, Ueda S, et al: Local administration of interferon for malignant brain tumors. Cancer Treat Rep 67:833-835, 1983 19. Nakamura O, Maruo K, Ueyama Y, et at: Interactions of human fibroblast interferon with chemotherapeutic agents and radiation against human gliomas in nude mice. Neurol Res 8:152-156, 1986 J. Neurosurg. / Volume 6 9 / D e c e m b e r , 1988 20. Nakamura O, Nomyra K, Maruo K, et al: [Antineoplastic effect of Hu-IFN-C/and other anticancer drugs on malignant brain tumors in athymic nude mice.] No Shinkei Geka 13:503-508, 1985 (Jpn) 21. Nakarnura O, Teramoto A, Yamamoto H, et at: [Effect of human fibroblast interferon on malignant brain tumors.] No To Shinkei 35:905-911, 1983 (Jpn) 22. Nederman T, Benediktsson G: Effects of interferon on growth rate and radiation sensitivity of cultured, human glioma cells. Acta Radiol (Oncol) 21:231-234, 1982 23. Nobuhara M, Kanamori T, Ashida Y, et al: [Basic study of interferon-c/: Part IV. Antitumor effect on nude mousetransplanted human tumors.] Gall To Kagaku Ryoho 13: 2117-2122, 1986 (Jpn) 24. Obbens EAMT, Feun LG, Leavens ME, et al: Phase I clinical trial of intralesional or intraventricular leukocyte interferon for intracranial malignancies. J Neurooncol 3: 61-67, 1985 25. Otsuka S, Handa H, Yamashita J, et al: Single agent therapy of interferon for brain turnouts: correlation between natural killer activity and clinical course. Aeta Neurochir 73:13-23, 1984 26. Piguet V, Carrel S, Diserens AL, et al: Heterogeneity of the induction of HLA-DR expression of human immune interferon on glioma cell lines and their clones. J N C I 76: 223-228, 1986 27. Takiguchi M, Ting JPY, Buessow SC, et al: Response of glioma cells to interferon-gamma: increase in class II RNA, protein and mixed lymphocyte reaction-stimulating ability. Eur J lmmanol 15:809-814, 1985 28. Tanaka N, Nagao S, Tohgo A, et al: Effects of human fibroblast interferon on human gliomas transplanted into nude mice. Gann 74:308-316, 1983 29. Wakabayashi T, Yoshida J, Kobayashi T, et al: [Effect of interferon on malignant brain tumor.] Gan To Kagaku Ryoho 9:1400-1406, 1982 (Jpn) 30. Yates AJ, Stephens RE, Elder PJ, et al: Effects of interferon and gangliosides on growth of cultured human glioma and fetal brain cells. Cancer Res 45:1033-1039, 1985 31. Yoshida J, Wakabayashi T, Kato K, et al: [Combination therapy with IFN-C/, ACNU and radiation OAR) in malignant brain tumors.] Gan To Kagaku Ryoho 13: 520-524, 1986 (Jpn) 32. Yung WKA, Castellanos AM, Moser RP: Intravenous recombinant beta interferon (IFN-c/ser) in patients with malignant gliomas. Neurology 37 (Suppl 1):334, 1987 (Abstract) Manuscript received March 4, 1988. This work was supported in part by a grant from Biogen Research Corporation, Cambridge, Massachusetts, and in part by National Institutes of Health Grant 5P50-NS20023 from the Specialized Center of Research on Malignant Human Gliomas and Medulloblastomas. Address reprint requests to: M. Stephen Mahaley, Jr., M.D., Division of Neurological Surgery, University of Alabama, University Station, Birmingham, Alabama 35294. 829