Interferon in Oncological Practice_Review of Interferon

7/30/2019 Interferon in Oncological Practice_Review of Interferon

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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


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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).


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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


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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


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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


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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


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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)


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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


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


9/22


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


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)


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


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


11/22


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


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


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


13/22


[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


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


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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


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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.

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