[CANCER RESEARCH 47, 6397-6401, December 1, 1987]
Effects of 7-Interferon on the Endocrine System: Results from a Phase I Study1
David Goldstein, Jon Gockerman, Ranga Krishnan, James Ritchie, Jr., Chak Yuen Tso, Linda Edwards Hood,
Everett Ellinwood, and John Laszlo2
Departments of Medicine ¡D.G., J. G., C. Y. T., L. E. H., J. L.¡and Psychiatry [R. K.. J. R., E. E.], Duke Medical Center, Durham, North Carolina 27710
ABSTRACT
MATERIALS
Interferon causes profound biological changes when given to patients
with cancer and many of these could not be predicted from in vitro or
animal model systems. We documented significant changes in hormonal
levels for a group of 18 patients who were participants in a Phase I 7interferon trial. Adrenocorticotropic hormone, cortisol, and growth hor
mone were all significantly elevated 2 h after treatment with 7-intcrfcron,
with cortisol and adrenocorticotropic hormone returning to base line by
24 h. A placebo group failed to show this change, suggesting a specific
interferon effect. Possible mechanisms for these findings and implications
for the use of interferons are discussed.
Eighteen patients were entered into this study on the basis of their
eligibility for the interferon Phase I study, the criteria for which included
having incurable, histologically proven malignant disease refractory to
standard methods of therapy, or for which there was no known effective
therapy. All patients were over 18 years of age, were relatively free of
debility and comorbid conditions, and had a Karnofsky performance
status of >70% and life expectancy of more than 16 weeks. The study
was carefully explained to each patient prior to obtaining signed con
sent.
The patients were part of a larger Phase I study and thus were on a
variety of dose regimens; three received an escalating dose schedule,
with doses ranging from 100 to 500 megaunits/m2 (1 megaunit = 10'
units, NIH reference standard; see Table 1). Seven patients received
three separate courses of 60 megaunits/m2. Each course to a patient
included three different infusion times, 20 min, 4 h, and 24 h, spaced
1 week apart and with the sequence selected randomly. Another eight
patients were assigned randomly to receive either 1 or 30 megaunits/
m2, but before they received the first dose of interferon they were also
INTRODUCTION
The anticancer properties of interferons have been of unusual
interest to researchers in that these are potent biological sub
stances which have toxicities different from those of other
chemotherapeutic agents and can stimulate elements of the
immune system. In fact, the mechanism of action of interferons
against cancer is not known but is thought to be a combination
of indirect immunostimulation of the host plus direct cytotoxicity of cancer cells.
An unexplained paradox with regard to immunostimulation
is that a- and 7-interferons are potent in vitro stimulators of
NK3 cells but they have much less than the expected effect
when given to patients. Some of these issues have been reviewed
recently (1). One possible explanation for the in vitro-in vivo
differences could be the role of hormone mediators, and that
issue was explored in this study.
A Phase I study conducted between July 1984 and July 1985
measured the clinical toxicity and immune responsiveness of
recombinant human 7-interferon in patients with cancer (1). In
that study, as with earlier studies on a-interferon, we have been
impressed with stress effects on patients such as fever, fatigue,
depression, hypotension, and hypertension; again noted were
inconsistent effects on the immune response. Since a number
of hormone receptors are found on lymphocytes we decided to
explore these issues further by measuring a series of hormones,
specifically, cortisol, ACTH, growth hormone, and TSH.
Cortisol, a known modulator of immune responsiveness, was
measured because of a previous report suggesting structural
homology and biological relatedness of human leukocyte inter
feron and ACTH (2). TSH because of a report suggesting
suppression of thyroid function in interferon treated patients
(3); and growth hormone because of its recognized elevation in
stressful situations, in a fashion parallel to that for cortisol (4).
AND METHODS
randomized to determine whether they would get placebo (saline) or
the interferon therapy as the initial infusion, with the other given 1
week later. Thereafter these patients all received a further seven courses
of interferon, at that dose, biweekly for a total of 4 weeks to assess the
effects of chronic administration.
Cortisol, ACTH, and growth hormone levels were measured in all
18 patients and TSH levels were measured in 7. Since some patients
had several courses of interferon at different concentrations, a total of
31 courses of interferon were available for analysis of cortisol response,
28 courses for ACTH, 18 for growth hormone, and 7 for TSH. The
placebo group also had all 4 hormones measured. Cortisol levels were
recorded for all 8 patients, ACTH in 6, growth hormone in 5, and TSH
in 7. The number of determinations of each hormone at various dose
levels of interferon is shown in Table 2. All infusions were given between
7:30 and 8:30 a.m. to minimize the effects of diurnal variations on the
steroid levels measured. Most 2-h hormone levels were therefore mea
sured between 10:30 and 11:30 a.m., except for 4 samples taken between
2:00 and 2:30 p.m. (after 4-h infusions).
All hormonal assays were performed by the Duke Clinical Psychobiology Laboratory. Cortisol was measured by a competitive proteinbinding method (5); the intraassay coefficient of variation was 5.6%
and the interassay coefficient of variation was 8.9%. ACTH was mea
sured by radioimmunoassay (6). The antiserum was produced against
the thyroglobulin conjugate of ACTH 11-24, which is highly specific
for ACTH 1-39; the sensitivity of the assay is 0.22 fmol/liter plasma
(1.0 pg/ml). The intraassay CV was 7% and the interassay CV was
12%.
Although a-interferon has been shown to possess no direct ACTHlike activity, this has not been shown for 7-interferon. At the onset of
this study we assayed a representative preparation of the 7-interferon
that was given our patients (Biogen, Cambridge, MA; lot 10M04). No
Received 5/11/87; revised 8/17/87; accepted 8/20/87.
detectable cross-reactivity was seen in our cortisol assay up to a level
The costs of publication of this article were defrayed in pan by the payment
of 100 fjg interferon/ml.
of page charges. This article must therefore be hereby marked advertisement in
In our ACTH assay, 7-interferon dissolved in ACTH stripped serum
accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
had a 50% inhibitory' concentration of 160.37 ¿ig/ml.Given the specific
1We appreciate the financial support of Biogen Corporation for the hormone
assays. The Phase I study of-y-interferon was supported by Contract N01-CMactivity of the lot used (1400 unhs.Vg), this means that approximately
07334-22 from the Biological Response Modifier Program, National Cancer
225,000 units of interferon/ml would appear as 44 fmol/ml of ACTH.
Institute, and by Grant 28294-08 of Mental Health, Department of Health and
Thus we concluded that whenever possible we would have direct 7Human Services.
2 Present address: Vice President for Research, American Cancer Society, 90
interferon measurements made on our subjects. Only two subjects had
Park Avenue, New York, NY 10016. To whom requests for reprints should be
interferon levels in a range which significantly compromised ACTH
addressed.
determinations. (The six ACTH levels taken on the high dose patients,
3The abbreviations used are: NK, natural killer; ACTH, adrenocorticotropic
i.e., >100 megaunits/m2, were not included in our analysis).
hormone; TSH, thyroid stimulating hormone; CV, coefficient of variation; SI,
Growth hormone was measured by immunoradiometric assay using
international units.
6397
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EFFECTS
OF -»-INTERFERON ON THE ENDOCRINE
60
Table l Interferon study design
Patients
Dose/schedules1
400"1
min-t,
200 300
40060
300
over 420
I]60
^Q Qyc|-
~
p = .0002
50
100 300
4001
SYSTEM
40
s* so
h<"RANDOMIZE/<X<RANDOMIZE2over 24
20
I MU/m2
/ /Crossover2
\
10
I MU/m2
o
Pré
2 Hr
24 Hr
Placebo2
Placebo
60
5030 MU/m2
MU/m2Crossover
30
40
\X
/
Placebo
2
/
\
§30
Placebo
S
20
" All doses are in megaunits/m2.
Table 2 Number of courses at each dose level for which hormone levels were
measured
PRE
Dose
(megaunits/m2)1
30
60
100200
300
400
PlaceboCortisol
hormone
(JV=31)4
<JV=31)4
4
IS
13
2
163
3
3
8ACTH<JV=28)4
6Growth
Range
MedianGrowth
hormone
Range
MedianBase
line(Normal,
8-16ng/dl)
8.3-42.3 iig/dl
24.6 Mg/dl
test)(Normal,
P < 0.002 (signed rank
0.2-6.6
0-12.1
2.9
P <test)(Normal,
0.02 (signed
fmol/liter)
fmol/liter
fmol/liter
rank
<5 ng/ml)
0.2-13.1 ng/ml
1.1 ng/ml
P < 0.0042
24 HR
Fig. l. A, changes in Cortisol over the 24-h period after a single dose of -,
interferon. Pre, base line level prior to infusion; 2 Hr, 2 h postinfusion; 24 Hr, 24
h postinfusion. (Eight patients whose levels were taken at the end of their 4-h
infusion are plotted at 2 h for convenience.)
, courses where an elevation was
seen.
, courses where no elevation was seen. B, changes in cortisol over the
same 24-h period distributed as a range with the median and interquartile ranges
marked.
4
31
16
1
1
3
3
5TSH(N-l)4
Table 3
Cortisol
Range
MedianACTH
2 HR
[includes a points
at O hr post 4 hr
infusion]
h7.3-56.5
ii/dl
„g/dl0-18.5
36.4
fmol/liter
fmol/liter0.2-39
4.87
ng/ml
5.4 ng/ml
two monoclonal antibodies (Hybritech, San Diego, CA) (7). The assay
has a sensitivity of 0.2 ng/ml (SI: 2 ^g/liter) with an intraassay CV of
6.7% and an ¡nterassayCV of 15% (normal values, 0-5.6 jig/ml). TSH
was measured by a single step monoclonal immunoradiometric assay
(Hybritech Kit-CA), which is sensitive to 0.2 jjIU/ml (SI 2 milliunits/
ml). Interassay CV was 9% and intraassay CV was 5% (8).
The Wilcoxon signed rank test was used to assess the statistical
significance of change in hormone levels from base line to the value at
2 h and the change from 2 h to 24 h.
RESULTS
Cortisol levels rose significantly (P < 0.01) after interferon
infusion, 23 of 31 courses being elevated (see Table 3). Fig. 1
shows the induced changes superimposed on one another (the
data at 2 h includes eight values taken at the end of the 4-h
infusion but plotted for convenience as 2 h; those eight patients
did not have 24-h data available). Of note were the relatively
high base line readings [median, 24.6 Mg/dl: (SI 678.7 nmol/
liter); range, 8.3-42.3 (SI 229-1167)] and the marked increase
at 2 h after the infusion of interferon [median, 36.4 nig/dl (SI
1004 nmol/liter); range, 7.3-56.5 (SI 201-1559). Interestingly,
those patients who had a base line level of 20 ng/dl or higher
were more likely to show an elevation than those with a lower
base line reading (21 of 24 versus 2 of 7; P < 0.002).
ACTH levels also rose from base line (P < 0.04) (one-sided
sign test) but save for one very high result were just above the
upper normal range for our laboratory (see Fig. 2). The median
ACTH level was 4.87 fmol/ml (22.1 pg/ml), and the range was
0-18.5 fmol/ml (0-84 pg/ml; (normal, 0.22-6.6 fmol/ml) (130 pg/ml) but the minor degree of cross-reactivity with yinterferon made the levels reached difficult to interpret (see
Table 3).
Those interferon doses for which hormone levels were mea
sured included 1, 30, and 60 megaunits/m2. The ACTH levels
for the group of patients who received >megaunits/m2 were
excluded because of high serum interferon levels (i.e., >5000
units/ml) which make ACTH levels unreliable. No interferon
dose-response (or infusion rate) relationship was noted for
either cortisol or ACTH; however, the subgroups were too small
to allow meaningful analysis.
In order to determine whether these hormonal changes were
due to interferon and not a nonspecific response to stress, eight
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EFFECTS
OF 7-INTERFERON
ON THE ENDOCRINE
SYSTEM
20
18
p < 0.02
16
14
£i12
SÃ-E 10
8
6
4
2
0
2 Hr
Pré
24 Hr
20
IS
0.036
Fig. 4. Changes in ACTH over the 24-h period after placebo was administered.
Pre, base line level prior to infusion; 2 hr, 2 h postinfusion; 24 hrs, 24 h
postinfusion. Symbols refer to each of individual 8 patients studied.
patients. The rise seen at 2 h postinfusion was again significant
(P < 0.004); see Table 3. The seven patients who had TSH
levels measured showed a decrease at 2 h after interferon, but
this was not significantly different from the response to placebo.
NK (natural killer) activity was also studied prior to and after
each course of interferon but no significant change was noted
(1). There were no clinical responses seen in this group of
patients and thus no correlations between outcome and cortisol
levels could be assessed (1).
It is noteworthy that, over the range of temperature and
cortisol observed, there was a positive correlation between
temperature and cortisol. Formally, Spearman's rank correla
ISI4-
.10-
PRE
2HR
24 HR
Fig. 2. A, changes in ACTH over the same 24-h period after a single dose of
7-interferon. B, changes in ACTH over the same 24-h period displayed in a linear
range with the median and quartile ranges marked. Pre, base line level prior to
infusion.
tion coefficient is 0.41 (The probability is 0.08 that the corre
lation coefficient can be this large or larger by randomness
alone, if the two variables were truly uncorrelated).
The side effects noted with 7-interferon included fever, chills,
diarrhea, nausea, vomiting, mental changes, and hypotension;
all were reversible.
DISCUSSION
40
5 36
* 32
ï »
S 24
^ 20
l
16
I
12
O
8
In order to maximize the therapeutic effects of the interferons
two major problems need elucidation: (a) the basis of the
toxicity of interferon, notably malaise, fever, fatigue, hypoten
sion and hypertension, arrhythmias, and neurological changes;
and (b), the basis of the inconsistent immunostimulation. In
the case of a-interferon one dose and schedule will result in
substantial augmentation of NK activity in some patients but
4
not in others (9); further certain dose schedules are effective
O
but not others (10, 11). This contrasts with the consistent in
2 hr
24 hrs
Pre
vitro effectiveness of interferon in stimulating NK activity (12).
p - 0.036
No adequate explanation exists for the marked disparity be
Fig. 3. Changes in Cortisol over the 24-h period after placebo was administered.
Pre, base line level prior to infusion; 2 hr, 2 h postinfusion; 24 hrs, 24 h
tween in vitro and in vivo ¡ninninosiimulatory effects of inter
postinfusion. Symbols refer to each of the individual 8 patients studied.
feron.
We suggest that certain aspects of both problems may ema
patients were treated with a placebo course (saline) and the nate from the endocrine changes associated with interferon. In
pattern of cortisol elevation was then compared to the same this study we have shown that 7-interferon treatment is asso
patients' response to interferon. Four patients received placebo
ciated with significant elevations of cortisol, ACTH, and growth
alternating with 1 megaunit/m2 and 4 received 30 megaunits/
hormone. While we do not have data on cortisol binding glob
m2 alternating with placebo (saline) in a blind and randomized
ulin (which could be abnormal in malignancy) and therefore
cannot be certain about the physiological significance of the
fashion; the results are shown in Fig. 3. There was a striking
levels, there is a significant elevation which cannot be explained
difference between placebo and interferon. While most patients
started with relatively high levels of cortisol, all levels had by anything other than the infusion. Elevation of serum cortisol
decreased by 2 h after the placebo infusion; by contrast, all the levels has also been noted with a-interferon given to normal
interferon infusions resulted in an elevation above base line. A volunteers (13) and patients with malignancies (14, 15). Thus
similar pattern was found for ACTH (Fig. 4). (Note that all the endocrine phenomena we report do not appear to be re
these blood samples were drawn between 11 and 12 a.m.; thus stricted to 7-interferon.
Both the relatively high basal and the postinfusion levels were
the decrease in level for the placebo group could be due to
similar to those experienced in severe stressful situations such
diurnal variation.)
as cardiac catheterization or the period just prior to surgery
Growth hormone levels showed striking elevations in some
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EFFECTS OF ^-INTERFERON ON THE ENDOCRINE SYSTEM
(16, 17). In the cardiac catheterization study cortisol levels
increased by 60 min after the procedure; the majority were
maximal by 2 h and were still above base line at 4 h. The
median level at 2 h was 17 ^g/dl (range, 6-77 /zg/dl) (17). In
the surgical study preoperative procedures such as insertion of
intravenous cannulas or enemas led to increases in cortisols
within the first hour which rapidly returned to normal; the
median level was 18.2 (range, 14.1-27.2) (16).
The fatigue and behavioral changes (confusion, loss of atten
tion span, irritability, depression) experienced by patients given
interferon seem to parallel many of the neurological and behav
ioral changes noted with Cushing's syndrome (18, 19), partic
ularly when the latter has a rapid onset due to tumors and
paraneoplastic syndrome, or to steroid overmedication. This
raises the possibility that the neurological toxicities of inter
feron may have a direct relationship to the consistent elevation
of corticosteroid from repeated administration. The absence of
the other classical features of Cushing's syndrome is not sur
prising given the duration of interferon treatment, since the
physical changes may take several years to manifest themselves.
While the effect of any single dose is transient (i.e., cortisol
level is normal within 24 h of treatment), the use of repeated
doses of interferon would lead to repeated elevations over a
substantial period of time which could thus contribute to neu
rological effects.
With regard to the immune system, it has been demonstrated
previously that hydrocortisone will diminish murine (20, 21)
and human (22,23) NK activity in vitro and in vivo. We recently
found that hydrocortisone, at levels achieved in these human
experiments, will blunt the augmentation of NK activity pro
duced in vitro by both a- and -y-interferon." Thus we reason
that failure to obtain consistent NK augmentation in vivo may
reflect the confounding effect of the induced cortisol elevation.
If these hypotheses are correct and if it is important to
stimulate NK activity, then our Findings have particular impli
cations for dose scheduling. Since one of the major actions of
interferon is recruitment of pre-NK cells, daily administration
could result in daily (although transient) suppression of the
activated circulating NK cells mediated by increased hydrocor
tisone levels (21). However, there is some evidence that preNK cells are relatively steroid resistant (i.e., they can subse
quently be stimulated to NK activity by interferon) (21, 22).
Consequently, an intermittent schedule of interferon adminis
tration may cause a more sustained NK response over time,
since the supply of pre-NK cells might not be depleted as
rapidly. Since the optimal immunomodulatory dose of -y-interferon appears to be substantially lower than the maximal tol
erated dose, it will be important to restudy these effects at those
lower dose levels.
It is particularly noteworthy that most patients in our study
had relatively high base line cortisol levels. This suggests that
administration of cancer therapy, or perhaps just the outpatient
clinic experience itself, has patients in a high state of arousal
(at least under such experimental conditions), with probable
effects on their immune status if they are having daily treat
ments.
We attribute the reduction in cortisol level seen in the placebo
group to a decrease in patient anxiety after the i.v. line is
inserted and infusion therapy has begun; alternatively, it could
be due to the absence of fever and other symptoms. This also
has significant implications for the administration of treatment
in the outpatient setting, and the possible use of relaxation
techniques and/or anxiolytic agents is now being studied under
carefully controlled conditions (24-26).
4 Unpublished data.
The response of growth hormone was similar to that of
cortisol, with elevation occurring after interferon but not with
placebo (data not shown). Since both cortisol and growth hor
mone have been shown to rise in parallel under some circum
stances of stress (4), a common triggering factor, i.e., interferon,
seems possible (even though the final pathways of activation
are different). However, the variability of growth hormone
secretion, which is a well documented phenomenon even in
normals, makes the significance of our findings difficult to
evaluate.
With regard to TSH, although we noted a drop in TSH levels,
this same pattern was also demonstrated in the placebo group,
and no conclusions can be drawn regarding interferon effects.
There are several possible mechanisms by which 7-interferon
could cause the hormonal changes we observed. 7-Interferon
may have a corticotropin-releasing factor or ACTH-like action
(our data on cross-reactivity between high levels of 7-interferon
and ACTH lend some support to this). This would not, however,
explain the similar increases in cortisol output seen following
a-interferon (13-15), since the early suggestion of homology
between ACTH and interferon has been refuted (27,28). Several
studies have shown that activated lymphocytes can produce
hormonally active peptides (29-31). In vitro studies have also
shown that murine adrenal tissue can be stimulated by the
supernatants of activated lymphocytes (32, 33), lending further
support to this view. Since interferons are known to cause
activation of lymphocytes, this could be the pathway by which
observed hormonal changes take place.
A number of receptors have been documented on NK cells
and/or lymphocytes, including glucocorticoid (34), vasoactive
intestinal peptide (35), 0-endorphin (36), and /3-adrenergic (37)
receptors. Thus, the variety of hormones released by interferon
treatment may have multiple competing effects on the cellular
immune system, and their possible interactions will require
more study. An alternative hypothesis may be that interferon
acts as a pyrogen with regard to endocrine stimulation. In
studies done on normal volunteers (38-40), it has been shown
that the adrenal gland is quite sensitive to the effects of a
pyrogen. There is brisk stimulation, with a peak occurring 2-3
h after administration and often preceding the rise in tempera
ture.
The range and median level of corticosteroid were higher in
our study than those reported in several of the pyrogen studies.
This may indicate either that interferon causes a more marked
pyrogenic reaction than the bacterial pyrogen used previously
or that the hypothesized activation of lymphocyte products is
also important. Of interest a recent study of recombinant interleukin 2 showed rises in both ACTH and cortisol. The elevation
in ACTH was much higher than those recorded in our study
thus lending support to the possibility of a direct lymphoadrenal
axis rather than simply a pyrogenic response (41).
Irrespective of the etiology, either a direct effect of the
interferon or an indirect physiological response to the stress of
this type of therapy, the net effect is still a clear association of
elevation of corticosteroids beyond the normal range with in
terferon therapy. We believe that this is an important phenom
enon to document because such an association may have im
portant confounding effects on the desired immunological stim
ulation. In this regard our findings, that those patients with
higher base line levels (>20 ßg/dl)(SI 551.8 nmol/liter) were
more likely to show an elevation, identify a possible subgroup
of patients who may require alternative schedules of treatment.
These findings are in accord with recently described hyperplasia
and hyperresponsiveness of the adrenal gland under certain
conditions (42).
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EFFECTS
OF -y-INTERFERON
ON THE ENDOCRINE
The diurnal pattern in toxicity noted both in humans treated
with interferon (43) and in mice treated with tumor necrosis
factor (44) lends further support to our contention that activa
tion of the adrenocortical system is relevant to the toxicity of
interferon and possibly other biological agents. In both cases
there was less toxicity without any detectable alteration in
efficacy by evening administration. Since the diurnal pattern of
cortisol secretion is such that cortisol levels are low in the
evenings than any associated increase at that time would be less
likely to elevate cortisol above normal levels. By contrast in the
morning hours the base line levels are higher and any interferon
induced elevation would have a more profound effect.
While no direct blockers of glucocorticoid action are cur
rently in use, we are investigating nonspecific ways of blocking
what appears to be a generalized acute stress hormone response
to interferon. Overcoming this potentially deleterious hormone
response may be a significant factor in making interferon ther
apy less toxic to the patient and more efficacious in stimulating
the immune response. The potential therapeutic implications
for lymphokines such as interferon underscore the need for
further research into the associated physiological responses
which may occur that could abrogate their effectiveness.
ACKNOWLEDGMENTS
We appreciate the critical reading of the manuscript by Dr. Marc
Drezner.
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SYSTEM
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Effects of γ-Interferon on the Endocrine System: Results from a
Phase I Study
David Goldstein, Jon Gockerman, Ranga Krishnan, et al.
Cancer Res 1987;47:6397-6401.
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