immunosuppressive drugs and cancer

Immunosuppressive drugs and cancer

Thierry Vial *, Jacques Descotes

Lyon Poison Centre and Pharmacovigilance Unit, Unit 5 Place d’Arsonval, Hopital Edouard Herriot, 69437 Lyon cedex 03, France

Abstract

Among the many adverse effects induced by immunosuppressive drugs, cancers are a major cause of morbidity and

mortality. This review is based on the most recent clinical data. Epidemiological studies and cancer registries have

consistently shown an increased risk of malignancies in transplant patients although the calculated risk (4�/500-fold

increase) differs markedly between studies essentially because of differences in methodologies and selection of patients.

Skin and lip cancers, lymphomas and Kaposi’s sarcomas are the main types of cancer in these patients. A number of

risk factors have been identified, such as latent viral infections, the treatment regimen and the level of

immunosuppression. The increasing use of immunosuppressive drugs in nontransplant patients is useful to delineate

more accurately the consequences of mild-to-moderate immunosuppression.

# 2002 Elsevier Science Ireland Ltd. All rights reserved.

Keywords: Immunosuppression; Cancer; Immunosuppressive drugs; Adverse effects

1. Introduction

Since the discovery of potent immunosuppres-

sive drugs, a wide experience has been acquired in

the field of transplantation and autoimmune

diseases. In both areas, new immunosuppressive

drugs have appeared or are still under clinical

investigation. Cancer represents a possible major

risk of any immunosuppressive treatment, and the

aim of this review is to examine the currently

available literature, both in transplant and non-

transplant patients. The increasing use of immu-

nosuppressive drugs in non-transplant patients

indeed offers the opportunity to delineate more

accurately the consequences of mild-to-moderate

immunosuppression with respect to the risk of

malignancies.

2. Cancers in transplant patients

Immunosuppressive drugs used in transplant

patients are associated with a large spectrum of

adverse effects, and the risk of cancer which has

been known since the late 1960s represents a major

cause of morbidity and/or mortality, and late

failure in patients otherwise living with wellfunctioning grafts. Although this risk is obviously

acceptable in cardiac or hepatic transplantation, it

may become a major outcome in renal transplant

patient because of longer periods of survival and

the availability of dialysis. It should also be

considered in the light of the increased number

* Corresponding author. Tel.: �/33-472-11-6984; fax: �/33-

472-11-6985.

E-mail address: [email protected] (T. Vial).

Toxicology 185 (2003) 229�/240

www.elsevier.com/locate/toxicol

0300-483X/02/$ - see front matter # 2002 Elsevier Science Ireland Ltd. All rights reserved.

PII: S 0 3 0 0 - 4 8 3 X ( 0 2 ) 0 0 6 1 2 - 1

mailto:[email protected]

of transplanted patients. About 450 000 renaltransplants have been performed worldwide, and

approximately 3000 transplantations are per-

formed each year in France.

The overall survival rate has improved year after

year and is in the range of 50�/70% at 10 years, to

reach 90% in renal transplantation. Based on these

figures, about 25 000 transplanted patients are

living in France. The availability of new immuno-suppressive agents is also of concern. Whereas two

agents were used in the pioneering years of

transplantation (azathioprine and corticosteroids),

the development of new agents has led to use more

active regimens containing three or more different

drugs over a short span of time.

2.1. Epidemiology of cancer in transplant patients

Cancers in transplant patient has been the

matter of continuous survey, and a large amount

of data has accumulated from single or multiple

center experience. However, estimates of the risk

and type of cancer vary widely from one study to

another, and this reflects geographical differences,

the use of different immunosuppressive regimens,

different prophylactic antiviral treatments, thelength of follow-up, the type of organ transplanta-

tion, and different methods to calculate the

incidence rate. Comparison between studies is,

therefore, difficult.

Two approaches are currently available to study

the risk of cancer in transplant patients. Large

studies performed in single centers or collaborative

studies provide information on the incidence ofcancer with possible comparison to the available

data from the general population. From various

studies, the cumulative risk of cancer in renal

transplant patients was estimated to increase from

13�/18% at 10 years to 34�/50% at 20 years and 60�/

70% at 25 years (Bouwes Bavinck et al., 1996;

Gaya et al., 1995; Hiesse et al., 1997; Hoshida et

al., 1997; London et al., 1995; Montagnino et al.,1996; Mihalov et al., 1996; Newell et al., 1996;

Opelz and Henderson, 1993; Stewart et al., 1995).

A very long-term surveillance is, therefore, neces-

sary to best define the incidence or the type of

cancer. Overall, the risk of cancer is 3�/8-fold

higher as compared with age-matched controls in

the general population, but the incidence variedconsiderably for individual cancers. The relevance

of such comparisons can be criticized because

transplant recipients are not representative of the

general population. In a more useful approach, the

incidence of cancer in renal transplant patients was

found to be significantly higher as compared with

that of patients under regular dialysis (Montag-

nino et al., 1996).Another way to explore post-transplant cancer

is the use of registries, of which the Cincinnati

Transplant Tumor Registry (CTTR) is the largest.

A recent update of this registry was particularly

useful to define comprehensively the characteris-

tics of the various type of neoplasms observed in

organ transplant recipients. By July 1998, the

CTTR had collected data on 11 483 cancers thatarose in 10 787 patients, mostly in American renal

transplant patients (Penn, 2000). Skin and lip

cancers were the most common and represented

38% of all cancers. Post-transplant lymphoproli-

ferative disorders (PTLD) accounted for 17% of

cancers and Kaposi’s sarcoma for 4%. Other types

of cancers included renal carcinomas, uterine

cervical and anogenital carcinomas, hepato-biliarycarcinomas, and various sarcomas.

The increased risk of various cancers has also

been estimated in several epidemiological studies

and ranged from a 4 to 500-fold increase as

compared with the general population. By con-

trast, the incidence of common neoplasms encoun-

tered in the general population is not increased,

and some studies have even shown a reducedincidence of several solid cancers, such as lung,

breast, prostate and colon cancers (Gaya et al.,

1995; London et al., 1995; Stewart et al., 1995). In

children, studies showed that the most common

neoplasms were non-Hodgkin lymphomas, which

represented about half of cancers, and skin cancers

(Gagnadoux, 1997). Overall, the median time to

the diagnosis of cancer was 46 months aftertransplantation, and the shortest median delay

was 12 months for Kaposi’s sarcoma and lym-

phoma.

Only the most frequent type of cancers will be

discussed in this review with emphasis on specific

characteristics and risk factors in transplant pa-

tients.

T. Vial, J. Descotes / Toxicology 185 (2003) 229�/240230

2.1.1. Skin and lip cancers

Skin and lip cancers are the most frequent and

accounted for 40�/50% of all neoplastic diseases

after transplantation. There are wide geographical

differences in the prevalence of skin cancers, and

the incidence linearly increases with the length of

follow-up. For example, the estimated incidence

was 45% at 10 years and 70% at 20 years in

Australia (Bouwes Bavinck et al., 1996), and 5�/

10% at 10 years and 30�/40% at 20 years in several

European countries (Gaya et al., 1995; London et

al., 1995; Penn, 2000). In azathioprine-treated

renal transplant patients, premalignant dysplastic

keratotic lesions were shown to increase linearly by

6.8% per year after the first 3.5 years following

transplantation, and were ultimately observed in

all 167 patients within 16 years of transplantation

(Taylor and Shuster, 1992). Multiple skin cancers

are also frequent and more than 100 skin cancers

can be identified in a single patient. Squamous-cell

carcinomas are usually more aggressive than those

observed in the general population, and about 5%

of patients died from skin cancers. As opposed to

their counterpart in the general population, squa-

mous-cell carcinomas are the most frequent and

occurred in younger patients.

Several risk factors may predispose patients to

the development of skin cancers. The most com-

mon localization is on areas of sun-exposed skin.

Obviously, these differences are largely, but not

solely, explained by the influence of heavy solar

ultraviolet irradiation which causes direct damage

to DNA, induces local immunological unrespon-

siveness, and facilitates the proliferation of human

papillomaviruses in already immunosuppressed

patients. However, infection with human papillo-

mavirus is not a prerequisite to the development of

skin cancers. There is as yet a controversy as to

whether immunogenetic factors play a role in the

development of skin cancers, and HLA-DR homo-

zygosity has been associated with an increased risk

in several studies (Ong et al., 1999; Penn, 2000).

Although azathioprine has been considered a risk

factor in previous studies, more recent data were

unable to confirm a relationship of skin cancers

with a specific immunosuppressive drug.

2.1.2. Lymphomas

PTLD are a particular concern and the com-

monest cancers in the first year after transplanta-

tion. In one study, the overall mortality in patients

with PTLD was 34% (Niaudet, 1998). Histological

and immunophenotypic studies have shown a wide

spectrum of PTLD, ranging from benign lymphoid

hyperplasia to malignant lymphoma (Penn, 2000).

Most of the cases were B-cell lymphomas. Fromvarious studies, estimates of the incidence of

PTLD is 0.2�/1% in renal transplant patients,

2.5% in liver transplant patients and 1.2�/3% in

heart transplant patients (Opelz and Henderson,

1993; Penn, 2000). About 70% of cases occurred

during the first year of transplantation, and the

incidence rapidly decreased after the first year to

stabilize with rates of 0.04�/0.3% in the subsequentyears (Opelz and Henderson, 1993). This suggests

that the development of lymphoma depends on

factors present at the time of transplantation.

Allograft was the most frequently involved site,

suggesting that the local immune response in the

graft largely contributed to the development of

PTLD. Multiple organ involvement is frequent.

Overimmunosuppression is an important factorfor the development of PTLD, as shown by

complete regression of PTLD in about 40% of

patients after discontinuation or reduction of the

immunosuppressive regimen. It is also worth

noting that an increased incidence has been

discussed each time after the adjunction of a new

immunosuppressive drug in the post-transplant

regimen. This has been described as the ‘learningcurve’, which corresponded to the time spent to

reach the optimal dosage regimen (Penn, 2000).

This is also confirmed by the more frequent

incidence in nonrenal transplant patients who

usually received a more heavily immunosuppres-

sive regimen. Several studies have showed that

Epstein-Barr virus (EBV) is significantly asso-

ciated with the development of PTLD. In onestudy, EBV infection was found in 70% of renal

transplant patients who developed PTLD, of

whom 41% were EBV seronegative before trans-

plantation (Niaudet, 1998). Transplant children

diagnosed with PTLD were also significantly more

likely to be EBV seronegative before transplanta-

tion as compared with patients who did not

T. Vial, J. Descotes / Toxicology 185 (2003) 229�/240 231

develop PTLD (Newell et al., 1996). EBV serone-gative status and young age at transplantation are,

therefore, strong risk factors.

2.1.3. Kaposi’s sarcoma

The excess risk of Kaposi’s sarcoma is particu-

larly elevated in transplant patients, especially in

several Mediterranean ethnic groups (Penn, 2000).

Non visceral localizations with typical skin lesionsare the most frequent. A significant association

between pretransplant human herpes virus 8

infection and the further development of Kaposi’s

sarcoma has been evidenced (Cattani et al., 2000).

2.2. Risk factors and mechanisms

Multiple factors with complex interactions areprobably involved in the observed pattern and

increased incidence of neoplasms in transplanta-

tion. They include severely depressed immunity

with an impaired immune surveillance against

various carcinogens and the subsequent elimina-

tion of malignant clones, chronic stimulation of

the immune system, genetic susceptibility, envir-

onmental factors, the activation of oncogenicviruses, and a possible mutagenic effect of the

drugs. Among the characteristics of cancers in

transplant patients, their occurrence in relatively

young patients, a severe clinical aggressiveness,

and a rather short time in onset after transplanta-

tion, are noticeable. The length of exposure to

immunosuppressant drugs is a significant risk

factor (London et al., 1995).

2.2.1. Role of latent viral infections

The short time to onset of certain tumors

strongly suggests that viruses may play an im-

portant role in the pathophysiological mechanism

of cancers. As previously indicated, several types

of cancers have been associated with various

chronic viral infections. A likely explanation is

that immunosuppression impaired immune sur-veillance of virus-transformed cells, increased the

frequency of virus infections, or both. From a

theoretical point of view, the use of antiviral drugs

active against viruses, which are commonly im-

plicated as cofactors, can be expected to produce a

reduction in the incidence of these cancers. Un-

fortunately, there is yet no evidence for a positiveeffect of antiviral drugs.

2.2.2. Role of the treatment regimen

Whilst there is no doubt that the incidence of

malignancies is increased in the transplant popula-

tion, there have been controversies as to which

factors, namely the type of immunosuppressive

regimens, total dosage and duration of treatment,

or the degree of immunosuppression, are the mostrelevant to determining risk. Whether a specific

immunosuppressive drug or regimen is more

strongly associated with a risk of cancer has been

the matter of debate, in particular since the

introduction of new agents that allowed the use

of triple or quadruple immunosuppressive regi-

mens.

The direct or indirect oncogenic effect ofazathioprine has been discussed. In one study,

azathioprine was considered as the main causative

factor of premalignant dysplastic keratotic lesions,

and that was possibly due to a carcinogenic effect

rather than immunosuppression itself (Taylor and

Shuster, 1992). The main difference between

azathioprine-based regimen and currently used

cyclosporine- or tacrolimus-based regimen is theshorter average time elapsing before the occur-

rence of cancer in cyclosporine- or tacrolimus-

treated patients, i.e. about 40 versus 90 months

(Gruber et al., 1994; Hiesse et al., 1997; Hoshida et

al., 1997).

Despite some initial suggestion that cyclospor-

ine was associated with an unexpectedly higher

incidence of lymphomas and Kaposi’s sarcomas,there is no convincing evidence that this drug

specifically increases the risk of tumors as com-

pared with other immunosuppressive regimens, in

particular conventional azathioprine-based regi-

mens (Jensen et al., 1999; Montagnino et al., 1996;

Penn, 1996; Sheil et al., 1991). Several studies have

even suggested that cyclosporine might produce a

lower incidence of cancers (Gruber et al., 1994;Hiesse et al., 1997; Sheil et al., 1991). Although

cyclosporine has no genotoxic activity and no

DNA-binding properties, a recent in vitro and in

vivo experiment indicated that cyclosporine might

directly promote tumor growth by a non-immune

mechanism that acts on the tumor itself via


transforming-growth-factor beta (TGF-b) recep-tors (Hojo et al., 1999). It was, therefore, suggested

that cyclosporine could exacerbate tumor growth

in patients with existing tumor by a mechanism

that is independent and/or complementary to its

immunosuppressive effects. The clinical relevance

of these rather provocative data awaits further

careful clinical confirmation. At the moment,

more recent analysis of clinical experience hasnot provided clear evidence for a cyclosporine-

specific effect and has instead supported a major

role of its immunosuppressive effect (Jensen et al.,

1999).

Tacrolimus (FK506) shares very similar immu-

nosuppressive properties and is used as an alter-

native to cyclosporine as baseline regimen in

transplant patients. On a weight basis, tacrolimusis approximately ten times more potent in vivo and

100 times more potent in vitro than cyclosporine.

The incidence and pathological features of tacro-

limus-induced post-transplant cancers were

deemed to be very similar to those observed with

other immunosuppressive agents, in particular

cyclosporine (Penn, 2000). In general, studies

that compared the incidence of malignancies intacrolimus-based and cyclosporine-based regimens

failed to identify significant differences between

the two regimens (Wiesner, 1998), although recent

data found a 5-fold higher rate of PTLD in

pediatric liver transplant patients on tacrolimus-

based treatments as compared with cyclosporine-

based treatments (Younes et al., 2000). However, a

more accurate clinical surveillance in tacrolimus-treated patients may have introduced a bias.

Again, and as suggested by other studies, excessive

immunosuppression as a result of prior OKT3 or

antithymocyte globulin administration, or high

tacrolimus blood levels, and more frequent EBV

infections in tacolimus-treated patients, are also a

likely explanation (Cox et al., 1995; Sokal et al.,

1997).Preliminary follow-up suggested that mycophe-

nolate mofetil might be associated with a slight

and dose-dependent increase in the incidence of

malignancies, but longer periods of follow-up are

awaited to provide more accurate analysis and to

more carefully explore the role of overimmuno-

suppression (Mathew, 1998).

Excessive immunosuppression is a major con-sequence of OKT3 treatments. As expected, OKT3

has been lengthily discussed as a significant risk

factor for secondary neoplasias, particularly

PTLD, and especially when high doses, increased

treatment duration, sequential courses or early

retreatments, are used. Whether the increased risk

of neoplasias observed after OKT3-based immu-

nosuppression is due to the drug itself or reflectsthe overall degree of immunosuppression has been

a matter of vivid debate and conflicting results

have emerged from the literature (Sgro, 1995). One

study found that the rate of non-Hodgkin’s

lymphomas was higher in patients receiving

OKT3 prophylaxis versus polyclonal antibodies

(Opelz and Henderson, 1993). Another large study

confirmed that immunosuppression with polyclo-nal and monoclonal OKT3 antibodies indepen-

dently increased the risk for virus-mediated cancer,

i.e. non-Hodgkin’s lymphoma and genital carci-

nomas (Hibbers et al., 1999). Whereas PTLD

developed in 4.3�/6.6% of patients undergoing

primary immunosuppression with cyclosporine or

tacrolimus, the incidence strongly increased in

those who required additional immunosuppressionfor refractory rejection, and reached 11% when

either OKT3 or tacrolimus was used, and 28%

when both drugs were used together (Newell et al.,

1996). Using data from the manufacturer and the

literature, it was found that PTLD can occur very

shortly after the use of OKT3 (Bertin et al., 1996).

The median time to the occurrence of PTLD was

only 53 days after the first dose of OKT3 and 90days after transplantation. PTLD also occurred

faster in patients who had received multiple

courses and/or elevated cumulative dosage of

OKT3, or in those who had received OKT3 plus

polyclonal antibodies. Such findings strongly sug-

gested that intense immunosuppression rather

than OKT3 itself is the most important factor.

Although the role of high cumulative doses orrepeated courses as a risk factor is not definitely

proven, it has been recommended not to exceed 14

days of treatment with cumulative doses of 70 mg.

The monoclonal antibodies to the interleukin-2

receptor, basiliximab and daclizumab, which are

used to prevent acute rejection after renal trans-

plantation, have not yet been associated with an


additional increased risk of malignancies. How-ever, follow-up of these patients is still insufficient

to allowed definite conclusions.

2.2.3. Role of the level of immunosuppression

Several indirect lines of evidence argues strongly

for a major role of the level of immunosuppression

and the number of immunosupressant drugs used

rather than a particular agent in the risk of cancer:

�/ Partial or complete regression of lymphoproli-

ferative disorders and Kaposi’s sarcomas has

been observed after the reduction of immuno-

suppressive therapy (Penn, 2000).

�/ The incidence of cancers is significantly higherin renal transplant patients receiving triple

therapy regimens as compared with double

therapy (Kehinde et al., 1994).

�/ As compared with renal transplant patients,

cardiac transplant patients undergo more ag-

gressive immunosuppressive therapy and this

accounts for a higher incidence of lymphomas

in these patients (Penn, 1993). For example, therate of non-Hodgkin’s lymphomas in the first

post-transplantation year was 0.2% in kidney

and 1.2% in heart recipients in a large multi-

center study involving more than 52 000 pa-

tients (Opelz and Henderson, 1993).

�/ A dose-dependent effect of cyclosporine on the

incidence of cancers has been suggested. In this

study, patients were randomly allocated at 1year after transplantation, to either a low or a

high therapeutic range for cyclosporine (Dantal

et al., 1998). A significantly higher frequency of

new cancers was observed in the normal group

as compared with the low-dose group, and most

of malignancies were skin cancers (Dantal et al.,

1998). In addition, patients from the normal-

dose group had more frequent pre-epithelioma-tous lesions or warts and multiple skin lesions,

and more frequent episodes of virus infection.

3. Cancers in non-transplant patients

The increasing use of immunosuppressive drugs

in nontransplant patients offers the opportunity to

delineate more acutely the consequences of mild-

to-moderate immunosuppression in the occurrenceof cancers. Several immunosuppressants are cur-

rently used in various autoimmune diseases or

chronic inflammatory disorders, such as multiple

sclerosis, rheumatoid arthritis, systemic lupus

erythematosus, and chronic inflammatory bowel

disorders. The available data will be reviewed for

several of these drugs.

3.1. Azathioprine and 6-mercaptopurine

Azathioprine is used in a variety of autoimmune

or chronic inflammatory disorders, such as rheu-

matoid arthritis, dermatomyositis, systemic lupus

erythematosus, skin and inflammatory bowel dis-

eases. Several case reports discussed the possible

role of long-term azathioprine treatment in the

occurrence of promptly reversible EBV-associatedlymphomas, acute myeloid leukemias, rapidly

aggressive squamous-cell carcinomas, soft-tissue

carcinomas or fatal Merkel cell carcinomas. Con-

flicting results have emerged from epidemiological

studies, and there is as yet no definite evidence that

azathioprine actually increases the risk of cancers.

Whereas an increased risk of non-Hodgkin’s

lymphomas has been found in rheumatoid arthritispatients (Silman et al., 1988), another study did

not detect any increase in the overall incidence of

cancers in azathioprine-treated patients as com-

pared with unexposed patients (Jones et al., 1996).

However death more often resulted from malig-

nancies in these patients. Results obtained in

patients treated for inflammatory bowel disease

were also unable to suggest a more frequentincidence of cancers (Connell et al., 1994; Korelitz

et al., 1999). Data provided by a case-control

study, which used a database of 1191 patients

treated for multiple sclerosis, were the most

interesting (Confavreux et al., 1996). The relative

risk of cancers was 1.3 in patients treated for less

than 5 years, 2.0 for 5�/10 years, and 4.4 for more

than 10 years of treatment. Although none of theseresults were significant, an association was found

for cumulative dosage in excess of 600 g. Taken

together, these results suggest that azathioprine

carries a low risk of cancers in the non-transplant

patient, but they cannot exclude a dose-dependent

increase in risk during prolonged treatment.


3.2. Cyclophosphamide

Although cyclophosphamide is mainly indicated

in oncological patients or in conditioning regimens

for bone marrow transplantation, its immunosup-

pressant properties have also been used in trans-

plantation and several chronic inflammatory

disorders. Its ability to promote the occurrence

of bladder cancers was documented in patientstreated for cancer or nonmalignant diseases.

Acrolein or phosphoramid mustard, two major

toxic metabolites of cyclophosphamide, are the

probable causative agents. However, long-term

cyclophosphamide treatment in non cancer pa-

tients has also been associated with an increased

incidence of certain neoplasms, the type of which

suggests a possible additional consequence of animmunosuppressive effect. In rheumatoid

arthritis, there was an excess of bladder cancers,

skin cancers and myeloproliferative disorders after

20 years of follow-up in the cyclophosphamide

group as compared with the control group (Radis

et al., 1993), and a 11-fold increase in the

incidence of lymphomas was found in patients

treated for Wegener’ granulomatosis as comparedwith the general population (Hoffman et al., 1992).

Such findings were not present in patients with

systemic lupus erythematosus who had previous

exposure to cyclophosphamide (Petterson et al.,

1992).

3.3. Cyclosporine

Cyclosporine is increasingly used in nontrans-

plant patients, and low-dose cyclosporine has been

evaluated in the treatment of rheumatoid arthritis,

psoriasis, diabetes mellitus, and several other

autoimmune diseases. The possibilities that long-

term low-dose cyclosporine might also carries the

risk of malignancies in nontransplant patients has

been explored in very few studies. In patientstreated for autoimmune diseases, the overall

incidence of lymphomas was estimated to be

0.14% (Feutren, 1992). However, the results of

available studies are rather conflicting and usually

based on a limited number of patients or a short

duration of follow-up, i.e. less than 60 months.

One study in rheumatoid arthritis patients foundan increase in the relative risk of malignancies in

cyclosporine-treated patients as compared with

those given corticosteroids, but the risk was not

different from that observed in patients treated

with disease-modifying antirheumatic drugs

(Arellano and Krupp, 1993). A more recent

survey was also unable to detect an increased

incidence of malignancies in cyclosporine-treatedpatients compared with control patients who had

never received cyclosporine (Van Den Borne et al.,

1998). Additional results from this study even

suggested a protective rather than a tumor-pro-

moting effect, and patients treated with cyclospor-

ine for more than 1 year had a lower risk of

malignancies than those who had received the drug

for less than 1 year (Landewe et al., 1999). In acohort of 1223 patients treated for psoriasis, the

relative risk of malignancies was 5.6 (95% CI: 3.9�/

8) in cyclosporine-treated patients as compared

with the control population, and it was mostly

due to an increased risk of skin cancers or

lymphomas (Arellano, 1997). However, this was

comparable to the increased risk of cancers

observed in patients treated with other immuno-suppressants, such as methotrexate. Finally, a

recent study suggested that cyclosporine might

produce a higher incidence of cancers and lym-

phoproliferative disorders in rheumatoid arthritis

patients as compared with the general population,

but the data was collected from multiple sources

(Beauparlant et al., 1999).

3.4. Infliximab and etenercept

In the last few years, a new era has begun for the

treatment of chronic inflammatory disorders, such

as inflammatory bowel diseases or rheumatoid

arthritis. The patho-physiological mechanisms of

these diseases largely involve tumor necrosis factor

(TNF), which plays a pivotal role in the inflam-

matory response. Two different therapeutic ap-proaches have been investigated to decrease the

activity of TNF: anti-TNF-a antibodies or soluble

TNF receptors.

Infliximab is a chimeric IgG antibody specifi-

cally directed against TNF-a. This antibody pro-

duces a dose-dependent neutralization of the


cytotoxic effects of TNF. Although TNF exerts

multiple effects within the immune system, TNF

blockade by infliximab leads to a limited and

rather selective immune suppression. It has been

recently approved in the treatment of Crohn’s

disease and rheumatoid arthritis. In rheumatoid

arthritis, the efficacy has only been demonstrated

in association with methotrexate. The safety of

infliximab is still poorly evaluated, and the current

database contains information on only 913 pa-

tients from 12 clinical trials. Reports of lympho-

mas have emerged as a possible major concern. Of

the 771 patients who received infliximab, 18 were

known to have developed malignancies. Interest-

ingly, seven of these malignancies were lympho-

proliferative disorders. However, it was felt that

the data was insufficient because the incidence was

close to what is expected in a comparable popula-

tion. Although this assumption is particularly true

in rheumatoid arthritis patients who had a 2�/3-

fold increase in the risk of non-Hodgkin lympho-

mas, this has not clearly demonstrated in patients

with Crohn’s disease. Details provided for six of

these cases indicated that these patients also

received concomitant immunosuppressive drugs,

such as prednisone, methotrexate or azathioprine

(Bickston et al., 1999). Overall, the evidence of an

increased risk of lymphomas associated with

infliximab is still limited, and a careful surveillance

is required, especially in patients receiving other

immunosuppressive agents. Indeed, the initial

experience with infliximab found that the overall

incidence of infections was almost twice higher in

infliximab-treated patients than in placebo-

treated patients, although there was no increased

risk of opportunistic viral or fungal infections

(Schaibe, 2000). Since its marketing, several cases

of opportunistic infections, such as listeriosis,

aspergillosis or tuberculosis have been published

(Martinez et al., 2001; Morelli and Wilson, 2000;

Warris et al., 2001). Therefore, there is some

evidence that infliximab can affect the normal

immune response, and the occurrence of

cancers should deserve careful attention in the

next future.

At the moment, etanercept has not been asso-

ciated with the occurrence of cancer.

3.5. Methotrexate

Methotrexate, a folic-acid antagonist which

inhibits dihydrofolate reductase, has been used as

an anticancer agent for several years. Low-dosage

methotrexate (7.5�/15 mg/week) also exerts immu-

nosuppressive and anti-inflammatory properties,

and this is the purpose for its use in several

diseases characterized by inflammation or cellularproliferation. It has become one of the most widely

used disease-modifying anti-rheumatic drugs

(DMARDs) in rheumatoid arthritis, and also has

significant efficacy in psoriasis, asthma and in-

flammatory bowel diseases or systematic lupus

erythematosus. Multiple biochemical events at a

variety of cellular sites are thought to explain the

mechanisms by which methotrexate acts on thesediseases. Methotrexate also reduces immune sur-

veillance by decreasing immunoglobulin produc-

tion, cellular immune response, leukocyte

chemotaxis, or cytokine secretion. On this basis,

an increased risk of malignancy could, therefore,

be expected.

Several in vitro studies have suggested that

methotrexate might be mutagenic and carcino-genic, but the direct oncogenic potential of meth-

otrexate has never been clearly demonstrated in

humans. As regards to the use of immunosuppres-

sive low-dose methotrexate, there is still no con-

clusive evidence that methotrexate enhances the

risk of cancers. Current data is mostly based on

sporadic case reports of various type of cancers,

such as malignant melanomas, multiple myelomas,lymphomas, leukemias or solid cancers, and co-

hort studies without control groups, which

strongly hamper an objective assessment of meth-

otrexate treatment (Kanik and Cash, 1997). Sev-

eral studies failed to demonstrate any significant

difference in the incidence of cancers in rheuma-

toid arthritis or psoriasis patients as compared

with what is expected in the general population(Bologna et al., 1997; Bailin et al., 1975). In a large

retrospective study, which involved more than

16 000 rheumatoid arthritis patients, 39 cases of

hematological malignancies, which mostly con-

sisted of non-Hodgkin’s lymphomas, were identi-

fied (Moder et al., 1995). Further analysis did not

find any association between methotrexate and the


development of a particular type of hematological

malignancies. There was also no relationship with

the cumulative or peak doses, or the duration of

treatment. Although this type of study cannot

formerly exclude an increased risk, it shows that

the risk is obviously very small.Even though these epidemiological data are

reassuring, a possible increased risk of lympho-

proliferative disorders in rheumatoid arthritis

patients treated with methotrexate remains a

matter of concern. Indeed, an accumulated num-

ber of case reports have specifically drawn the

attention on methotrexate-induced lymphomas.

Several findings argue for methotrexate-induced

immunosuppression and a possible association

between methotrexate and the occurrence of

lymphoproliferative disorders:

�/ patients who develop lymphoma usually had

the typical features of lymphoproliferative dis-

orders that were found in transplant patients or

patients with congenital or acquired immune

deficiency syndromes (Georgescu et al., 1997).

Disorders ranged from benign lymphoid hyper-

plasia to non-Hodgkin’s lymphoma, and morerarely Hodgkin’s disease. The predominant type

of lymphoma is large, B cell non-Hodgkin’s

lymphoma, which is the most frequently ob-

served in transplant patients,

�/ methotrexate discontinuation resulted in the

spontaneous remission of lymphoproliferation

in several patients (Salloum et al., 1996).

Although it is based mostly on case reports,the possible association of methotrexate expo-

sure with reversible cases of lymphoprolifera-

tion is the strongest evidence that methotrexate

may actually increase the risk of cancers,

�/ several studies have shown that methotrexate

may increase the risk of various infections. In

particular, opportunistic infections have been

more frequently reported in rheumatoid arthri-tis patients treated with methotrexate than in

those receiving cyclosporine, azathioprine or

cyclophosphamide,

�/ even though the pathophysiological mechan-

isms of methotrexate-induced lymphomas are

unclear, an increased incidence of infections

with the pro-oncogenic EBV is supposed to play

a major role. Interestingly, the presence of EBVwas found in approximately half of methotrex-

ate-treated patients who developed lymphopro-

liferation (Kamel et al., 1999; Georgescu et al.,

1997), an incidence which is closer to that found

in AIDS or transplant patients than in the

general population,

�/ although rheumatoid arthritis has sometimes

been associated with an increased incidence ofhematological malignancies, in particular non-

Hodgkin’s lymphomas and multiple myelomas,

these cases have some dissimilarities with those

associated with methotrexate treatment. The

characteristics of lymphomas in rheumatoid

arthritis patients not treated with methotrexate

were more closely related to those found in the

general population. In addition, the majority oflymphomas that occurred in these patients were

not associated with EBV infection (Kamel et al.,

1999).

It is yet unknown whether methotrexate or the

underlying disease as an intrinsic factor contribut-

ing to an immunosuppressive state is the most

important factor in the occurrence of lymphopro-

liferation. In addition, associated co-morbidity,

genetic backgrounds, environmental factors, the

severity and the length of the disease, as well as the

concomitant use of other drugs should be con-

sidered as cofactors. To the opinion of several

investigators, the disease activity could be a key

factor (Baecklund et al., 1998). Indeed, several

studies have consistently found an increased

frequency of hematological malignancies in rheu-

matoid arthritis patients, in particular non-Hodg-

kin’s lymphomas and multiple myelomas, whereas

the risk of other cancers was not affected (Beau-

parlant et al., 1999; Kamel et al., 1999). The

increased risk was in the range of 3�/4-fold and

was independent of drug therapy. In addition,

studies in patients treated with methotrexate for

other diseases, such as psoriasis, have been unable

to demonstrate any abnormal frequency of malig-

nancies (Kanik and Cash, 1997).

Obviously, most patients treated with low-dose

methotrexate do not exhibit overt signs of im-

munosuppression, and methotrexate alone cannot

be considered a major risk factor of lymphopro-


liferation. The overall conclusion is that metho-trexate can accentuate the immune abnormalities

already present in a subset of patients with

rheumatoid arthritis, and that its immunosuppres-

sive effects are powerful enough only in a re-

stricted population or in the presence of EBV

infection. It is also still possible that insufficient

follow-up in these studies may account for the lack

of significant increase in the incidence of malig-nancies.

4. Conclusion

Recent clinical data give a more accurate

estimate of the risk of cancers associated with

immunosuppressive drug regimens in transplant

patients. Data on less potently immunosuppressive

drug regimens suggest that an increased risk ofcancers is also likely, but a more extensive and

long-term follow-up is still needed to reach a more

reliable estimate of the actual risk.

References

Arellano, F., 1997. Risk of cancer with cyclosporine in

psoriasis. Int. J. Dermatol. 36 (Suppl.), 15�/17.

Arellano, F., Krupp, P., 1993. Malignancies in rheumatoid

arthritis patients treated with cyclosporin A. Br. J. Rheu-

matol. 32 (Suppl. 1), 72�/75.

Baecklund, E., Ekbom, A., Sparen, P., et al., 1998. Disease

activity and risk of lymphoma in patients with rheumatoid

arthritis: nested case-control study. Br. Med. J. 317, 180�/

181.

Bailin, P.L., Tindall, J.P., Roenigk, H.H., Hogan, M.D., 1975.

Is methotrexate therapy for psoriasis carcinogenic? A

modified retrospective-prospective analysis. J. Am Med.

Assoc. 232, 359�/362.

Beauparlant, P., Papp, K., Haraoui, B., 1999. The incidence of

cancer associated with the treatment of rheumatoid arthri-

tis. Semin. Arthritis Rheum. 29, 148�/158.

Bertin, D., Haverty, T., Sanders, M., et al., 1996. Posttrans-

plant development of lymphoproliferative disorders and

other malignancies following orthoclone OKT3 therapy. In:

Lieberman, R., Mukherjee, A. (Eds.), Principles of Drug

Development in Transplantation and Autoimmunity, pp.

633�/641.

Bickston, S.J., Lichtenstein, G.R., Arseneau, K.O., et al., 1999.

The relationship between infliximab treatment and lym-

phoma in Crohn’s disease. Gastroenterology 117, 1433�/

1437.

Bologna, C., Picot, M.C., Jorgensen, C., et al., 1997. Study of

eight cases of cancer in 426 rheumatoid arthritis patients

treated with methotrexate. Ann. Rheum. Dis. 56, 97�/102.

Bouwes Bavinck, J.N., Hardie, D.R., Green, A., et al., 1996.

The risk of skin cancer in renal transplant recipients in

Quennsland, Australia. A follow-up study. Transplantation

61, 715�/721.

Cattani, P., Nanni, G., Graffeo, R., et al., 2000. Pretransplan-

tation human herpes virus 8 seropositivity as a risk factor

for Kaposi’sarcoma in kidney transplant recipients. Trans-

plant. Proc. 32, 526�/527.

Confavreux, C., Saddier, P., Grimaud, J., et al., 1996. A risk of

cancer from azathioprine therapy in multiple sclerosis: a

case control study. Neurology 46, 1607�/1612.

Connell, W., Kamm, M., Dickson, M., et al., 1994. Long-term

neoplasia risk after azathioprine treatment in inflammatory

bowel disease. Lancet 343, 1249�/1252.

Cox, K., Lawrence-Miyasaki, L., Garcia-Kennedy, R., et al.,

1995. An increased incidence of Epstein�/barr virus infec-

tion and lymphoproliferative disorder in young children on

FK506 after liver transplantation. Transplantation 59, 524�/

529.

Dantal, J., Hourmant, M., Cantarovich, D., et al., 1998. Effect

of long-term immunosuppression in kidney-graft recipients

on cancer incidence: randomised comparison of two cyclos-

porin regimens. Lancet 351, 623�/628.

Feutren, G., 1992. The optimal use of cyclosporin A in

autoimmune diseases. J. Autoimmun. 5 (Suppl. A), 183�/

195.

Gagnadoux, M.F., 1997. Le risque tumoral en transplantation

pediatrique. Ann. Pediatr. 44, 187�/192.

Gaya, S., Rees, A., Lechler, R., et al., 1995. Malignant disease

in patients with long-term renal transplantation. Transplan-

tation 59, 1705�/1709.

Georgescu, L., Quinn, G.C., Schwartzman, S., Paget, S.A.,

1997. Lymphoma in patients with rheumatoid arthritis:

association with the disease state or methotrexate treatment.

Semin. Arthritis Rheum. 26, 794�/804.

Gruber, S.A., Gillingham, K., Sothern, R.B., et al., 1994. De

novo cancer in cyclosporine-treated and non-cyclosporine-

treated adult primary renal allograft recipients. Clin.

Transplant. 8, 388�/395.

Hibbers, A.D., Trevillian, P.R., Wlodarzcyk, J.H., et al., 1999.

Cancer risk associated with ATG/OKT3 in renal transplan-

tation. Transplant. Proc. 31, 1271�/1272.

Hiesse, C., Rieu, P., Kriaa, F., et al., 1997. Malignancy after

renal transplantation: analysis of incidence and risk factors

in 1700 patients followed during a 25-year period. Trans-

plant. Proc. 29, 831�/834.

Hoffman, G.S., Kerr, G.S., Leavitt, R.Y., et al., 1992. Wegener

granulomatosis: an analysis of 158 patients. Ann. Intern.

Med. 116, 488�/498.

Hojo, M., Morimoto, T., Maluccio, M., et al., 1999. Cyclos-

porine induces cancer progression by a cell-autonomous

mechanism. Nature 397, 530�/534.


Hoshida, Y., Tsukuma, H., Yasunaga, Y., et al., 1997. Cancer

risk after renal transplantation in Japan. Int. J. Cancer 71,

517�/520.

Jensen, P., Hansen, S., Moller, B., et al., 1999. Skin cancer in

kidney and heart transplant recipients and different long-

term immunosuppressive therapy regimens. J. Am. Acad.

Dermatol. 40, 177�/186.

Jones, M., Symmons, D., Finn, J., Wolfe, F., 1996. Does

exposure to immunosuppressive therapy increase the 10 year

malignancy and mortality risks in rheumatoid arthritis? A

matched cohort study. Br. J. Rheumatol. 35, 738�/745.

Kamel, O.W., Holly, E.A., van de Rijn, M., et al., 1999. A

population based, case control study of non-Hodgkin’s

lymphoma in patients with rheumatoid arthritis. J. Rheu-

matol. 26, 1680�/1767.

Kanik, K.S., Cash, J.M., 1997. Does methotrexate increase the

risk of infection or malignancy. Rheum. Dis. Clin. North.

Am. 4, 955�/967.

Kehinde, E., Petermann, A., Morgan, J., et al., 1994. Triple

therapy and incidence of de novo cancer in renal transplant

recipients. Br. J. Surg. 81, 985�/986.

Korelitz, B.I., Mirsky, F.J., Fleisher, M.R., et al., 1999.

Malignant neoplasms subsequent to treatment of inflam-

matory bowel disease with 6-mercaptopurine. Am. J.

Gastroenterol. 94, 3248�/3253.

Landewe, R.B., van den Borne, B.E., Breedveld, F.C., Dijk-

mans, B.A., 1999. Does cyclosporin A cause cancer. Nat.

Med. 5, 714.

London, N., Farmery, S., Will, E., et al., 1995. Risk of

neoplasia in renal transplant patients. Lancet 346, 403�/406.

Martinez, O.N., Noiseux, C.R., Martin, J.A.C., et al., 2001.

Reactivation tuberculosis in a patient with anti-TNF alfa

treatment. Am. J. Gastroenterol. 96, 1665�/1666.

Tricontinental Mycophenolate Mofetil Renal Transplantation

Study Group, Mathew, T.H., 1998. A blinded, long-term,

randomized multicenter study of mycophenolate mofetil in

cadaveric renal transplantation. Results at three years.

Transplantation 65, 1450�/1454.

Mihalov, M.L., Gattuso, P., Abraham, K., et al., 1996.

Incidence of post-transplant malignancy among 674 solid-

organ-transplant recipients at a single center. Clin. Trans-

plant. 10, 248�/255.

Moder, K.G., Tefferi, A., Cohen, M.D., Menke, D.M., 1995.

Hematologic malignancies and the use of methotrexate in

rheumatoid arthritis: a retrospective study. Am. J. Med. 99,

276�/281.

Montagnino, G., Lorca, E., Tarantino, A., et al., 1996. Cancer

incidence in 854 kidney transplant recipients from a single

institution: comparison with normal population and with

patients under dialytic treatment. Clin. Transplant. 10, 461�/

469.

Morelli, J., Wilson, F.A., 2000. Does administration of

infliximab increase susceptibility to listeriosis. Am. J.

Gastroenterol. 95, 841�/842.

Newell, K.A., Alonso, E.M., Whitington, P.F., et al., 1996.

Posttransplant lymphoproliferative disease in pediatric liver

transplantation. Transplantation 62, 370�/375.

Niaudet, P., 1998. Postransplant lymphoproliferative disease

following renal transplantation: a multicenter retrospective

study of 41 cases observed between 1992 and 1996. French

Speaking Transplantation Workshop. Transplant. Proc. 30,

2816�/2817.

Ong, C.S., Keogh, A.M., Kossard, S., et al., 1999. Skin cancer

in Australian heart transplant recipients. J. Am. Acad.

Dermatol. 40, 27�/34.

Opelz, G., Henderson, R., 1993. Incidence of non-Hodgkin

lymphoma in kidney and heart transplant recipients. Lancet

342, 1514�/1516.

Penn, I., 1993. Tumors after renal and cardiac transplantation.

Hematol. Oncol. Clin. North Am. 7, 431�/445.

Penn, I., 1996. Cancers in cyclosporine-treated versus

azathioprine-treated patients. Transplant. Proc. 28, 876�/

878.

Penn, I., 2000. Post-transplant malignancy. The role of

immunosuppression. Drug Safety 23, 101�/113.

Petterson, T., Pukkala, E., Teppo, L., Friman, C., 1992.

Increased risk of cancer in patients with systemic lupus

erythematosus. Ann. Rheum. Dis. 51, 437�/439.

Radis, C., Kwoh, C., Morgan, M., et al., 1993. Risk of

malignancy in cyclophosphamide treated patients with

rheumatoid arthritis: a 20-year follow-up study. Arthritis

Rheum. 36 (Suppl), R19.

Salloum, E., Cooper, D.L., Howe, G.H., et al., 1996. Sponta-

neous regression of lymphoproliferative disorders in pa-

tients treated with methotrexate for rheumatoid arthritis

and other rheumatic disease. J. Clin. Oncol. 14, 1943�/1949.

Schaibe, T.F., 2000. Long term safety of infliximab. Can. J.

Gastroenterol. 14 (Suppl. C), 29�/32.

Sgro, C., 1995. Side-effects of a monoclonal antibody, mur-

omonab CD3/orthoclone OKT3. Toxicology 105, 23�/29.

Sheil, A., Disney, A., Mathew, T., et al., 1991. Cancer

development in cadaveric donor renal allograft recipients

treated with azathioprine (AZA) or cyclosporine (CyA) or

AZA/CyA. Transplant. Proc. 23, 1111�/1112.

Silman, A., Petrie, J., Hazleman, B., Evans, S., 1988. Lympho-

proliferative cancer and other malignancy in patients with

rheumatoid arthritis treated with azathioprine: a 20 year

follow up study. Ann. Rheum. Dis. 47, 988�/992.

Sokal, E.M., Antunes, H., Beguin, C., et al., 1997. Early signs

and risk factors for the increased incidence of epstein-barr

virus-related posttransplant lymphoproliferative diseases in

pediatric liver transplant recipients treated with tacrolimus.


Stewart, T., Tsai, S.C.J., Grayson, H., et al., 1995. Incidence of

de-novo breast cancer in women chronically immunosup-

pressed after organ transplantation. Lancet 346, 796�/798.

Taylor, A., Shuster, S., 1992. Skin cancer after renal transplan-

tation: the causal role of azathioprine. Acta Dermatol.

Venereol. 72, 115�/119.

Van Den Borne, B.E.E.M., Landewe, R.B.M., Houkes, I., et

al., 1998. No increased risk of malignancies and mortality in

cyclosporin A-treated patients with rheumatoid arthritis.

Arthritis Rheum. 41, 1930�/1937.


Warris, A., Bjorneklett, A., Gastaud, P., 2001. Invasive

pulmonary aspergillosis associated with infliximab therapy.

New Engl. J. Med. 344, 1099�/1100.

Wiesner, R.H., 1998. A long term comparison of tacrolimus

(FK506) versus cyclosporin in liver transplantation: a report

of the United States FK506 Study Group. Transplantation

66, 493�/499.

Younes, B.S., McDiarmid, S.V., Martin, M.G., et al., 2000. The

effect of immunosuppression on posttransplant lymphopro-

liferative disease in pediatric liver transplant patients.



immunosuppressive drugs and cancer

Documents