Journal of Cancer Therapy, 2013, 4, 460-465 Published Online March 2013 (
Biological Therapy and Risk of Malignancies: A Literature
Gilda Sandri1, Valentina Cestelli2, Maria Teresa Mascia1
1Department of Diagnostic, Clinical and Public Health Medicine University of Modena and Reggio Emilia, Modena, Italy; 2Rheu-
matology Unit, Department of Medical and Surgical Sciences for Children and Adults, University of Modena and Reggio Emilia,
Modena, Italy.
Received January 23rd, 2013; revised February 26th, 2013; accepted March 8th, 2013
Data from literature show that the overall risk of cancer does not as a result from treatment with these drugs. The only
cancer for which various authors have reported an increased risk, in some cases, are skin cancers, different from
melanoma and melanoma. Recent results of large observational studies and meta-analyzes indicate the absence of an
increased risk of lymphoma related to therapy with anti-TNF-α. It has been reported, by some authors, that there is a
possible increased risk of lung cancer, especially in patients with chronic obstructive pulmonary disease. There is
limited information in literature abou t the effects of biolog ics in patients with a h istory of can cer. Mo st o f the gu id elines
indicate that treatment with biologics can be considered with caution and only in patients free of cancer since at least 5
years. Some studies report a lower oncological risk with etanercept compared to monoclonal antibodies, especially in
the case of lymphoma. However, this data has not been confirmed in other studies, and has been associated with a
limited period of time after starting therapy. Information about the latest biological therapies is still poor. Therefore,
there is not sufficient evidence for a preferential use of certain drugs rather than others.
Keywords: Anti-TNF-α; Skin Cancer; Lymphoma; Rheumatoid Arthritis
1. Introduction
In chronic inflammatory diseases that require long-term
treatment with immunosuppressive therapies, there has
always been concern that such treatments could increase
the risk of developing cancer.
Biological agents acting through complex mechanisms
of immunomodulation and some cytokines inhibited by
these treatments (such as TNF-α) exert important biolo-
gical effects, although not fully defined, which can coun-
teract the processes of carcinogenesis and tumor progres-
Even if overall data so far issued on cancer risk in pa-
tients with biological ag ents are encouraging, it should be
noted that the assessment of such risk is comp licat e d b y a
number of factors including the following: 1) Rheuma-
toid Arthritis (RA) gives rise to a differential risk for va-
rious types of tumors (increased or decreased, in some
cases) compared to the general population; 2) develop-
ment period of a neoplasm is often long and it can exceed
the period of observation of many studies; 3) tumors are
relatively rare adverse events and the analysis of their
impact requires data of very large populations, in order to
achieve a sufficient statistical power; 4) in clinical trials
enrollment of patients with a history of cancer or high
risk cancer is usually excluded; 5) in clinical practice
there may be a bias in the selection of patients for ther-
apy with biological agents. These issues must be consid-
ered in interpreting data provided by clinical and obser-
vational trials. So even if there are no specific contrain-
dications for the use of biological drugs in relation to the
risk of cancer, guidelines and consensus statements agree
to maintain a high lev el of vigilance for the po ssible risk
of developing cancer in patients receiving biologic thera-
2. RA and Malignancies
Several epidemiological studies show that patients with
RA, if compared with the general population, have an in-
creased risk to develop certain type of malignancies, es-
pecially lymphoma and cancers of the hematopoietic
system, lung and skin cancer other than melanoma, while
the risk for colorectal, breast and endometrial cancers
(lower risk by use of non-steroidal anti inflammatory
drugs or cyclo-oxygenase-2) is reduced [1-7]. The rela-
tionship between RA and lymphoma has been investi-
gated with particular attention. A meta-analysis of stud-
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Biological Therapy and Risk of Malignancies: A Literature Review 461
ies investigating the risk of overall and four specific ma-
lignancies in patients with rheumatoid arth ritis compared
with the general population showed a doubled risk of
lymphoma with a standardized incidence ratio (SIR) of
2.08 (IC 95% 1.80 - 2.39) [8]. The risk was highest for
Hodgkin’s lymphoma (SIR 3.29 [95% CI 2.56 - 4.22])
compared to a non-Hodgkin’s lymphoma (SIR 1.95 [95%
CI 1.70 - 2.24]). The risk of developing lung cancer was
also increased, SIR 1.63 (95% CI 1.43 - 1.87) and the
risk of developing colorectal or breast cancer was slightly
reduced in patients with RA, respectively SIR 0.77 (95%
CI 0.65 - 0.90) and SIR 0.84 (95% CI 0.79 - 0.90) [8].
3. Anti-TNF-α and Risk of Malignancies
The relationship between anti-TNF-α and cancers is not
fully understood and it is likely that this cytokine plays
different roles in different stages of tumors and neoplas-
tic processes. Therefore the inhibition of TNF-α may re-
sult in various effects on the oncological risk depending
on the type of tumor and conditions of the patient. As far
as the overall risk of developing cancer (regardless of the
type of cancer) is concerned, almost all studies indicate
that the risk is not increased in patients with RA treated
with anti-TNF-α compared to the general population or
control groups that are not exposed to such therapy. An
overall increase in the incidence of cancers related to bio-
logics in large observational studies has not been de-
tected, including those carried out on the national Regis-
ters (NDB for Rheumatic Diseases for the US, Swedish
Biologics Register for Sweden, BSRBR for the United
Kingdom, BIOBADASER for Spain, LOHREN for Italy
and RABBIT for Germany) and the meta-analyses of
clinical trials [4,9-17]. Just in another meta-analysis con-
cerning a clinical trial of infliximab and adalimumab it
was found that there was a significant increase in the
overall risk of developing cancer in patients treated with
biological agents compared to those who were not (OR
3.3 [95% CI 1.2 to 9.1]) [18]. The increased risk was
most evident in patients treated with higher doses. It is
not clear what the main reason for this discrepancy of
data in relation to other evidence of the literature is due
to; some authors attribute it to methodological problems
(such as the possible lack of identification of cases for
the highest percentage of drop-outs in groups of compa-
rison) [19]. A meta-analysis of etanercept, made by the
same group of researchers using methods similar to the
previous, showed a smaller increase in the risk of cancer
with etanercept, but this was not significant (HR 1.84
[95% CI 0.79 to 4.28]) [20]. A recent meta-analysis of
data presented in studies of registry and prospective ob-
servational studies confirm that the anti-TNF-α does not
appear to increase the overall risk of developing cancer,
with an estimated cumulative risk calculated at 0.95 (9 5%
CI 0.85 - 1.05) [21]. An observational study of Askling
and coll. conducted on a Swedish database has analyzed
the risk of cancer development in time after initiation of
anti-TNF-α therapy and the duration of such therapy
without encountering an increase of the oncological risk
linked to these two variables [9]. Another study has as-
sessed whether biological agents could influence the
prognosis of tumors wh ich have arisen in the course or at
the end of therapy by examining any changes in clinical
presentation and the outcome of these malignancies [22].
No significant differences were found in the clinical pre-
sentation of cancers or in the survival among patients
exposed to anti-TNF-α compared with those not treated
with the same therapies.
3.1. Lymphatic and Hematopoietic Tumors
We cannot define whether anti-TNF-α may increase the
risk of lymphoma, also due to the difficulty in correctly
estimating the risk in patients with RA who already have
an increased risk of lymphoma compared to the general
population. However, the main observational studies have
not shown an increased incidence of malignant lym-
phoma or cancers of the hematopo ietic system in patients
treated with anti-TNF-α compared with cohorts of pa-
tients with RA or other patients treated with traditional
drugs (DMARDs) [2,4,15,23,24]. Studies conducted on
the records of the US NDB for Rheumatic Diseases and
on the Swedish Biologics Register do not show an in-
creased risk. In the study co nducted by the US on 19,591
patients with RA (55% were treated with anti-TNF-α)
between 1998 and 2005, the odds ratio (OR) for lym-
phoma in patients treated vs those not treated with bio-
logical agents corresponds to 1.0 (95% CI 0.6 to 1.8) [23].
Askling and coll. have reported 500 cases of tumors of
the hematopoietic system in three Swedish cohorts of
patients with RA which were an alyzed: a cohort study of
prevalence, a cohort of incidence and a cohort treated
with anti-TNF-α (n = 4160, 1999-2003) [2]. Patients af-
fected by RA, compared to the general population,
showed an increased risk in the development of lym-
phoma and leukemia. The relative risk (RR) of lym-
phoma in patients receiving biological therapy compared
with the cohort prevalence was 1.1 (95% CI 0.6 - 2.1). In
a subsequent study by the same group which extended
the follow-up to 2006 by analyzing data on 67,743 pa-
tients with RA, 26 cases of malignant lymphoma among
6604 patients treated with anti-TNF-α were observed vs
336 cases compared to the population not treated with
these drugs, resulting in an RR of 1.35 (95% CI 0.82 -
2.11) [24]. The observational study of Geborek and coll.
detected an increased risk of lymphoma related to anti-
TNF-α therapy (RR 4.9 [IC 95% 0.9 - 26.2]), but such
study was conducted on a limited number of cases and
there is the possibility of methodological issues that may
have influenced these results [14]. In the prospective
Copyright © 2013 SciRes. JCT
Biological Therapy and Risk of Malignancies: A Literature Review
study on the RATIO register it is not possible to quantify
the potential risk of lymphoma associated with the use of
anti-TNF-α (this registry reports all cases of lymphoma
occurred in French population in patients receiving these
therapies, regardless of their disease, between 2004 and
2006, without a control cohort consisting of patients not
treated with anti-TNF-α) [25]. Among 38 cases of lym-
phoma reported, 27 were patients with RA, with a SIR of
treated patients compared with the general population of
2.3 (95% CI 1.6 - 3.3), which reflects an increased risk of
lymphoma in RA related disease activity. Therefore, data
of major studies give evidence of the absence of an in-
creased risk of lymphoma or cancer of the hematopoietic
system related to anti-TNF-α therapy.
3.2. Solid Tumors
Treatment with anti-TNF-α does not imply an increase in
the overall risk of developing solid tumors [3,4,15]. H ow-
ever, several observational studies and meta-analyses
show an increased incidence of skin cancers other than
melanoma (NMSC) and some cases of melanoma in pa-
tients treated with biological drugs compared to control
groups [3,4,16,21,26]. In particular, the study of Wolfe
and coll. on the US NDB for Rheumatic Diseases has
found an OR of 1.5 (95% CI 1.2 - 1.8) for NMSC and an
OR of 2.3 (95% CI 0.9 - 5.4) for melanoma in patients
treated with anti-TNF-α therapy vs those not exposed to
such therapy [4]. The study conducted on the Swedish
registers for NMSC shows a SIR of 3.6 (95% CI 1.50 -
6.5) in cohorts treated with biologics compared to 1.66
(95% CI 1.50 - 1.84) in the prevalence cohort [3]. A re-
cent meta-analysis of clinical trials of infliximab, ada-
limumab and etanercept shows an increased risk of deve-
loping NMSC related to therapy with an ti-TNF-α [26,16].
However not all studies have found an increased risk for
skin cancer in patien ts exposed to anti-TNF-α, especially
if they have chronic bronchitis [11,27].
4. Are There Different Effects on the Risk
Cancer among Anti-TNF-α?
Some data indicate different effects on the risk of cancer
among infliximab, adalimumab and etanercept, as only a
few studies have individually analyzed these three drugs.
In the study of the French RATIO register which evalu-
ated the risk of lymphoma in patients treated with anti-
TNF-α vs the general population, the risk of lymphoma
with etanercept was lower with a SIR of 0.9 (CI 95% 0.4
- 1.8), compared with the risk of lymphoma with ada-
limumab and infliximab [25]. Likely TNF-α inhibitors
(similarly to methotrexate) exert a double effect on the
risk of lymphoma: a beneficial effect which reduces the
disease’s activity and a detrimental one which depresses
the immunosurveillance by the lymphocytes T; in the case
of etanercept the prevailing effect would appear favor-
able. One hypothesis to explain the lower incidence of
lymphoma observed with etanercept (a soluble fusion
protein) compared to monoclonal antibodies, is probably
due to the higher affinity and stability of binding to the
TNF-α membrane with respect to infliximab and adali-
mumab, which would lead to stronger effects on the
function of immune surveillance by T suppressor lym-
phocyte compared to etanercept [35]. Also in the meta-
analysis by Bongartz and coll., the overall cancer risk
found in studies of adalimumab and infliximab was su-
perior to that observed in studies of etanercept [18,20]. In
a study of Swedish registers, differences were observed
between the three anti-TNF-α on the overall risk of de-
veloping cancer but only during the first year after the
start of biological therapy [9]. It is not clear why differ-
ences between drugs are found only at the beginning of
treatment; this could be determined by actual differences
in the biological activity but also by other external fac-
tors that are difficult to control in an observational study.
There are no significant differences identified between
anti-TNF-α therapies on the risk of malignancy in the va-
rious locations in the studies on the US NDB for Rheu-
matic Diseases [4,23]. Therefore the question whether
etanercept, infliximab, adalimumab are more or less as-
sociated with clinically significant differences in the risk
of developing cancer remains controversial.
5. Effects of Treatment with Anti-TNF-α
Therapy in Patients with a History of
There is limited information concerning the risk of can-
cer related to therapy with biologic drugs in RA patients
previously affected by cancer as these patients are gene-
rally excluded from clinical trials. Moreover, guidelines
often advise particular caution in the use of these the-
rapies in patients with a history of malignancy. An ob-
servational study evaluated the incidence of tumors in
239 patients enrolled in the British register BSRBR in
which a malignancy had been reported (except carcinoma
in situ and NMSC) [10]; 177 patients had received ther-
apy with anti-TNF-α and 117 were treated with DM-
ARDs. During a follow-up of 3 years the mean incidence
of cancer was 25.3 events/1000 patient-years in the co-
hort treated with biologics vs 38.3/1000 patient-years in
the comparison group, with an incidence rate ratio (IRR)
of 0.58 (95% CI 0.23 - 1.43) for patients treated with
anti-TNF-α vs DMARDs. A sensitivity analysis made
with the exclusion of time from the first tumor did not
significantly alter this data; such data also indicate that
patients with a previous diagnosis of melanoma may
have a higher risk of developing a new cancer. Accord-
ing to the results of this study the risk of malignancy in
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Biological Therapy and Risk of Malignancies: A Literature Review 463
patients with a tumor does not seem to be increased by
previous therapy with biological drugs. However, it is
important to consider a possible selection bias in the
choice of treatment to be applied to patients, which could
have influenced results of this investigation. Even in the
study of the German register RABBIT, the risk of recur-
rence of earlier tumors in 122 patients, of whom 58 re-
ceived anti-TNF-α, 9 anakinra and 55 DMARDs was
analyzed [13]; fifteen occurrences of cancer were re-
ported in 14 patients and the IRR between anti-TNF-α
and DMARDs was 1.4 (p = ns). Also in this study the
limited series does not allow definitive conclusion s about
the risk of cancer linked to biological therapies in pa-
tients with a previous malignancy.
6. Cancer Risk with Other Biologics Drugs
Data concerning biological drugs with a different mecha-
nism of action than that of anti-TNF-α (as well as new
generation anti-TNF-α) for an assessment of the risk of
cancer are still limited. The information derives mainly
from clinical trials and there are still no data about safety
from large observational studies. There was no reported
increased risk of solid tumors or lymphoma with ritu-
ximab [28]. As far as the risk of developing lymphoma in
patients with rheu matoid arthritis is concerned , the studies
of Slimani [29] and van Vollenhoven’s [30] would sug-
gest a protective role of rituximab. In the clinical de-
velopment program of abatacept (which includes 4134
patients treated with this drug in clinical trials and 41,529
in observational studies), 51 tumors were reported and
the overall incidence of cancer (excluding NMSC) and of
four types of tumor evaluated (breast, colorectal, lung
and lymphoma) in patients treated with abatacept was
generally similar to that found in populatio ns affected by
RA [31]. Similarly, there were no problems linked to the
possibility of an increased risk of tumors in studies on
tocilizumab. An interim post marketing surveillance an a-
lysis of 3881 patients treated with tocilizu mab showed an
incidence rate of malignancy of 18 events year/100 pa-
tients [32].
7. Discussion
It is difficult define wheth er anti-TNF-α may increase the
risk of lymphoma in RA because patients with RA al-
ready have an increased risk of lymphoma compared to
the general population. However, the main observational
studies have not shown an increased incidence of malig-
nant lymphoma probably because the main risk factor for
lymphoma seems to lie in the severity of the disease, as
demonstrated in a case-control study conducted on the
Swedish Inpatient Register during 1964-1995 that showed
a direct correlation between disease activity and the risk
of lymphoma, with an increase of the latter in the sub-
group of patients with the highest activity of disease [33].
Therefore chronic inflammation plays a key role in the
risk of lymphoma. In order to explain this effect it was
assumed that in RA persistent immune stimulation can
lead to a clonal selection in B lymphocytes inducing ma-
lignant transformation in CD5+ cells and reduce the num-
ber and functional activity of T suppressor lymphocytes
(like those directed against the oncogenic virus, Epstein-
Barr) [8]. Another study of the Swedish group investi-
gated the possibility of a common genetic susceptibility
for the development of lymphoma and RA, evaluating
whether the increased risk of lymphoma was detectable
even before diagnosis of RA [34]. It was observed that
the risk increased only in the ten years following the di-
agnosis of RA, confirming the importance of the disease
as a determining factor for the increased risk of lym-
phoma. It was not always possible to assess the actual
role of therapy as the risk of cancer related to RA was
calculated on populations treate d with different th erapies.
Unlike some immunosuppressive agents, such as azathio-
prine for which an association with lymphoma has been
highlighted, therapy with DMARDs seems not to be as-
sociated with an increased risk of lymphoma, even though
cases of EBV-positive lymphoma were reported in pa-
tients treated with methotrexate, which regressed after
discontinuation of the drug [33-35]. The potential effect
of induction of EBV-related lymphomas by methotrexate
is probably outset by the beneficial effect of this drug on
the reduction of disease activity with a favorable result,
as potential effect of induction of anti-TNF-α related
lymphomas is outset by efficacy of these drugs on sever-
ity of the disease and chronic inflammation [35].
8. Conclusion
Patients starting anti-TNF-α therapy should be informed
that there is no conclusive evidence for an increase in
risk of developing solid tumors or lymphomas above that
which would be expected for RA population, but ongoing
vigilance is required. Patients should be investigated for
potential malignancy if clinically suspected, and anti-
TNF-α treatment should be stopped if malignancy is con-
firmed. Caution should be exercised in the use of these
therapies in patients with previous malignancy. Patients
should be advised that the treatment with anti-TNF-α
may increase the risk of non-melanoma skin cancer and it
is necessary preventative skin care and continuous skin
surveillance. There are no significant differences identi-
fied between anti-TNF-α therapies on the risk of malig-
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