of 22
7/30/2019 Interferon in Oncological Practice_Review of Interferon
1/22
Interferon in Oncological Practice: Review of InterferonBiology, Clinical Applications, and Toxicities
ERIC JONASCH, FRANK G. HALUSKA
Massachusetts General Hospital, Boston, Massachusetts, USA
Key Words.Interferon Cancer Clinical applications Toxicity Management
ABSTRACT
For the past 40 years, various forms of interferon
(IFN) have been evaluated as therapy in a number of
malignant and non-malignant diseases. With the advent
of gene cloning, large quantities of pure IFN became
available for clinical study. This paper reviews the biol-
ogy, pharmacology, and clinical applications of IFN for-
mulations most commonly used in oncology. It thenreviews the most common side effects seen in patients
treated with IFN, and makes recommendations for the
management of IFN-induced toxicity.
The major oncological indications for IFN include
melanoma, renal cell carcinoma, AIDS-related Kaposis
sarcoma, follicular lymphoma, hairy cell leukemia,
and chronic myelogenous leukemia. Unfortunately,
IFN therapy is associated with significant toxicity,
which can be divided into constitutional, neuropsychi-
atric, hematologic, and hepatic effects. These toxicities
have a major impact on the patients quality of life, and
on the physicians ability to optimally treat the patient.
Careful attention to all aspects of patient care canresult in improved tolerability of this difficult but
promising therapy. Conclusion: a better understanding
of IFN biology, indications, side effect profiles, and tox-
icity management will aid in optimizing its use in the
treatment of patients with cancer. The Oncologist
2001;6:34-55
The Oncologist 2001;6:34-55 www.TheOncologist.com
Correspondence: Eric Jonasch, M.D., Cox 640, Division of Hematology-Oncology, 55 Fruit Street, Boston, Massachusetts02114, USA. Telephone: 617-724-6582; Fax: 617-726-6974; e-mail: [email protected] Received March 31, 2000;accepted for publication October 3, 2000. AlphaMed Press 1083-7159/2001/$5.00/0
INTRODUCTION
In 1957Isaacs andLindeman described a factor that con-
ferred the property of viral interference [1]. The term inter-
feron (IFN) was coined to describe this new substance. Over
the next 40 years, the IFNs have been evaluated as therapeu-
tic modalities in a large number of malignant and nonmalig-
nant diseases. Research has revealed diverse mechanisms of
action, including antiviral, immune-enhancing and cytostatic
activities.
In oncology, the IFNs are an important treatment for a
number of solid tumors and hematological malignancies.
These include melanoma, renal cell carcinoma, AIDS-
related Kaposis sarcoma (KS), follicular lymphoma, hairy
cell leukemia, and chronic myelogenous leukemia (CML).
IFN therapy is associated with significant side effects
which have an impact on the patients quality of life and the
physicians ability to optimally treat the patient. An under-
standing of IFN biology, interactions, indications for use,
side-effect profiles, and the management of IFN toxicities
will aid in the optimal application of these agents in the
management of patients with cancer.
In this report, we review the classification of the IFNs and
summarize their major mechanisms of action. We then
describe the indications for IFN therapy in oncological prac-
tice and review the etiology and management of IFN-related
side effects.
IFN CLASSIFICATION
After the discovery of IFN, initial attempts at purifica-
tion were met with little success, defying efforts at classifi-
cation. Early clinical trials used crude preparations that were
less than 1% IFN by weight [2]. It was only in 1978 and
thereafter that IFN was purified to homogeneity in amounts
that allowed chemical and physical characterization. The
initial nomenclature of, , and IFN was used to catego-
rize the major HPLC peaks, but was quickly adopted to des-
ignate leukocyte, fibroblast, and immune IFNs, respectively[2]. Table 1 summarizes some of the major properties of the
various IFN subtypes.
In 1980, at a meeting jointly sponsored by the National
Institute of Allergy and Infectious Diseases and the World
Health Organization, nomenclature was formally adopted
7/30/2019 Interferon in Oncological Practice_Review of Interferon
2/22
Jonasch, Haluska 35
classifying IFNs into three cate-
gories based on antigenic speci-
ficity. IFNs were categorized as
alpha (), beta (), and gamma
(), corresponding to the previ-ous designations of leukocyte,
fibroblast and immune IFN [3].
More recently, IFNs were
divided into two major sub-
groups by virtue of their ability
to bind to common receptor
types [4-6]. Type I IFNs all bind
to a type I IFN receptor, and
include IFN-, IFN-, IFN-,
and IFN-. IFN-is the sole type
II IFN, and binds to a distincttype II receptor [7].
Almost all cell types produce
type I IFNs. The prototypical
production sites for IFN- and
IFN- are leukocytes and fibro-
blasts, respectively. Their induc-
tion usually follows exposure to
viruses, double-stranded RNA,
polypeptides, and cytokines [8].
The type II IFN-is produced in
T cells and natural killer (NK)
cells following a number of
immunological stimuli, includ-
ing T cell-specific antigens,
staphylococcal enterotoxin A,
and the combination of phytohemagglutinin and phorbol
ester [2, 8]. Unlike IFN- and -, it is not directly induced
in cells following viral infection.
BIOLOGICAL PROPERTIES OF IFNS
The IFNs possess a broad spectrum of activity and are
involved in complex interactions. They display antiviral
activity, impact cellular metabolism and differentiation, and
possess antitumor activity. The antitumor effects appear to be
due to a combination of direct antiproliferative, as well as
indirect immune-mediated effects. Figure 1 summarizes the
intracellular signaling, and Figures 2 and 3 summarize the
major effects of IFN- and -on NK cells, antigen-presenting
cells, macrophages, T cells, and tumor cells.
Table 1. IFN classification and properties
IFN IFN Receptor Prototypic Direct Anti- Stimulates MHC Stimulates MHC Stimulates NKType categories type cell of origin proliferative effects class I expression class II expression cell activation
Type I Alpha () I Leukocyte Yes Yes No Yes
Beta () I Fibroblast Yes Yes Slightly Yes
Omega () I Leukocyte Yes Yes No Yes
Tao () I OvineTrophoblast
Type II Gamma () II T-cells Yes Yes Yes Less than type INK cells IFNs, delayed
P
PP
P P
P
P
P
P
P
P P
P
P
P
P
P
P
P
P
P
IFN-AR1
IFN-AR
2
TYK2
STAT1
STAT2
JAK1
IFN-
IFN-
STAT1
STAT1
JAK1
JAK1
JAK2
IFN-G
R2
IFN-G
R2
IFN
-GR1
IFN
-GR1
STAT1
STAT1
STAT1
STAT1
GAS ISGISGISRE
STAT1
STAT2
ISGF3
P
Cytoplasm
Nucleus
IFN-
STAT1
STAT2
Figure 1. For the type I IFNs, there are two receptor subunits known, IFNAR-1 and IFNAR-2, which bind the
Janus-activated kinase (Jak) molecules Tyk2 and Jak1, respectively. For IFN-, there are two receptor subunits
known: IFNGR-1 and IFNGR-2, which associate with Jak1 and Jak2, respectively. Upon binding of IFN to its recep-
tor, the receptor undergoes oligomerization, with transphosphorylation of Jaks followed by phosphorylation of the
cytoplasmic tails of the receptor molecules. This provides a docking site for the signal transducers and activators of
transcription (Stats) which are then phosphorylated by the Jaks. The phosphorylated Stat dimers are released from
the receptor molecules, and translocate to the nucleus, where they activate transcription of IFN-stimulated genes(ISGs). In the case of type I IFNs, ISGs can be identified by the presence of an IFN-stimulated response element
(ISRE) in their promoter regions. Enhancers of IFN--inducible genes contain a unique element called the IFN-
activation site (GAS).
7/30/2019 Interferon in Oncological Practice_Review of Interferon
3/22
36 Interferon in Oncological Practice
CURRENTLY AVAILABLE PREPARATIONS
The cloning of the IFN genes resulted in the availabil-
ity of large quantities of pure IFN- and -, allowing sub-
stantive research to be done on the clinical efficacy of the
IFNs in malignant and nonmalignant diseases. The clini-
cal indications for the IFN subtypes are summarized in
Table 2.
IFN-2a (Roferon A; Roche Laboratories; Nutley, NJ)and IFN-2b (Intron-A; Schering-Plough Corporation;
Kenilworth, NJ) are now produced by recombinant (r)DNA
technology. The molecular sequences of the two rIFNs differ
from one another by a single amino acid at position 23 [9].
IFN alfacon-1 (Infergen, Amgen; Thousand Oaks, CA) is a
recombinant non-naturally occurring IFN, whose 166 amino-
acid sequence was derived by scanning the sequences of sev-
eral natural IFN- subtypes and assigning the most frequently
observed amino acid in each corresponding position. Four
additional changes were made to facilitate molecular con-
struction. IFN-n3 (Alferon N; Interferon Sciences Inc.;New Brunswick, NJ) is derived from human leukocytes.
T-cell
NK cell/macrophage
Tumorcell
Antiangiogenic
Th1 differentiation
Growth inhibition?
MHC I expression
Tumor-specific antigenexpression
Adhesion moleculeexpression
Direct cytostaticeffects
IFN-production
Cellular cytotoxicity
IL-1 production
Proliferation
IFN-
Figure 2. IFN-possesses pleiotropic and potentially antagonistic activity
in immune cells and tumors. Both stimulatory and inhibitory effects are
seen in the T-cell population. A stimulatory effect is seen in natural killer
(NK) cells and macrophages, which may be antagonized by the IFN-medi-
ated upregulation of major histocompatibility-1 (MHC1) in tumor cells.Direct cytostatic effects are seen in tumor cells, as well as upregulation of
tumor-specific antigens and adhesion molecules. IFN- may also have
antiangiogenic effects mediated indirectly by IFN-(Fig. 3).
T-cell
MacrophageAPC
Tumorcell
Antiangiogenic
Increased activation(in synergy with IL-2)
MHC class I upregulation
Decreased proliferation
Activation
MHC class IIupregulation
IFN-
Figure 3. IFN-is an activator of T-cells and macrophages, working in concert
with interleukin-2 (IL-2).IFN-is capable of upregulating both MHC classes I
and II, and has demonstrated direct inhibitory effects on tumor proliferation. IFN-
is presumed to induce its antiangiogenic effects through the secretion of IFN-
inducible protein 10 (IP-10) and monokine induced by IFN-(MIG).
Table 2. IFN clinical indications
IFN type Trade name Manufacturing technique FDA-approved indications
IFN-2a Roferon A rDNA NHLHairy cell leukemiaCMLAIDS-related KSChronic hepatitis C
IFN-2b Intron A rDNA Follicular lymphomaHairy cell leukemia
AIDS-related KSMalignant melanomaCondyloma accuminataChronic hepatitis BChronic hepatitis C
IFN alfacon-1 Infergen rDNA Chronic hepatitis C
IFN-n3 Alferon N Purified from human leukocytes Condyloma accuminata
IFN-1a Avonex rDNA Relapsing-remitting MS(Chinese hamster ovary cells)
IFN-1b Betaseron rDNA Relapsing-remitting MS(E. coli)
IFN- Actimmune rDNA Chronic granulomatous disease
7/30/2019 Interferon in Oncological Practice_Review of Interferon
4/22
Jonasch, Haluska 37
IFN-1b is manufactured by bacterial fermentation of a
strain ofEscherichia coli that bears a genetically engineered
plasmid containing the gene for human IFN betaser17. The
native gene was obtained from human fibroblasts and altered
in a way that substitutes serine for the cysteine residue found
at position 17 [10]. IFN-1b has 165 amino acids and an
approximate molecular weight of 18,500 Da and does not
include the carbohydrate side chains found in the natural
product. It is given s.c. every other day [11].
IFN-1a (Avonex; Biogen Inc; Cambridge, MA) and IFN-
1b (Betaseron; Berlex; Richmond, CA) are recombinant
proteins. IFN-1a is a 166-amino acid glycoprotein with a
predicted molecular weight of approximately 22,500 Da. It
is produced by mammalian cells (Chinese hamster ovary
cells) into which the human IFN- gene has been intro-
duced. The amino acid sequence of IFN-1a is identical to
that of natural human IFN-. IFN-1a is also U.S. Food and
Drug Administration (FDA)-approved for treatment of
relapsing-remitting multiple sclerosis (MS) to reduce fre-
quency of relapses [12]. It may be preferable to IFN-1b
because of the convenience of weekly administration, the
relative lack of injection site reactions, and lower incidence
of neutralizing antibodies.
IFN-(Actimmune; Genentech Inc; San Francisco, CA),
is produced using rDNA technology. It is FDA-approved for
use in chronic granulomatous disease.
PHARMACOKINETICS
As with most peptides, oral delivery of the IFNs is notpractical due to proteolytic degradation. Subcutaneous and
i.m. absorption of IFN- and IFN- is >80%, and 30%-
70%, respectively [13]. These routes of administration
result in a protracted distribution phase, with maximal
serum or plasma concentrations occurring after 1 to 8 h, fol-
lowed by measurable concentrations for 4 to 24 h after
injection for both IFN- and -. After i.m. administration,
IFN- levels peak between 3 and 15 h, and then decline at
a rate consistent with a 10-h elimination half-life. At thera-
peutic dosages of 0.25 mg s.c., serum concentrations of
IFN- are low or undetectable [14]. Intravenous adminis-
tration of IFN- or - results in a biexponential decrease in
serum concentration, and IFN- levels decline monoexpo-
nentially. Terminal elimination half-lives range from 4-16 h
for IFN-, 1-2 h for IFN- and 25 to 35 min for IFN-[15-
17]. Serum concentrations are generally measurable for
between 8 and 24 h after i.v. injection of IFN- and up to
4 h after i.v. injection of IFN- and -.
The relationship between dose and biological response
varies among disease types. A number of surrogate markers
have been investigated to better define the dose-response
relationship of IFN. 25 oligoadenylate synthetase (2-5A),
an enzyme induced by both IFN- and -, is involved in
IFN-mediated viral RNA degradation [18]. Introduction of
2-5A into cells [19] or expression of 2-5A cDNA inhibited
cell growth rates [20]. Increased 2-5A levels were also
shown to correlate with decreased cell cycling in mela-
noma cell cultures treated with IFN [21], suggesting a
causal role in its antiproliferative action. Using 2-5A activ-
ity as a marker for response, a two- to sixfold increase in
2-5A activity was seen over a 300-fold dose range i.m.
using human lymphoblastoid IFN- [22]. Other biological
markers used to evaluate IFN response include neopterin
and 2 microglobulin. Neopterin is a pteridine derivative
originally found in cultures of stimulated T lymphocytes
[23] whose serum and urinary levels correlated with thera-
peutic IFN dosages in the treatment of hairy cell leukemia
[24, 25]. Small studies in melanoma [26-28] provide con-
flicting data on the utility of neopterin levels in predicting
response to immunotherapy. The human MxA protein is a
GTPase with antiviral activity against orthomyxoviruses
and certain other negative-strand DNA viruses [29].
Unlike 2-5A, 2 microglobulin and neopterin, MxA gene
expression is induced solely by type I IFNs [30, 31], and
holds promise for future cancer immunology studies. In
aggregate, these markers provide laboratory confirmation
of immunological stimulation by IFN, but do not provide
consistent predictive information on the use of IFN therapy
in cancer.
APPLICATION OF IFN THERAPY IN ONCOLOGICALPRACTICE
The IFNs have been used to treat a number of malig-
nancies, with varying degrees of success. The following
section summarizes the most common applications of IFN
in current oncological practice.
Hairy Cell Leukemia
The first report of IFN response in patients with hairy
cell leukemia was recorded in 1984 [32]. In this study,
seven patients were treated with 3 106 U of partially puri-
fied leukocyte IFN- i.m. daily (qd). Three patients had a
complete remission (CR), four had a partial remission (PR),
and remissions were maintained for 6 to 10 months. Subse-
quently, 30 patients with hairy cell leukemia were treated
with IFN-2a, including seven who were previously
untreated. Nine (30%) CR and 17 (56%) PR were confirmed
by bone marrow core biopsies. All patients peripheral blood
hematologic indices either improved or normalized [33]. A
multicenter phase II study of 64 patients published in 1986
confirmed the drugs efficacy in hairy cell leukemia [34].
IFN-2a and 2b were FDA-approved for use in hairy cell
leukemia in 1986. IFN- is usually given over a two-year
7/30/2019 Interferon in Oncological Practice_Review of Interferon
5/22
38 Interferon in Oncological Practice
period at 3 106 U/day. Unfortunately, upon cessation of
therapy, almost all patients will relapse. Although approved
for use, IFN- has been superceded by more effective thera-
pies in hairy cell leukemia, including 2-deoxycoformycin
and cladribine.
CML
Early Studies
Preclinical studies performed in the late 1970s sug-
gested IFN therapy had antiproliferative effects on granulo-
cyte precursors [35]. In 1983, Talpaz et al. reported on seven
patients with CML treated with IFN- 9-15 106 U i.m. qd
[36], five of whom developed a hematologic remission. In
1986, the same group reported on 17 patients with early-
phase CML who were treated with rIFN-2a, 5 106 U/m2
i.m. qd [37]. Fourteen patients responded to the treatment,
13 of whom had a complete hematologic remission (CHR)and one had a partial hematologic remission (PHR).
Cytogenetic analysis revealed that 20%-25% of patients
experienced long-term suppression of the Philadelphia (Ph)
chromosome. At least 30 uncontrolled observational studies
have been published looking at the effect of IFN- therapy
on patients in chronic-phase CML [38]. These studies vary
greatly with respect to their reporting of outcome measures,
and overall survival is often not recorded. Most studies
record an association between cytogenetic remission and
improved survival by landmark analysis*, with a minority
failing to show such an association [39]. (*Landmark analy-
sis is an assessment of outcome following the stratification
of patients according to a particular endpoint, in this case the
achievement of cytogenetic remission.)
IFN Monotherapy
In 1994, the Italian Cooperative Group published a
study of 322 patients with untreated or minimally treated
CML randomized between IFN-2a and conventional
chemotherapy [40]. The rate of karyotypic response was
30% in the IFN group versus 5% in the chemotherapy
group. Median time to progression and overall survival
were significantly longer in the IFN groups. Table 3 sum-
marizes the five randomized studies comparing chemother-apy (busulfan and/or hydroxyurea) to IFN- therapy
[40-44]. Four of these studies conclude that IFN therapy is
better than chemotherapy in patients with early chronic-
phase CML [40-43]. In all but one of these studies, IFN was
given as monotherapy. TheBenelux study [45] randomized
patients to IFN plus hydroxyurea as needed to keep the
Table 3. CML: randomized studies
Author Year n Study Hematologic response (%) Median
patients design CHR PHR survival (mos)Broustet[44] 1991 30 IFN 53 N/A N/A
28 Hydroxurea 82 N/A N/A
Hehlmann [41] 1994 133 IFN 31 52 66*
186 Busulfan 23 69 45*
194 Hydroxyurea 39 51 56
Italian 1994 218 IFN CHR + PHR = 45% 72Cooperative 104 Hydroxyurea/ CHR + PHR = 46% 52Group [40] Busulfan (p = 0.002)
Allan [42] 1995 293 IFN 69 18 61
294 Hydroxyurea/ N/A N/A 41Busulfan (p = 0.0009)
Ohnishi [43] 1995 80 IFN 39 39 Not reached, but improved79 Busulfan 54 43 survival in IFN arm (p = 0.029)
Benelux [45] 1998 100 IFN 62 N/A 64Hydroxyurea
95 Hydroxyurea 38 N/A 68 NS
Guilhot[50] 1997 361 IFN 55 N/A Not reached, but improvedHydroxyurea survival in IFN-cytarabine
360 IFN 66 N/A arm (p = 0.02)
HydroxyureaCytarabine (p = 0.003)
NS = not significant; *statistically significant
7/30/2019 Interferon in Oncological Practice_Review of Interferon
6/22
Jonasch, Haluska 39
WBC count below 10 109 versus hydroxyurea alone, with
no survival benefit noted in the IFN arm. Differences in
trial design, inclusion criteria, treatment and documentation
of response make direct comparisons between these trials
difficult, but the evidence supports a benefit to IFN- therapy
in patients with early chronic-phase CML.
Combination Therapy
In the late 1980s, cytarabine (ara-C) was shown to sup-
press CML clones selectively in vitro [46] and demon-
strated in vivo antitumor efficacy when given as a low-dose
continuous infusion [47]. In 1992, Kantarjian et al. pub-
lished a report on 60 patients with advanced phases of CML
who received combination therapy with IFN- 5 106
U/m2 daily, and low-dose ara-C 15 mg/m2 daily for two
weeks every four weeks until remission, then for one week
every month as maintenance, compared to historical con-
trols receiving IFN- therapy alone. Patients receiving
IFN- plus ara-C had a better CHR rate compared with
those treated with IFN-, a trend for better Ph suppression
and longer survival [48]. More recently, Kantarjian et al.
compared 140 patients with chronic-phase CML receiving
IFN- at 5 106 and ara-C 10 mg daily to historical con-
trols receiving IFN- alone or IFN- with intermittent ara-
C [49]. The study group demonstrated a CHR in 92% of
patients, with cytogenetic response in 74% of patients, 31%
of which were complete, results that were significantly bet-
ter than the control groups. The time to blastic transforma-
tion and overall survival was the same as in the controlgroups. Several other observational studies report a poten-
tial benefit to the combination of IFN and ara-C.
Subsequently, a randomized study by Guilhot et al. indi-
cated the 360 patients receiving IFN-2b, hydroxyurea, and
ara-C demonstrated a significant improvement in overall
survival and cytogenetic response when compared with 361
patients receiving IFN-2b and hydroxyurea alone [50]
(Table 3).
IFN-
IFN-has been used as therapy in chronic-phase CML.
In 1987, Kurzrock et al. reported that 6 of 30 patients with
chronic-phase CML treated with rIFN-demonstrated CHR,
and varying degrees of cytogenetic improvement [51].
Subsequent studies using combinations of IFN- and IFN-
failed to show an improvement over treatment with IFN-
alone [52, 53], and IFN-is not recommended for treatment
of CML.
Bone Marrow Transplantation and IFN
Concern has been raised about prior IFN- therapy
having a negative influence on allogeneic bone marrow
transplant outcomes. Several recent studies have suggested
this is not the case in patients who received a matched-
related donor [54-56], but one report suggests adverse out-
comes for patients who received a greater than six-month
course of IFN- prior to undergoing a matched-unrelated
donor transplant [57].
Summary
The major decision in otherwise healthy patients with
CML is whether to treat with IFN- initially, or to proceed
with early allogeneic bone marrow transplantation. Outcomes
after transplantation reveal lower overall survival initially
when compared to IFN therapy, with a crossing-over of sur-
vival curves at approximately seven years after diagnosis [38].
There appears to be a survival plateau in the transplant patient
population, but not in the IFN--treated patient population.
Unfortunately, most of the transplant data are nonrandomized,
and there have been no direct valid comparisons between IFN
therapy and transplantation in CML. The recommendations
made in an American Society of Hematology-sponsored
review [38] do not strongly favor IFN- therapy or allogeneic
bone marrow transplantation therapy, but indicate that both
should be considered. The patients age, stage of disease,
comorbid conditions, and the patients and physicians thresh-
old for risk and treatment-related morbidity need to be taken
into consideration when making such a decision.
FOLLICULAR LYMPHOMA
IFN- was first used in the treatment of patients with fol-licular lymphoma in the early 1980s [58]. Early-phase studies
showed a 50% objective response rate. Subsequently, two
phase III trials randomized patients between single alkylat-
ing agents with or without IFN-, demonstrating improved
remission duration, but no overall survival improvement [58-
61]. In addition, two randomized phase III trials evaluated the
addition of IFN to combination cytoreductive chemotherapy
[62, 63]. In only one of these studies was there an improved
median progression-free survival and overall survival in the
group of patients receiving IFN [63].
The role of IFN- as maintenance therapy for patients
with low-grade non-Hodgkins lymphoma (NHL) who
achieved tumor bulk reduction after cytoreductive chemo-
therapy has also been evaluated [58, 64-69]. Most studies
demonstrated an increased failure-free survival in patients
on maintenance IFN, but no clear-cut increase in overall
survival. One randomized study of IFN-2b maintenance
therapy did reveal an overall survival advantage [69].
Based on the above studies, some authors recommend
that IFN- therapy be used in combination with chemother-
apy in clinically aggressive follicular NHL, and as mainte-
nance therapy in patients with high tumor burden after
7/30/2019 Interferon in Oncological Practice_Review of Interferon
7/22
40 Interferon in Oncological Practice
cytoreductive therapy [58]. These recommendations have
not been universally accepted. We recommend that IFN-
be used in an investigational setting to better define its role
in the treatment of follicular lymphoma.
RENAL CELL CARCINOMA (RCC)
IFN has been extensively used in the treatment of RRC.
Although there is no clear role for its use in the adjuvant set-
ting, extensive work has been done to define its role in the
management of metastatic disease. The following sections
summarize these findings.
IFN Monotherapy
Single-agent IFN has been used in over 50 clinical trials
in the treatment of metastatic RCC. Response rates in these
trials range between 0% and 50%, with a mean of approxi-
mately 15% for IFN- and 10% for IFN-. There does not
appear to be a clear dose-response curve in the treatment ofmetastatic RCC with rIFN-2a or IFN-2b [70]. Stratifi-
cation of trials among those with average daily doses of 10 million units per day does not reveal any sta-
tistically significant differences in outcome. A retrospective
analysis of prognostic markers of response suggested that
pretreatment nephrectomy and lung metastases as sole site of
metastatic disease were markers for better outcome. Overall
performance status is another important prognostic factor
predicting response to therapy [71].
Several randomized studies have been published to
quantify the benefit of IFN in metastatic RCC (Table 4A).The Medical Research Council Renal Cancer Collaborators
trial randomized 350 patients with metastatic RCC between
IFN-2b and medroxyprogesterone acetate (MPA) [71]. An
interim analysis was performed when time-to-progression
data were available for 335 patients, showing a statistically
significant improvement in median survival in favor of the IFN
arm. Pyrhonen et al. prospectively randomized 160 patients
with locally advanced or metastatic RCC between vinblas-
tine (VBL) alone and IFN-2a plus VBL for 12 months or
until progression of disease [72]. Both the response rates and
median survival were superior in the IFN arm.
Role of Nephrectomy
The benefit of preimmunotherapy nephrectomy was
addressed by the Southwest Oncology Group (SWOG) in a
randomized trial designed to determine whether nephrec-
tomy prior to systemic therapy with IFN prolonged survival
(Table 4A). Patients with operable metastatic renal cancer
were randomized to two arms: immediate IFN therapy or
radical nephrectomy followed by IFN therapy. Between
June 1991 and October 1998, 246 patients were random-
ized. Median survival was significantly improved in thenephrectomy arm, but the response rate to IFN was a low
4% in both arms, suggesting the survival advantage was
mainly due to surgical debulking, and not because surgery
improved the efficacy of IFN therapy.
Combination with Interleukin 2 (IL-2)
Subsequent efforts have been made to evaluate IFN
together with other biological response modifiers including
IL-2, or in combination with chemotherapeutic agents, in par-
ticular 5-fluorouracil (5-FU). The combination of IFN- and
IL-2 has been extensively investigated in patients withmetastatic RCC. Phase I and II trials have demonstrated
response rates of approximately 20%, with 5% CR [73].
Treatment schedules, cytokine doses, patient selection criteria
and response criteria differ from study to study. Table 4B
Table 4A. RCC: randomized studies
Author Year n Study Response Medianpatients design rates (%) survival (mos)
IFN and Chemo- or Hormonal Therapy
MRC [71] 1999 174 IFN 10 MU s.c. tiw 12 wks 14 6.0
176 MPA 300 mg PO qd 12 wks 7 8.5*
Pyrhonen [72] 1999 81 VBL 0.1 mg/kg q 3 wks 2.5 8.7
79 VBL 0.1 mg/kg q 3 wks 16.5 15.6
IFN 3 MU s.c. tiw wk 1 then (p = 0.0025) (p = 0.0049)
IFn18 MU s.c. tiw
* statistically significant
IFN Nephrectomy
SWOG [156] 2000 123 Nephrectomy 4 8.1
123 Nephrectomy plus 4 12.5
IFN 5 MU/m2 s.c. tiw until progression (p = 0.033)
7/30/2019 Interferon in Oncological Practice_Review of Interferon
8/22
Jonasch, Haluska 41
summarizes seven randomized trials assessing the efficacy of
combination cytokine therapy in metastatic RCC. In a phase
II trial, Atkins et al. randomly assigned patients to receive
treatment with either IL-2 alone or IL-2 and IFN-. After 28
patients were entered onto each arm, the IL-2/IFN arm was
closed because of a failure to meet predetermined efficacy
criteria. An additional 43 patients (total 71) were assigned to
receive IL-2 alone. Responses were seen in 3 of 28 patients
(11%) on IL-2/IFN- and 12 of 71 patients (17%) on IL-2
alone. The Groupe Franais dImmunotherapie randomized
425 patients with metastatic RCC to a continuous i.v. infusion
of IL-2, s.c. injections of IFN-2a, or both [74]. Response
Table 4B. RCC: randomized studies
Author Year n Study Response Medianpatients design rates (%) survival (mos)
IFN and IL-2
Atkins [157] 1993 71 IL-2 0.6 MIU/kg i.v. q 8 h 14 11 15.5days 1-5 and 15-19
28 IL-2 0.36 MIU/kg i.v. q 8 h 14 17 16IFN 3 MU/m2 IV q 8 h 14 NS NSdays 1-5 and 15-19
Lissoni [78] 1993 15 IL-2 3 MIU s.c. bid 5 days/wk 6 wks 33 Survival at one
15 IL-2 3 MIU s.c. bid 5 days/wk 6 wks 26 year: NS
IFN 5 MU/m2 s.c. tiw NS
Lummen [79] 1996 30 IFN-200 g s.c. q wk 0 13.0
30 IL-2 4.8 MIU/m2 s.c. qid days 1, 22 23 13.0IL-2 4.8 MIU/m2 s.c. bid days 2, 23IL-2 2.4 MIU/m2 s.c. bid days 3-5, 8-12, (p = 0.01) (p = 0.49)IL-2 15-19, 24-26, 29-33, 36-40
IFN 3 MU/m2
days 3, 5, 24, 26IFN 6 MU/m2 days 8, 10, 12, 15, 17,IFN 19, 29, 31, 33, 36, 38, 40
Negrier[74] 1998 138 IL-2 18 MIU/m2 qd CI 6.5 12days 1-5, 15-19 2 ; then days 1-5 q 3 wks
147 IFN 18 MU s.c. tiw 10 wks 7.5 13
140 IL-2 18 MIU/m2 CI qd days 1-5, 15-19 2; 18.6 17then days 1-5 q 3 wk (p = 0.01) (p = 0.55)IFN 6 MU s.c. tiw in the wks IL-2 is given.
Jayson [77] 1998 29 IL-2 18 MIU s.c. days 1-5 3-4 wks 7 14.6
29 IL-2 18 MIU s.c. days 1-5 3-4 wks 0 12.5IFN 9 MU tiw 3-4 wks (p = 0.98)
Boccardo [75] 1998 22 IL-2 18 MIU/m2 CI qd days 1-4 wks 1,3, 22.7 307, 9, 13, 17, 21, 25
22 IFN 6 MU/m2 IM days 1, 3, 5 52 wks 9.0 18
22 IL-2 18 MIU/m2 CI qd days 1-4 wks 1,5, 9, 9.0 1313, 17, 21 NS NS
IFN 6 MU/m2 i.m. days 1, 3, 5 wks 2-4, 6-8,10-12, 14-16, 18-20, 22-24
Henriksson [76] 1998 63 Tamoxifen 40 mg PO qd 3.2* 13.3
65 Tamoxifen 40 mg PO qd 7.7* 11.8
IL-2 4.8 MIU/m2 q 8 h days 1, 22 NSIL-2 4.8 MIU/m2 q 12 h days 2, 23IL-2 2.4 MIU/m2 q 12 h day 3-5, 8-12,IL-2 15-19, 24-26, 29-33, 36-40
IFN 3 MU/m2 days 3, 5, 24, 26,IFN 6 MU/m2 days 8, 10, 12, 15, 17,IFN 19, 29, 31, 33, 36, 38, 40
NS = not significant; *complete response only
7/30/2019 Interferon in Oncological Practice_Review of Interferon
9/22
42 Interferon in Oncological Practice
rates and event-free survival rates were significantly better
in the combination therapy group, but overall survival rates
were not significantly different. The other randomized stud-
ies assessing the role of combination IFN and IL-2 therapy
failed to demonstrate a survival advantage to this combina-
tion when compared with cytokine monotherapy [75-79]
(Table 4B). In summary, as numerous studies have failed to
show a survival advantage for patients with metastatic RCC
receiving combination cytokine therapy, it cannot be rec-
ommended as standard treatment.
Combination with IL-2 and 5-FU
Combinations of IFN-, IL-2, and 5-FU have been
evaluated in metastatic RCC. In vitro data suggest
improved efficacy of 5-FU when given in combination with
IFN- [80, 81]. An overall response rate of approximately
30% has been seen in most studies [73, 82-90]. Two recent
randomized studies presented in abstract form address theefficacy of chemoimmunotherapy in metastatic RCC [91,
92] (Table 4C). Negrier et al. randomized 131 patients
between IL-2, IFN and IL-2, IFN and 5-FU, and reported no
significant difference in response between the two treatment
arms. Atzpodien et al. randomized patients between
Tamoxifen and IFN, IL-2 and i.v. 5-FU, and found a highly
significant improvement in response rate and survival in the
combination therapy arm. The results from the Atzpodien
study are encouraging, but in the absence of a confirmatory
study, are insufficient to make IL-2, IFN, and 5-FU standard
care in metastatic RCC.
Summary
In conclusion, IFN monotherapy in patients with metasta-
tic RCC provides a modest but significant prolongation of
survival with manageable side effects. A subset of patients,
in particular those with good performance status, lung-only
disease and resected primaries, may benefit from combina-
tion chemoimmunotherapy, but more data are needed to
determine whether combination therapy is superior to IFN
alone. At the current time, the best approach is to enter
patients into well-designed phase III trials that will help
answer these questions.
MELANOMA
In 1980, Bart et al. reported on the inhibition of B16
melanoma in vitro and in vivo by murine IFN [93]. Subsequent
phase I studies using partially purified leukocyte IFN at doses
below 10 106 U/day resulted in few responses [94]. Other
reports using rIFN-2a 12 106 U/m2 three times a week (tiw)
[95], and 50 106 tiw i.m., respectively [96], for three months
revealed response rates at both dose levels of around 20%. IFN
monotherapy in patients with metastatic melanoma inducesresponses in approximately 15% and CR rates on the order of
5% [97]. Predictors of favorable response were uninterrupted
schedules of therapy regardless of route, with no clear advan-
tage of lower or higher dosages in the range between 10 106
U/m2 and 50 106 U/m2 qd or tiw. Intermittent cyclic therapy
was associated with a poorer outcome [97]. Suggestions of
response durability set IFN apart from DTIC as a therapy for
metastatic melanoma [98].
Combination Therapy
More recently, IFN- has been used in the context of com-bination therapy for the treatment of metastatic melanoma.
Numerous trials have been performed combining IFN with
IL-2, with single-agent chemotherapy, and with Tamoxifen
(Table 5A). The addition of IFN to IL-2 did not result in a
Table 4C. RCC: randomized studies
Author Year n Study Response Medianpatients design rates (%) survival (mos)
Chemoimmunotherapy
Negrier[91] 1997 70 IL-2 9 MIU s.c. days 1-6 wks 1, 3, 5, 7 1.4 N/AIFN 6 MU s.c. days 1, 3, 5 wks 1,3, 5, 7
61 IL-2 9 MIU s.c. days 1-6 wks 1, 3, 5, 7 8.2IFN 6 MU s.c. days 1, 3, 5 wks 1,3, 5, 75-FU 600 mg/m2 CI days 1-5 wks 1, 5 (p = 0.10)
Atzpodien [92] 1997 41 IL-2 10 MIU/m2 s.c. bid days 3-5 wks 39 >42 mos1, 4; 5 MIU/m2 s.c. days 1, 3, 5 wks 2,3IFN 6 MU/m2 s.c. day 1 wks 1, 4 anddays 1, 3, 5 wks 2, 3IFN 9 MU/m2 days 1, 3, 5 wks 5-85-FU 1,000 mg/m2 q wk wks 5-8
37 Tamoxifen 45 mg/m2 PO bid wks 1-8 0 14(p < 0.04)
7/30/2019 Interferon in Oncological Practice_Review of Interferon
10/22
Jonasch, Haluska 43
significantly greater response rate or survival, with signifi-
cantly more side effects [99]. An early study looking at the
combination of IFN and DTIC chemotherapy was promising
[100], but subsequent investigations failed to demonstrate
an advantage to this combination [101-103].
Chemoimmunotherapy has been assessed in patients
with metastatic melanoma [104-109]. Table 5B summarizessome of the major studies looking at this treatment modality.
Although increased response rates have been shown in most
of these trials, this has not translated into an increase in over-
all survival. A recent abstract from the M.D. Anderson
Cancer Center randomized patients between cisplatin, VBL
and DTIC (CVD) and CVD plus sequential infusion IL-2 and
IFN therapy. This study demonstrated a survival improve-
ment in the chemoimmunotherapy arm that approached sta-
tistical significance [110]. The major question in treating
patients with metastatic melanoma who are eligible for these
trials is whether the severe toxicities encountered with
chemoimmunotherapy are worth the as-yet unproven survival
benefits. The Eastern Cooperative Oncology Group (ECOG)
3695/Cancer and Leukemia Group B (CALGB) 509802, a
study currently accruing patients and randomizing them to
CVD or concomitant CVD plus IL-2 and IFN, will hopefully
provide information to help answer this question.
Adjuvant Therapy
Several trials looked at the role of IFN- in the adjuvant
setting for melanoma patients at high risk for relapse, includ-
ing patients with deep primary lesions and those with lymph
node involvement [111-116]. Studies using relatively low
doses of IFN (3 106 U tiw) failed to show an overall survival
benefit in this patient group. In 1996, Kirkwood et al. pub-
lished the results of ECOG 1684, which demonstrated both a
disease-free and overall survival benefit for patients with
stage III (lymph node-positive) melanoma treated with maxi-
mally tolerated doses of IFN- [113]. The regimen used in
Table 5A. Melanoma: randomized studies
Author Year n Study Response Medianpatients design rates (%) survival (mos)
IL-2 and IFN
Sparano [99] 1993 44 IL-2 6 MU/m2 q 8 h i.v. 14 doses days 1-5, 15-19 5 10.2
41 IL-2 4.5 MU/m2 i.v. q 8 h 14 doses days 1-5, 15-19 10 9.7IFN- 3 MU/m2 i.v. q 8 h 14 doses days 1-5, 15-19 NS
IFN and chemotherapy
Falkson [100] 1991 31 DTIC 200 mg/m2 i.v. days 1-5 q 28 days 20 9.6
30 IFN- 15 MU/m2 i.v. M-F 3 wk, then 53 17.610 MU/m2 s.c tiw (p < 0.05) (p < 0.01)DTIC 200 mg/m2 i.v. days 1-5 q 28 d starting wk 4
Thomson [103] 1993 83 DTIC 800 mg/m2 i.v. q 21 days 17 7.8
87 DTIC (200-800 mg2) i.v. q 21 days 21 9.0IFN- 9 MU s.c. qd NS NS
Bajetta [102] 1994 82 DTIC 800 mg/m2 i.v. q 21 days 20 11
76 DTIC 800 mg/m2
i.v. q 21 days 28 13IFN- 3 MU s,c, tiw
84 DTIC 800 mg/m2 i.v. q 21 days 23 11IFN- 3 MU IM days 1-3, 6 MU days 4-6 NS NSthen 9 MU IM qd
Falkson [101] 1998 69 DTIC 200 mg/m2 i.v. days 1-5 q 28 days 15 9.99
68 IFN 15 MU/m2 i.v. days 1-5 wks 1-3, then 21 9.3510 MU/m2 s.c. tiwDTIC 200 mg/m2 i.v. days 1-5 q 28 days,starting day 22
66 DTIC 200 mg/m2 i.v. days 1-5 q 28 days 19 9.54Tamoxifen 20 mg PO qdIFN 15 MU/m2 i.v. days 1-5 wks 1-3, then10 MU/m2 s.c. tiw
68 DTIC 200 mg/m2 i.v. days 1-5 q 28 days 18 7.97Tamoxifen 20 mg PO qd NS (p = 0.85)
NS = not significant
7/30/2019 Interferon in Oncological Practice_Review of Interferon
11/22
44 Interferon in Oncological Practice
ECOG 1684 involved administration of IFN- at 20 106 U/m2
i.v. qd for five days/week for four weeks, followed by 10 106
U/m2 s.c. tiw for 11 months. Based on the findings from this
study, the FDA approved the uses of IFN- in stage III and
stage IIB melanoma. The follow-up study ECOG 1690 showed
a disease-free survival advantage in similar patient groups, but
an overall survival advantage was not seen [114]. Of note, over-
all survival of both the IFN and control groups in ECOG 1690
is higher than the IFN arm in ECOG 1684. This may be due toa number of reasons, including patient crossover, or a favorable
patient cohort in the control arm of ECOG 1690. Results from
ECOG 1694, which randomized patients between standard
high-dose IFN and GM-K, a ganglioside vaccine developed at
the Memorial Sloan-Kettering Cancer Center, will be available
soon. This study was closed prematurely, because a signifi-
cantly greater number of relapses occurred in the vaccine arm.
Summary
Although concerns have been raised regarding the toxicity
of IFN therapy, the authors recommend its use in the adjuvant
setting. For stage IV disease, the role of IFN- is less clear.
The promising response rates of chemoimmunotherapy have
not translated into a hoped-for prolongation in survival.
Nevertheless, in patients with good performance status, low
disease burden and favorable disease sites (lung, skin),
chemoimmunotherapy should be considered, preferably in
the setting of a clinical trial. Results from several studies will
be available in the near future to help clarify the role of IFN
therapy in both the adjuvant and metastatic settings.
KS
IFN has been used in the treatment of HIV-associated
KS since 1981 [117]. Initial treatment regimens employed
doses in the 20 106 U/d range, which were associated with
significant response rates, but also high levels of toxicity
[118]. In subsequent studies [119], the probability of
responding to therapy was correlated with CD4 count.
Patients with CD4 counts greater than 400/mm3 responded,
whereas none of those with CD4 counts of less than 150/mm3
had a response.
Table 5B. Melanoma: randomized studies
Author Year n Study Response Medianpatients design rates (%) survival (mos)
Chemoimmunotherapy
Keilholz [105] 1997 66 Starting d 3: IL-2 18 MIU/m2 i.v. CI over 6 h, 18 9IL-2then 18 MIU/m2 i.v. CI over 12 h, thenIL-218 MIU/m2 i.v. CI over 24 h, thenIL-24.5 MIU/m2 i.v. CI qd 3 daysIFN- 10 MU/m2 s.c. days 1-5
60 Starting d 3: IL-2 18 MIU/m2 i.v. CI over 6 h, 33 9IL-2then 18 MIU/m2 i.v. CI over 12 h, thenIL-218 MIU/m2 i.v. CI over 24 h, then (p = 0.04) NSIL-24.5 MIU/m2 i.v. CI qd 3 daysIFN- 10 MU/m2 s.c. days 1-5Cisplatin 100 mg/m2 day 1
Rosenberg [109] 1999 52 Cisplatin 25 mg/m2 i.v. days 2-4 and 23-25 27 15.8DTIC 220 mg/m2 i.v. days 2-4 and 23-25Tamoxifen 20 mg PO qd starting day 1
50 Cisplatin 25 mg/m2
i.v. days 2-4 and 23-25 44 10.7DTIC 220 mg/m2 i.v. days 2-4 and 23-25Tamoxifen 20 mg PO qd starting day 1IFN- 6 MU/m2 s.c. days 5-8 and 26-29 (p = 0.071) (p = 0.052)IL-2 0.72 MIU/kg i.v. q 8 h days 5-8 and 26-29to patient tolerance
Eton [110] 2000 92 Cisplatin 20 mg/m2 i.v. qd days 1-4, 22-25 25 9.5DTIC 800 mg/m2 i.v. day 1, 22VBL 2 mg/m2 i.v. days 1-4, 22-25
91 Cisplatin 20 mg/m2 i.v. qd days 1-4, 22-25 48 11.8DTIC 800 mg/m2 i.v. day 1, 22VBL 1.5 mg/m2 i.v. days 1-4, 22-25 (p = 0.001) (p = 0.055)IL-2 9 MIU/m2 CI days 5-8, 17-20, 26-29IFN 5 MU/m2 s.c. days 5-9, 17-21, 26-30
NS = not significant; CI = continuous infusion
7/30/2019 Interferon in Oncological Practice_Review of Interferon
12/22
Jonasch, Haluska 45
The combination of lower dosages of IFN- and zidovu-
dine (AZT) was found to be effective in treating HIV-associ-
ated KS, including those with lower CD4 counts [120], but
with dose-limiting hematological side effects. In 1991,
Scadden et al. reported that the use of GM-CSF as an adjunct
to combination IFN-/AZT therapy resulted in an improved
end-of-study absolute neutrophil count [121, 122]. Another
report indicated that although GM-CSF decreased the inci-
dence of neutropenia in patients on IFN- and AZT, other
IFN-related side effects precluded any dose escalation [123].
More recently, Shepherd et al. reported on treatment of HIV-
related KS with AZT and IFN- at two dose levels. All
patients received AZT 500 mg daily and were randomized to
receive IFN- 1 106 U or 8 106 U s.c. qd. Response was
reported in 31% of high-dose therapy and 8% of low-dose
therapy patients (p = .011). Response at both dose levels was
higher for patients with CD4 (+) counts greater than 150/mm3.
The median time to progression was longer for patients in the
8-million U arm (18 versus 13 weeks;p = .002). Both hema-
tologic and nonhematologic toxicities were higher in the high-
dose arm; 50 of 54 patients who received 8 106 U required
dose alterations in the first four months compared with only
19 of 53 patients who received 1 106 U (p = .0002) [124].
A phase I/II study assessed effectiveness of IFN-therapy
in the treatment of HIV-associated KS, and showed clinical
response in 3 of 17 patients [125]. There does not appear to be
any role for IFN-in the treatment of KS.
For widespread, symptomatic KS, combination cyto-
toxic chemotherapy is usually the treatment of choice[126]. Paclitaxel has recently been evaluated in the treat-
ment of AIDS-related KS demonstrating promising results
[127, 128]. The exciting initial findings with paclitaxel will
prompt direct comparisons between paclitaxel and IFN-.
Further study will allow us to determine the definitive role
for IFN- therapy in KS.
In summary IFN-, either as monotherapy or in combi-
nation with AZT, shows activity in HIV-positive patients
provided they possess relatively elevated CD4 (+) lympho-
cyte counts (i.e., greater than 150/mm3). For more advanced
disease, combination chemotherapy is currently the accepted
means of treatment for KS.
TOXICITIES
Treatment with IFN is always considered in the context of
its significant side-effect profile. Four major side effect groups
occur: constitutional, neuropsychiatric, hematologic, and
hepatic. These vary in degree, persistence and our ability to
manage them. Side effects can also be divided into those that
occur acutely but decrease over time, and those that are chronic.
The severity of many side effects appears to be directly related
to the dose and duration of IFN therapy [129]. This section
summarizes the major types of toxicity and their etiology, and
concludes with proposed toxicity management guidelines.
Acute Toxicity
Toxicity can be divided into acute and chronic manifesta-
tions. In the acute setting, the patients experience fevers, chills
and rigors, usually between 3 and 6 h after receiving IFN.
Patients may also experience headaches, myalgias, and
malaise. With prolonged and uninterrupted administration of
IFN, tolerance can develop to these symptoms. However,
treatment breaks as short as a few days can result in the rede-
velopment of rigors and chills. Transaminitis and neutropenia
may occur within the first few days of treatment, and can be
controlled by adjusting the IFN dose. Both resolve rapidly
upon cessation of treatment. If the transaminitis is not followed
closely, it can result in fatal hepatotoxicity [113].
Chronic Toxicity
The chronic symptoms experienced by patients on IFN
include fatigue (70%-100% of patients), anorexia (40%-70%),
and neuropsychiatric symptoms (up to 30%). These symp-
toms appear to be dose-related, and cumulative, worsening
over time [9].
Mechanisms of Toxicity
The mechanisms of IFN-induced toxicity are unclear, but
are most likely multifactorial. These will be summarized in
the following section.
Fatigue
Fatigue is the most common symptom associated with
chronic use of IFN-, occurring in more than 70% of patients.
It is frequently the dose-limiting toxicity [130]. The exact eti-
ology of the fatigue is unclear, but there appears to be both a
psychological and neuromuscular component [130, 131].
Chronic fatigue generally worsens with continued therapy,
does not exhibit tolerance, is dose-related, and does not
respond to therapy with steroids or antiinflammatory drugs.
Little research has been done to analyze the neuromuscular
axis in patients on IFN to determine whether there are clear
structural or biochemical changes that can be quantified.
Assessment with muscle biopsy and other diagnostic modali-
ties has not been performed. Clearly, further study into the eti-
ology of IFN-induced fatigue is needed to better manage this
prevalent and debilitating side effect. The first step will be to
build into clinical trials an accurate, objective and reproducible
evaluation of patient fatigue.
Neurological Toxicities
Central nervous system toxicities include somnolence,
confusion, lethargy, dizziness, and impaired mental status
7/30/2019 Interferon in Oncological Practice_Review of Interferon
13/22
46 Interferon in Oncological Practice
[9]. Peripheral nervous system toxicities include numbness
and tingling.
Duration of therapy appears to be the most important
factor in determining the degree of cognitive impairment
[132, 133]. Absolute dose appears to be less important.
Caraceni et al. evaluated neurotoxicities of 113 patients
receiving IFN- 3 106 U s.c. tiw for 36 months as part of a
randomized trial. Particular emphasis was placed on the devel-
opment of extrapyramidal signs and symptoms, psychiatric
symptoms, attention, memory, reasoning capability, psycho-
logical adaptation, and quality of life [134]. Significant differ-
ences between study and control groups included a higher
incidence of action tremor in the treatment group. Cognitive
performance did not differ between the two groups, but a
higher level of anxiety was recorded in the IFN group. In the
quality-of-life assessment, there was a significantly greater
number of patients who experienced fatigue.
Mood Disorders
Patients with cancer in general have a higher risk of
developing clinical depression [133]. A significant minority
of patients on IFN therapy becomes depressed, in some
cases leading to suicide. There are also several reports of
mania in patients on IFN [135-138]. Mood disorders can
occur in patients without predisposing factors or past history
of psychiatric problems.
In non-cancer patients, depression is associated with alter-
ations in a number of bodily systems, including the endocrine
system [133]. The mechanism by which IFN causes psychi-atric disturbances is poorly understood, and research into the
mechanisms underlying endogenous depression has been
performed in patients receiving IFN to better understand the
etiology of IFN-induced mood disturbances. Neuroendocrine
disturbances, including perturbation of the hypothalamic-
thyroid-adrenal axis and alteration in dopamine and sero-
tonin production have all been implicated [139], as have
alterations in the secretion of secondary cytokines, espe-
cially IL-1 [133].
Endocrine Dysfunction
In 1983,Ernstoff et al. reported that human leukocyte
IFN administration resulted in an increase in cortisol lev-
els via adrenocorticotropic hormone (ACTH) stimulation
[140]. More recent studies revealed that IFN- and IFN-
both induced ACTH, prolactin, growth hormone and corti-
sol levels in patients [141], although other investigators did
not find any effect of IFN- on anterior pituitary function
[142]. An assessment of IFN--induced endocrine stimu-
lation in patients with myeloproliferative disorders
revealed that on day 1 of therapy, a significant stimulation
of the hypothalamic-pituitary axis was apparent, an effect
that had disappeared by the third week of therapy [143].
The acute stimulatory effect of IFN- on cortisol release
appears to be mediated by the release of hypothalamic
corticotropin releasing hormone [143].
There have been reports of alterations in the levels of sex
hormones during IFN therapy, and male sexual dysfunction
does occur [139]. The hypothalamic-pituitary-gonadal axis
can be suppressed during acute and chronic illness, and this
effect appears to be cytokine-mediated [139]. Thus it is pos-
sible that IFN-induced alteration in sex hormone levels is
mediated via direct or indirect pathways.
Autoimmune-Mediated Thyroid Dysfunction
Thyroid dysfunction occurs in 8%-20% of patients
receiving IFN- therapy [139]. Numerous studies report the
development of overt or subclinical hyper- or hypothyroidism
in patients on IFN- for various malignancies [144-149]. The
pattern demonstrated by most patients is one of an autoim-mune thyroiditis, with a period of hyper- followed by hypo-
thyroidism [139]. A few patients with hepatitis C have
developed symptoms of Graves disease while on IFN-
[139]. Investigation into etiologies of IFN--induced thy-
roiditis suggests an indirect effect via activation of other
cytokines, including IFN-. Preexisting autoimmune dis-
ease or baseline serological abnormalities appear to predis-
pose patients to developing overt autoimmune disease
while on IFN- [147, 148]. Antithyroid antibodies occur in
up to 16% of women and 1.5% to 3% of men in the general
population, and individuals expressing baseline antithyroidantibodies have a 60% risk of developing clinical thyroid
disease during the course of therapy [139]. Treatment of MS
patients with IFN- was shown to induce antithyroid
autoantibodies and symptoms of overt hypothyroidism in a
small series of patients [150]. Treatment with IFN-para-
doxically did not appear to induce the same number of
autoimmune side effects as IFN- [151]. A recent study
correlated the degree of autoimmune disease with improved
prognosis in renal cancer patients treated with IFN- and
IL-2, suggesting that autoimmune disease while on cytokine
therapy is a marker for breaking immunologic tolerance in
patients with cancer [152].
Although it is unclear how much of the IFN-mediated
toxicity is due to endocrine dysfunction, a serum thyroid
stimulating hormone (TSH) determination is indicated in a
patient on IFN who complains of severe and persistent
fatigue, cold sensitivity, or other symptoms suggestive of
hypothyroidism.
STUDIES AND SIDE-EFFECT PROFILES
Due to the variation in dosing and schedule, dose adjust-
ment, duration of follow-up, data presentation, and disease
7/30/2019 Interferon in Oncological Practice_Review of Interferon
14/22
Jonasch, Haluska 47
type in which IFN has been administered, it is difficult
to make direct comparisons of side-effect profiles seen in
various studies.
Some general trends can be observed. In Table 6, side
effects resulting from treatment of melanoma, NHL and KS
with high-dose levels of IFN (10 106 to 50 106 U/m2) are
compared. Fatigue symptoms at this dose level occur at levels
approaching 90% in the studies that categorized this symptom.
A very high incidence of fevers is also recorded. The one study
that categorized depression recorded a rate of 47%. Other sideeffects are difficult to compare due to the incompleteness of the
data, but in general it appears that the incidence of severe toxi-
cities (grade III or greater) is much greater at these higher doses.
Table 7 summarizes the side-effect profiles of patients
who received IFN dosages in the range of 3 106 U to
5 106 U/m2 for a variety of cancers. Although direct com-
parisons may not be quantitative, and several studies only
recorded the incidence of grade 3 and higher toxicities, in
general the degree of constitutional toxicities appears to be
considerably lower than is seen in the studies with the higher
doses seen in Table 6, and the incidence of dose-limiting
hepatic, neuropsychiatric and hematologic toxicities appears
to be negligible.
QUALITY OF LIFE
Due to the substantial toxicities encountered during IFN
therapy, a number of groups have looked at the quality of life
of patients undergoing IFN therapy. Cole et al. evaluated the
quality of life of patients receiving high-dose IFN therapy in
the ECOG 1684 trial for stage III melanoma using the
Quality-Adjusted Time Without Symptoms and Toxicity(Q-TWiST) methodology [153], which estimates the mean
time spent in a series of clinical health states that differ in
terms of quality of life. Q-TWiST adjusts each time period
depending on how much value the patient places on the
quality of life of each health state [153]. Even if patients
were to place a very low value on the time spent on IFN,
there would still be a net prolongation in overall survival on
the ECOG 1684 trial.
The same Q-TWiST methodology was used to evaluate
the quality-of-life-adjusted survival in the previously men-
tioned trial randomizing patients to doxorubicin-based
Table 6. Summary of toxicities in patients receiving high-dose IFN for malignancies
Study Real[117] Creagan [96] Kirkwood[113] Creagan [116] Sertoli [159] Creagan [95] OConnell[160]
Disease/stage Kaposis/HIV Melanoma IV Melanoma III Melanoma III Melanoma IV Melanoma IV NHL, CLL
Type/dose IFN-2a 36 IFN-2a 50 IFN-2b 20 IFN-2a 20 IFN-2b IFN-2a 12 IFN- 12
MU IM qd MU/m2
i.m. MU/m2
IV MU/m2
i.m. tiw 10 MU/m2
i.m. MU/m2
i.m. MU/m2
i.m. tiw 4 wks, then tiw 12 wks 5 days/wk 12 wks tiw tiw 12 wks 8 wks, thentiw 4 wks, then until disease weekly if response,
10 MU/m2 s.c. progression and 25 MU/m2 tiwtiw 11 mo 4 wks if stable
disease
n patients on IFN 34 31 143 131 21 30 20
Degree of All Mod- All Grade All Grade All Grade Mod- All Severeseverity Grades Severe Grades III Grades III Grades III Severe Grades
% % % % % % % % % % %
Constitutional 97 48Fatigue 88 87 89 20 100 43 50 90 10Anorexia 74 58 55 3 13 47 55 10Weight loss 13Fevers 94 83 24 100 10 80 85 5Myalgias 74 63 7 27Headache 62 44 5 45 0
Hepatic 64 16 N/A N/A 19 0 0 10 5
Neuropsychiatric 83 28 11 2 5 3Depression 21Dizziness/vertigo 47Confusion 23 15 5
5 5
Hematologic 64 24 N/A N/A 29 0Thrombocytopenia 35 0Anemialeukopenia 45 0
7/30/2019 Interferon in Oncological Practice_Review of Interferon
15/22
48 Interferon in Oncological Practice
combination chemotherapy with or without IFN-2b for
the treatment of advanced follicular lymphoma [63, 154].
An advantage in terms of quality-adjusted survival was seen
in the patients receiving IFN regardless of the value placed
on the time patients were undergoing IFN therapy [154].
Kilbridge et al. interviewed 107 patients with superficial
melanomas who did not require IFN therapy, asking them
what value they place on a prolongation of life secondary to
IFN therapy, were they to need it. The authors assessed patient
preference for a particular health state as a function of toxicity
and outcome. A great majority of respondents indicated
they preferred experiencing even severe treatment-related
side effects for a gain in disease-free survival [155].
MANAGING IFN TOXICITY
Communication among all members of the treating team
is imperative in managing patients on IFN therapy. Each
team member is in a position to obtain complementary infor-
mation that, when put together, gives a complete picture of
the patients side-effect profile. The following section will
summarize management of the major IFN side effects.
Constitutional Side Effects
Constitutional side effects are managed with copious
hydration and acetaminophen. Acetominophen is useful in
controlling the shakes, fevers and myalgias experienced by the
patient at the onset of therapy. Nonsteroidal anti-inflammatory
medications may be used if acetaminophen is not adequate
in controlling these symptoms, but should be used only if
adequate control is not achieved with acetaminophen alone.
There is no recognized pharmacological antidote for
IFN-induced fatigue. It is equally unclear what can be done
to alleviate this symptom short of dose decrement, or cessa-
tion of treatment. Suggestions include mild exercise, good
nutritional intake, copious fluid ingestion, and stress man-
agement techniques. The treating team needs to remember
that a treatment-induced decrement in functional status can be
a serious blow to a patients self-esteem and sense of indepen-
dence [130], and that patients need encouragement and positive
feedback from their treating team. On the other hand, patients
also need to be told that it is acceptable to draw on social
resources, which include family, friends, or hospital-based
social services if the patients feel they are unable to cope.
Table 7. Summary of toxicities in patients receiving low-dose IFN for malignancies
Study Real[117] Grob [158] Doveil[115] Ozer [39] Kantarjian [49]
Disease/stage Kaposis/HIV Melanoma II Melanoma III CML chronic-phase CML chronic-phase
Type/dose IFN IFN-2a 3 IFN-2a 3 Mu IFN-2b 3 IFN-2b 5 IFN- 5MU i.m. qd s.c. tiw 18 mos MU i.m. MU/m2 s.c. qd MU/m2 s.c.
4 wks, then tiw 12 qd + Ara-Ctiw until disease mos 10 mg s.c. qdprogression until progression
n patients on IFN 36 248 50 107 140
Degree of severity All Grades All Grades Grade III Grade III Grade III Grade III% % % % % %
ConstitutionalFatigue 83 48
7/30/2019 Interferon in Oncological Practice_Review of Interferon
16/22
Jonasch, Haluska 49
Mood Disorders
Forty percent of patients on IFN will experience some
degree of mood impairment, and up to 10% may become
overtly depressed [113, 130]. It is important that the treatment
team be aware of the potential for depression, and to incorpo-
rate questions about the patients mood and emotional state
into the patients routine evaluation. Early psychiatric referral
is important, and IFN-related mood disorders can often be
managed with measures similar to those used to treat endoge-
nous depression. The occurrence of mania in patients on IFN
also needs to be kept in mind, especially after patients
undergo significant dose-reduction or treatment breaks [138].
The clinicians natural instinct is to interdict the use of IFN
in patients with any past history of depression, or a strong fam-
ily history of mood disorders. We recommend that patients
with any of the above risk factors be evaluated prior to treat-
ment by a psychiatrist versed in the assessment and manage-
ment of cancer patients, and ideally with prior experience in
treating IFN-related mood disorders [138]. These patients
should not be denied treatment, but should be followed closely
for signs of depression, with mood-related questions as part of
the review of systems at each visit.
Hepatotoxicity
In patients receiving high-dose i.v. IFN for stage III
melanoma, liver function tests (LFTs) need to be drawn at
least weekly, assessing for grade III transaminitis.
Withholding treatment until LFTs decrease to a grade I tox-
icity and restarting with a 30%-50% dose reduction is astandard approach. Recently, a report was published sug-
gesting that less aggressive dose reduction can be per-
formed with no decrease in patient safety or compliance
[161]. Once a steady-state level of treatment is achieved,
LFTs are fairly stable and assessment of liver function can
be decreased to monthly or bimonthy blood draws.
Hematologic Toxicity
Weekly blood draws assessing for grade III neutropenia
need to be performed in patients receiving high-dose i.v.
IFN. Dose-reduction algorithms are the same as those for
hepatotoxicity. In patients on s.c. IFN regimens, once a
steady-state of treatment is established, neutrophil counts
are fairly stable, although they may drift down further in
some patients. In general, blood draws can be decreased to
a monthly or even bimonthly schedule once stable dosing
occurs.
Endocrine Toxicity
Recognition of the occurrence of hypothyroidism is
important in the management of patients on IFN. Initially,
monthly TSH measurements should be performed, and if
three sequential values are stable and within a normal range,
bimonthly or quarterly evaluations may be sufficient.
SUMMARY AND RECOMMENDATIONS
IFN is a promising but incompletely understood anti-
cancer agent. Clinical trials have established a number of
indications for the IFNs in both the hematological and solid
tumor arenas, although the effectiveness of the IFNs is modest
in most applications of the agent.
The side-effect profiles of the IFNs are substantial, and at
high doses, daunting, making the choice of IFN therapy one
that has to be weighed against the near certainty of a decrement
in quality of life while on the agent. It is important that the
treating physician be aware of the four major categories of IFN
toxicity: constitutional, neuropsychiatric, hepatic, and hemato-
logic. An ongoing dialogue must occur between the patient
and the treating team to ensure that all aspects of IFN toxicity
are addressed. A number of steps can be taken to minimize themorbidity of IFN therapy, resulting in an improvement in both
quality of life and patient compliance.
IFN has been FDA-approved for use in a number of clin-
ical applications. Treatment with IFN outside of these recom-
mendations should be performed in the context of a clinical
trial designed to assess immunological endpoints and to care-
fully measure type and degree of toxicities. Companion stud-
ies designed to ask specific questions regarding the etiology
of IFN-induced toxicities should also be encouraged, as this
knowledge will be extremely useful in the evolution of IFN as
a useful agent in the oncological armamentarium.
REFERENCES
1 Isaacs A, Lindenman J. Virus interference I. The interferon.
Proc R Soc 1957;147:258-267.
2 Pestka S. The human interferon-alpha species and hybrid
proteins. Semin Oncol 1997;24(suppl 9):S9-4-S9-17.
3 Interferon nomenclature. Nature 1980;286:110.
4 Haque SJ, Williams BR. Signal transduction in the inter-
feron system. Semin Oncol 1998;25(suppl 1):14-22.
5 Aguet M, Grobke M, Dreiding P. Various human interferon
alpha subclasses cross-react with common receptors: their
binding affinities correlate with their specific biological
activities. Virology 1984;132:211-216.
6 Merlin G, Falcoff E, Aguet M. 125I-labelled human inter-
ferons alpha, beta and gamma: comparative receptor-binding
data. J Gen Virol 1985;66:1149-1152.
7 Pfeffer LM, Dinarello CA, Herberman RB et al. Biologicalproperties of recombinant alpha-interferons: 40th anniversaryof the discovery of interferons. Cancer Res 1998;58:2489-2499.
7/30/2019 Interferon in Oncological Practice_Review of Interferon
17/22
50 Interferon in Oncological Practice
8 Sreevalsan T. Biological therapy with Interferon-alfa and beta:
preclinical studies. In: DeVita VTJ, Hellman SMD, Rosenberg
SA, eds. Biologic Therapy of Cancer, Second Ed. Philadelphia:
J.B. Lippincott Company, 1995;347-364.
9 Weiss K. Safety profile of interferon-alpha therapy. Semin
Oncol 1998;25(suppl 1):9-13.
10 Mark DF, Lu SD, Creasey AA et al. Site-specific mutagene-
sis of the human fibroblast interferon gene. Proc Natl Acad
Sci USA 1984;81:5662-5666.
11 Witt PL, Storer BE, Bryan GT et al. Pharmacodynamics of
biological response in vivo after single and multiple doses of
interferon-beta. J Immunother 1993;13:191-200.
12 Jacobs LD, Cookfair DL, Rudick RA et al. Intramuscular inter-
feron beta-1a for disease progression in relapsing multiple scle-
rosis. The Multiple Sclerosis Collaborative Research Group
(MSCRG) [published erratum appears in Ann Neurol
1996;40:480]. Ann Neurol 1996;39:285-294.
13 Wills RJ. Clinical pharmacokinetics of interferons. Clin
Pharmacokinet 1990;19:390-399.
14 Goldstein D, Sielaff KM, Storer BE et al. Human biologic
response modification by interferon in the absence of measur-
able serum concentrations: a comparative trial of subcutaneous
and intravenous interferon-beta serine. J Natl Cancer Inst
1989;81:1061-1068.
15 Sarna G, Pertcheck M, Figlin R et al. Phase I study of recom-
binant beta ser 17 interferon in the treatment of cancer. Cancer
Treat Rep 1986;70:1365-1372.
16 Rinehart JJ, Malspeis L, Young D et al. Phase I/II trial of
human recombinant interferon gamma in renal cell carcinoma.
J Biol Response Mod 1986;5:300-308.
17 Shah I, Band J, Samson M et al. Pharmacokinetics and tolerance
of intravenous and intramuscular recombinant alpha 2 interferon
in patients with malignancies. Am J Hematol 1984;17:363-371.
18 Zhou A, Hassel BA, Silverman RH. Expression cloning of 2-
5A-dependent RNAase: a uniquely regulated mediator of
interferon action. Cell 1993;72:753-765.
19 Hovanessian AG, Wood JN. Anticellular and antiviral
effects of pppA(2p5A)n. Virology 1980;101:81-90.
20 Rysiecki G, Gewert DR, Williams BR. Constitutive expression
of a 2,5-oligoadenylate synthetase cDNA results in increased
antiviral activity and growth suppression. J Interferon Res
1989;9:649-657.21 Creasey AA, Eppstein DA, Marsh YV et al. Growth regula-
tion of melanoma cells by interferon and (2 -5)oligoadeny-
late synthetase. Mol Cell Biol 1983;3:780-786.
22 Merritt JA, Ball LA, Sielaff KM et al. Modulation of 2,5-
oligoadenylate synthetase in patients treated with alpha-inter-
feron: effects of dose, schedule, and route of administration.
J Interferon Res 1986;6:189-198.
23 Huber C, Fuchs D, Hausen A et al. Pteridines as a new
marker to detect human T cells activated by allogeneic or
modified self major histocompatibility complex (MHC)
determinants. J Immunol 1983;130:1047-1050.
24 Gastl G, Aulitzky W, Tilg H et al. A biological approach to
optimize interferon treatment in hairy cell leukemia.
Immunobiology 1986;172:262-268.
25 Huber C, Aulitzky W, Tilg H et al. Studies on the optimal
dose and the mode of action of alpha-interferon in the treat-
ment of hairy cell leukemia. Leukemia 1987;1:355-357.
26 Buzaid AC, Grimm EA, Ali-Osman F et al. Mechanism ofthe anti-tumour effect of biochemotherapy in melanoma:
preliminary results. Melanoma Res 1994;4:327-330.
27 Anderson CM, Buzaid AC, Sussman J et al. Nitric oxide and
neopterin levels and clinical response in stage III melanoma
patients receiving concurrent biochemotherapy. Melanoma Res
1998;8:149-155.
28 Bernengo MG, Quaglino P, Cappello N et al. Macrophage-
mediated immunostimulation modulates therapeutic efficacy
of interleukin-2 based chemoimmunotherapy in advanced
metastatic melanoma patients. Melanoma Res 2000;10:55-65.
29 Roers A, Hochkeppel HK, Horisberger MA et al. MxA gene
expression after live virus vaccination: a sensitive marker forendogenous type I interferon. J Infect Dis 1994;169:807-813.
30 Simon A, Fah J, Haller O et al. Interferon-regulated Mx genes
are not responsive to interleukin-1, tumor necrosis factor, and
other cytokines. J Virol 1991;65:968-971.
31 von Wussow P, Jakschies D, Hochkeppel HK et al. The human
intracellular Mx-homologous protein is specifically induced by
type I interferons. Eur J Immunol 1990;20:2015-2019.
32 Quesada JR, Reuben J, Manning JT et al. Alpha interferon for
induction of remission in hairy-cell leukemia. N Engl J Med
1984;310:15-18.
33 Quesada JR, Hersh EM, Manning J et al. Treatment of hairy
cell leukemia with recombinant alpha-interferon. Blood1986;68:493-497.
34 Golomb HM, Jacobs A, Fefer A et al. Alpha-2 interferon ther-
apy of hairy-cell leukemia: a multicenter study of 64 patients.
J Clin Oncol 1986;4:900-905.
35 Verma DS, Spitzer G, Gutterman JU et al. Human leukocyte
interferon preparation blocks granulopoietic differentiation.
Blood 1979;54:1423-1427.
36 Talpaz M, McCredie KB, Mavligit GM et al. Leukocyte inter-
feron-induced myeloid cytoreduction in chronic myelogenous
leukemia. Blood 1983;62:689-692.
37 Talpaz M, Kantarjian HM, McCredie K et al. Hematologic
remission and cytogenetic improvement induced by recombinant
human interferon alpha A in chronic myelogenous leukemia.
N Engl J Med 1986;314:1065-1069.
38 Silver RT, Woolf SH, Hehlmann R et al. An evidence-based
analysis of the effect of busulfan, hydroxyurea, interferon, and
allogeneic bone marrow transplantation in treating the chronic
phase of chronic myeloid leukemia: developed for the
American Society of Hematology. Blood 1999;94:1517-1536.
39 Ozer H, George SL, Schiffer CA et al. Prolonged subcutaneous
administration of recombinant alpha 2b interferon in patients
with previously untreated Philadelphia chromosome-positive
chronic-phase chronic myelogenous leukemia: effect on remis-
7/30/2019 Interferon in Oncological Practice_Review of Interferon
18/22
Jonasch, Haluska 51
sion duration and survival: Cancer and Leukemia Group B
study 8583. Blood 1993;82:2975-2984.
40 Interferon alfa-2a as compared with conventional chemother-
apy for the treatment of chronic myeloid leukemia. The Italian
Cooperative Study Group on Chronic Myeloid Leukemia. N
Engl J Med 1994;330:820-825.
41 Hehlmann R, Heimpel H, Hasford J et al. Randomized com-
parison of interferon-alpha with busulfan and hydroxyurea
in chronic myelogenous leukemia. The German CML Study
Group. Blood 1994;84:4064-4077.
42 Allan NC, Richards SM, Shepherd PC. UK Medical Research
Council randomised, multicentre trial of interferon- alpha n1
for chronic myeloid leukaemia: improved survival irrespective
of cytogenetic response. The UK Medical Research Councils
Working Parties for Therapeutic Trials in Adult Leukaemia.
Lancet 1995;345:1392-1397.
43 Ohnishi K, Ohno R, Tomonaga M et al. A randomized trial
comparing interferon-alpha with busulfan for newly diag-
nosed chronic myelogenous leukemia in chronic phase. Blood1995;86:906-916.
44 Broustet A, Reiffers J, Marit G et al. Hydroxyurea versus
interferon alfa-2b in chronic myelogenous leukaemia: prelim-
inary results of an open French multicentre randomized study.
Eur J Cancer 1991;27(suppl 4):S18-S21.
45 Randomized study on hydroxyurea alone versus hydroxyurea
combined with low-dose interferon-alpha 2b for chronic
myeloid leukemia. The Benelux CML Study Group. Blood
1998;91:2713-2721.
46 Sokal JE, Leong SS, Gomez GA. Preferential inhibition by
cytarabine of CFU-GM from patients with chronic granulocytic
leukemia. Cancer 1987;59:197-202.47 Robertson MJ, Tantravahi R, Griffin JD et al. Hematologic
remission and cytogenetic improvement after treatment of sta-
ble-phase chronic myelogenous leukemia with continuous infu-
sion of low-dose cytarabine. Am J Hematol 1993;43:95-102.
48 Kantarjian HM, Keating MJ, Estey EH et al. Treatment of
advanced stages of Philadelphia chromosome-positive
chronic myelogenous leukemia with interferon-alpha and
low-dose cytarabine. J Clin Oncol 1992;10:772-778.
49 Kantarjian HM, OBrien S, Smith TL et al. Treatment of
Philadelphia chromosome-positive early chronic phase chronic
myelogenous leukemia with daily doses of interferon alpha
and low-dose cytarabine. J Clin Oncol 1999;17:284-292.50 Guilhot F, Chastang C, Michallet M et al. Interferon alfa-2b
combined with cytarabine versus interferon alone in chronic
myelogenous leukemia. French Chronic Myeloid Leukemia
Study Group. N Engl J Med 1997;337:223-229.
51 Kurzrock R, Talpaz M, Kantarjian H et al. Therapy of chronic
myelogenous leukemia with recombinant interferon-gamma.
Blood 1987;70:943-947.
52 Kloke O, Wandl U, Opalka B et al. A prospective randomized
comparison of single-agent interferon (IFN)-alpha with the
combination of IFN-alpha and low-dose IFN-gamma in chronic
myelogenous leukaemia. Eur J Haematol 1992;48:93-98.
53 Wandl UB, Opalka B, Kloke O et al. Treatment of chronic
myelogenous leukemia with different cytokines. Semin Oncol
1992;19(suppl 4):88-94.
54 Rodriguez J, Cortes J, Smith T et al. Determinants of prog-
nosis in late chronic-phase chronic myelogenous leukemia.
J Clin Oncol 1998;16:3782-3787.
55 Tomas JF, Lopez-Lorenzo JL, Requena MJ et al. Absence ofinfluence of prior treatment with interferon on the outcome of
allogeneic bone marrow transplantation for chronic myeloid
leukemia. Bone Marrow Transplant 1998;22:47-51.
56 Zuffa E, Bandini G, Bonini A et al. Prior treatment with
alpha-interferon does not adversely affect the outcome of
allogeneic BMT in chronic phase chronic myeloid leukemia.
Haematologica 1998;83:231-236.
57 Morton AJ, Gooley T, Hansen JA et al. Association between
pretransplant interferon-alpha and outcome after unrelated
donor marrow transplantation for chronic myelogenous
leukemia in chronic phase. Blood 1998;92:394-401.
58 Ozer H, Wiernik PH, Giles F et al. Recombinant interferon-alpha therapy in patients with follicular lymphoma [published
erratum appears in Cancer 1998;83:593]. Cancer 1998;82:1821-
1830.
59 Price CG, Rohatiner AZ, Steward W et al. Interferon-alpha 2b
in the treatment of follicular lymphoma: preliminary results of
a trial in progress. Ann Oncol 1991;2(suppl 2):141-145.
60 Rohatiner A, Crowther D, Radford J et al. The role of inter-
feron in follicular lymphoma. Proc Am Soc Clin Oncol
1996;15:418.
61 Peterson BA, Petroni GR, Oken MM et al. Cyclophos-
phamide versus cyclophosphamide plus interferon alfa-2b in
follicular low-grade lymphomas: an intergroup phase III trial
(CALGB 8691 and EST 7486). Proc Am Soc Clin Oncol
1997;16:14a.
62 Smalley RV, Andersen JW, Hawkins MJ et al. Interferon alfa
combined with cytotoxic chemotherapy for patients with non-
Hodgkins lymphoma. N Engl J Med 1992;327:1336-1341.
63 Solal-Celigny P, Lepage E, Brousse N et al. Doxorubicin-con-
taining regimen with or without interferon alfa-2b for
advanced follicular lymphomas: final analysis of survival and
toxicity in the Groupe dEtude des Lymphomes Folliculaires
86 Trial. J Clin Oncol 1998;16:2332-2338.
64 McLaughlin P, Cabanillas F, Hagemeister FB et al. CHOP-
Bleo plus interferon for stage IV low-grade lymphoma. Ann
Oncol 1993;4:205-211.
65 Hiddemann W, Unterhalt M, Koch P et al. New aspects in the
treatment of advanced low-grade non-Hodgkins lymphomas:
prednimustine/mitoxantrone versus cyclophosphamide/vincris-
tine/prednisone followed by interferon alfa versus observation
onlya preliminary update of the German Low-Grade Lym-
phoma Study Group. Semin Hematol 1994;31(suppl 3):32-35.
66 Unterhalt M, Herrmann R, Tiemann M et al. Prednimustine,
mitoxantrone (PmM) vs cyclophosphamide, vincristine, pred-
nisone (COP) for the treatment of advanced low-grade non-
Hodgkins lymphoma. German Low-Grade Lymphoma Study
Group. Leukemia 1996;10:836-843.
7/30/2019 Interferon in Oncological Practice_Review of Interferon
19/22
52 Interferon in Oncological Practice
67 Unterhalt M, Herrmann R, Nahler M et al. Significant prolon-
gation of disease-free survival in advanced low grade non-
Hodgkins lymphomas (NHL) by interferon alfa maintenance.
Blood 1995;86:439a.
68 Hagenbeek A, Carde P, Somers R et al. Interferon-alfa-2a vs
control as maintenance therapy for low grade non-Hodgkins
lymphoma: results from a prospective randomized clinicaltrial. Proc Am Soc Clin Oncol 1995;14:386.
69 Aviles A, Duque G, Talavera A et al. Interferon alpha 2b as
maintenance therapy in low grade malignant lymphoma
improves duration of remission and survival. Leuk Lymphoma
1996;20:495-499.
70 Savage PD, Muss HB. Renal cell cancer. In: De Vita VT Jr,
Hellman S, Rosenberg SA, eds. Biologic Therapy of Cancer
Second Ed. Philadelphia: J.B. Lippincott Company,
1995;373-387.
71 Interferon-alpha and survival in metastatic renal carcinoma:
early results of a randomised controlled trial. Medical Research
Council Renal Cancer Collaborators. Lancet 1999;353:14-17.
72 Pyrhonen S, Salminen E, Ruutu M et al. Prospective ran-
domized trial of interferon alfa-2a plus vinblastine versus
vinblastine alone in patients with advanced renal cell cancer.
J Clin Oncol 1999;17:2859-2867.
73 Bukowski RM. Natural history and therapy of metastatic
renal cell carcinoma: the role of interleukin-2. Cancer
1997;80:1198-1220.
74 Negrier S, Escudier B, Lasset C et al. Recombinant human
interleukin-2, recombinant human interferon alfa-2a, or both in
metastatic renal-cell carcinoma. Groupe Francais dImmuno-
therapie. N Engl J Med 1998;338:1272-1278.
75 Boccardo F, Rubagotti A, Canobbio L et al. Interleukin-2,
interferon-alpha and interleukin-2 plus interferon-alpha in
renal cell carcinoma. A randomized phase II trial. Tumori
1998;84:534-539.
76 Henriksson R, Nilsson S, Colleen S et al. Survival in renal
cell carcinomaa randomized evaluation of tamoxifen vs
interleukin 2, alpha-interferon (leucocyte) and tamoxifen. Br
J Cancer 1998;77:1311-1317.
77 Jayson GC, Middleton M, Lee SM et al. A randomized phase
II trial of interleukin 2 and interleukin 2- interferon alpha in
advanced renal cancer. Br J Cancer 1998;78:366-369.
78 Lissoni P, Barni S, Ardizzoia A et al. A randomized study of
low-dose interleukin-2 subcutaneous immunotherapy versus
interleukin-2 plus interferon-alpha as first line therapy formetastatic renal cell carcinoma. Tumori 1993;79:397-400.
79 Lummen G, Goepel M, Mollhoff S et al. Phase II study of inter-
feron-gamma versus interleukin-2 and interferon-alpha 2b in
metastatic renal cell carcinoma. J Urol 1996;155:455-458.
80 Houghton JA, Morton CL, Adkins DA et al. Locus of the inter-
action among 5-fluorouracil, leucovorin, and interferon-alpha
2a in colon carcinoma cells. Cancer Res 1993;53:4243-4250.
81 Morita T, Tokue A. Biomodulation of 5-fluorouracil by
interferon-alpha in human renal carcinoma cells: relation-
ship to the expression of thymidine phosphorylase. Cancer
Chemother Pharmacol 1999;44:91-96.
82 Lopez Hanninen E, Kirchner H, Atzpodien J. Interleukin-2
based home therapy of metastatic renal cell carcinoma: risks
and benefits in 215 consecutive single institution patients.
J Urol 1996;155:19-25.
83 Hofmockel G, Langer W, Theiss M et al. Immunochemo-
therapy for metastatic renal cell carcinoma using a regimen
of interleukin-2, interferon-alpha and 5-fluorouracil. J Urol1996;156:18-21.