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scans (unpublished data).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