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Tumor necrosis factor-alpha inhibitors: Risk of malignancy

Tumor necrosis factor-alpha inhibitors: Risk of malignancy
Literature review current through: Jan 2024.
This topic last updated: Jan 03, 2024.

INTRODUCTION — Inhibitors of tumor necrosis factor (TNF)-alpha are important therapeutic agents used for a number of inflammatory conditions, including rheumatoid arthritis (RA), spondyloarthritis (SpA), inflammatory bowel disease (IBD), and psoriasis. TNF-alpha inhibitors offer a targeted strategy that contrasts with the nonspecific immunosuppressive agents traditionally used to treat most inflammatory diseases.

Despite their benefits, multiple potential adverse effects of TNF-alpha inhibition have been reported through both clinical trials and postmarketing surveillance. These include:

Malignancy

Injection site reactions

Infusion reactions

Demyelinating disease

Heart failure

Induction of autoimmunity

Infections

Abnormal liver function tests

Leukopenia

The risk of malignancy associated with targeted TNF-alpha inhibitor use will be reviewed here. Other adverse effects are discussed separately:

(See "Tumor necrosis factor-alpha inhibitors: An overview of adverse effects".)

(See "Tumor necrosis factor-alpha inhibitors: Induction of antibodies, autoantibodies, and autoimmune diseases".)

(See "Tumor necrosis factor-alpha inhibitors: Bacterial, viral, and fungal infections".)

(See "Risk of mycobacterial infection associated with biologic agents and JAK inhibitors".)

GENERAL ISSUES — Tumor necrosis factor (TNF)-alpha inhibitors are associated with potentially serious adverse effects. However, these risks must be interpreted in the context of the potential benefits of these medications, adverse effects of the disease itself, and adverse effects of alternative therapies. The adverse effects of conventional treatments and other targeted biologic agents, including the risk of malignancy induction, are also significant in many cases. Thus, the decision to use a TNF-alpha inhibitor must be an individual one, based upon the specific clinical features and the unique risk profile of a given patient.

Inhibitors of TNF-alpha — Five inhibitors of TNF-alpha are widely available for the treatment of rheumatoid arthritis (RA), inflammatory bowel disease (IBD), psoriasis, and several other inflammatory disorders (table 1). Biosimilar agents are becoming increasingly available in many countries and appear to have highly similar characteristics to their original versions. (See "Overview of biologic agents in the rheumatic diseases", section on 'Biosimilars for biologic agents'.)

TNF-alpha biology — TNF-alpha, originally known as cachexin or cachectin, was recognized in 1975 when it was associated with tumor lysis in a variety of in vitro and mouse models (hence the name "tumor necrosis factor") [1]. The biology of TNF-alpha is discussed in detail separately. (See "Tumor necrosis factor-alpha inhibitors: An overview of adverse effects", section on 'TNF-alpha biology'.)

The activity of TNF-alpha against tumors in laboratory models and, potentially, in humans raised the possibility that TNF-alpha inhibition might potentiate the clinical risk of malignancy. Experimental evidence of an anti-tumor effect for TNF-alpha led to the local administration of this cytokine for the treatment of some malignancies, usually in combination with other chemotherapeutic agents. (See "Cutaneous melanoma: In-transit metastases".)

Measures of risk

Standardized incidence ratios — In many formal analyses of the risk of malignancy posed by TNF-alpha inhibitor use, standardized incidence ratios (SIRs) have been used to assess the degree of risk among patients receiving TNF inhibitors compared with the baseline risk of malignancy in the general population. While providing an indication of malignancy risk associated with treatments, they cannot differentiate between the risk associated with treatment and the risk associated with the diagnosis.

SIR is defined in the following manner:

SIR = (Observed cases of malignancy/Expected cases of malignancy)

To estimate the number of expected cases of malignancy within a population over a specific period of time, investigators often refer to one of several large registries. In the United States, data can be obtained from the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) database, a population-based registry that includes all invasive cancers plus cancer of the urinary bladder and breast carcinoma in situ [2]. In many European countries, including Sweden, Denmark, and the United Kingdom, there are national cancer registries with mandatory reporting. These national registries have been used as a source of background population rates for comparison with patients treated with TNF inhibitors.

Relative risk — The relative risk (RR) presents the risk in patients exposed to a treatment compared with the risk in patients not exposed to a treatment, or exposed to an alternative treatment. The advantage of calculating RR is that it is more specific for analysis of treatment-associated risks compared with SIRs, which use data from the general population without the disease of interest.

There are many ways to calculate RR depending upon the nature of the data available (eg, a comparison of incident rates [incident rate ratio], a comparison on time to an event [hazard ratio]). For the purpose of this review, all RRs will be labelled "relative risk," regardless of the statistics used to calculate risk.

CHALLENGES IN ESTABLISHING MALIGNANCY RISK — Proof of a link between tumor necrosis factor (TNF)-alpha inhibitor use and the development of cancer is difficult for several reasons. These include:

Risk from underlying disease – Patients treated with TNF-alpha inhibitors may have an inherent predisposition to cancer based upon their underlying disease. As examples, patients with rheumatoid arthritis (RA) may have up to a 10 to 15 percent overall increase in the risk of cancer (relative risk [RR] 1.10 to 1.15) compared with the general population, and patients with ulcerative colitis have an increased risk of colon cancer [3-6]. The risk of malignancy is site-specific in RA, in which it appears to be increased for lymphoma and, perhaps, for lung cancer, but in which it appears to be potentially decreased for colorectal and breast cancer [7]. It can be difficult to distinguish the additional risk conferred by TNF-alpha inhibitors from the baseline risk, although many of the later studies have included analytic approaches that can account for this baseline risk.

Risk from other medications – Patients with immune-mediated disorders often receive other medications concomitantly with TNF-alpha inhibitors that increase the risk of cancer [8-10]. As an example, methotrexate (MTX), commonly used with TNF-alpha inhibitors in the treatment of RA, is associated with an elevated risk of lymphoma in some but not all studies [8,11,12]. Similar considerations apply for cyclophosphamide, chlorambucil, azathioprine, and other conventional immunosuppressive medications. (See "General toxicity of cyclophosphamide in rheumatic diseases" and "Major side effects of low-dose methotrexate", section on 'Common toxicities'.)

Exclusion of cancer patients from clinical trials – Patients with prior malignancy have been excluded from clinical trials with TNF inhibitors because of concern over a potentially increased risk of recurrent or new malignancy in such patients. Thus, data regarding cancer risk in this population of particular interest are limited. (See 'Cancer risk in patients with prior malignancy' below.)

Rarity of cancer as an outcome – Relative rarity of the outcome means that many studies may be too small individually to rule in or rule out, with certainty, an increased risk of malignancy; combined analysis across many studies may be required.

Fewer studies on certolizumab pegol and golimumab – The majority of studies have focused on etanercept, adalimumab, and infliximab, and studies of the newer TNF inhibitors, including certolizumab pegol and golimumab, are limited. It is not known whether the association between these newer TNF inhibitors and malignancy will be the same as that observed for the original three therapies, although it is likely that the observed risks will be similar.

STUDIES OF OVERALL CANCER RISK — In general, there is a preponderance of evidence that tumor necrosis factor (TNF) inhibitors do not increase the risk of most solid tumors, except for possibly some skin cancers. (See 'Evidence of increased risk' below and 'Evidence of no increased long-term risk' below.)

Rigorous clinical trials have been performed for TNF-alpha inhibitors in contrast to most nonbiologic disease-modifying antirheumatic drugs (DMARDs), facilitating detection of events that occur during the trial period. Long-term risks of cancer, however, cannot be determined from short-term randomized trials.

Although some meta-analyses of clinical trial data have found increased cancer risk with TNF inhibitor use, observational data, particularly from registries, have generally been unable to confirm these findings [3,12-18]. This discrepancy may result, in part, from the more complete reporting of malignancies in clinical trials than in the context of routine practice, in which, in the absence of a cancer registry, reporting may depend upon voluntary postmarketing surveillance. Evaluation of risk using observational studies is also highly dependent upon how cancers are identified and upon what comparator is chosen.

Despite most evidence suggesting no increase in malignancy risk overall, these analyses have assumed that the effect of TNF inhibitor therapies would be the same across all anatomical sites and malignancy subtypes. Instead, risks may be different for certain individual malignancies. (See 'Lymphoma risk' below and 'Solid malignancy risk' below and 'Skin cancer risk' below.)

Evidence of no increased long-term risk — Increasingly, evidence indicates that overall cancer risk does not increase over time in patients who use TNF inhibitors for rheumatoid arthritis (RA) rather than other therapies. Additional evidence suggests that these agents do not increase cancer risk in patients with inflammatory bowel disease (IBD) and other conditions. Several reports, including data for patients with RA, psoriasis and psoriatic arthritis, ankylosing spondylitis, Crohn disease, ulcerative colitis, and other conditions, have shown that risk may only be elevated for skin cancer but not for other cancers overall compared with patients receiving other DMARDs [15-18] (see 'Skin cancer risk' below). As examples of the evidence in RA and IBD:

Rheumatoid arthritis

A meta-analysis of six randomized trials involving 3419 patients with early RA, in which DMARD-naïve patients were treated with either a TNF inhibitor (infliximab, adalimumab, and etanercept) or with methotrexate (MTX), found no significant difference in the rate of malignancies between the two groups [18].

The following observations were made using population-based registry data from Sweden [3]:

-There was no overall elevation of cancer risk during 25,693 person-years of follow-up in 6366 patients newly started on TNF inhibitors compared with the biologic-naïve RA cohort of 61,160 patients. Similarly, there was no elevation in risk compared with patients who were starting MTX or nonbiologic DMARD combinations.

-Neither the incidence nor the relative risk (RR) of cancer increased with time after starting TNF inhibitor therapy or with cumulative duration of treatment.

-There were statistically significant differences in cancer risks between adalimumab, etanercept, and infliximab during the first year following the start of treatment, but these differences subsequently disappeared.

Similar observations were made using the Danish population-based registry, the Database for Biological Therapies in Rheumatology (DANBIO), which found no overall increase in cancer risk when comparing 3347 TNF inhibitor-treated RA patients with 3812 RA patients who had not been treated with a TNF inhibitor [19].

Further evidence that neither TNF inhibitors nor other biologic agents pose a significantly increased overall risk of malignancy comes from a 2012 meta-analysis of 63 randomized trials involving 29,423 patients, which compared patients treated for RA with TNF inhibitors or other biologic agents (either alone or in combination with nonbiologic DMARDs) with controls [20]. The study found no increase in the rate of malignancy in trials of at least 24 weeks' duration in patients receiving biologic agents overall or with any individual biologic agent, including TNF inhibitors, abatacept, rituximab, tocilizumab, or anakinra, except in one subset. There was a small increased risk at 52 weeks for patients receiving a TNF inhibitor plus MTX (odds ratio [OR] 2.1, 95% CI 1.1-3.9; absolute risk of 1.1 versus 0.5 percent), but differences among groups were not statistically significant with other analyses, other time points, or TNF inhibitor monotherapy. Thus, the importance of this finding is uncertain. A total of only 211 malignancies were observed during the 63 trials.

Inflammatory bowel disease – Several studies using different approaches have found that TNF inhibitor therapy in patients with IBD is not associated with increased cancer risk. As examples:

A study using a nationwide registry in Denmark, involving 56,146 patients with IBD, of whom 4553 were exposed to TNF inhibitor therapy, found that patients exposed to TNF inhibitors, with median follow-up of 3.7 years, did not experience an increased risk for malignancy compared with unexposed patients after full adjustment for multiple potential confounders [21]. Cancers occurred in a total of 81 patients (1.8 percent) in the exposed group and 3465 (6.7 percent) of the unexposed group. There was no evidence of a statistically significantly increased risk with time or based upon the accumulated dose during the period of exposure, although risk with a greater duration of exposure or follow-up could not be excluded.

Other analyses in patients with IBD, including both observational data and meta-analyses of data from randomized trials, have been limited by follow-up for no more than about a year or by a very small number of total cases of cancer among patients exposed to TNF inhibitors; however, these analyses have also failed to demonstrate any increased malignancy risk in this patient population [22-24].

Evidence of increased risk — Although the majority of evidence available has suggested no association between TNF inhibitor therapy and overall cancer risk, there has been interest in whether there may be an increased risk of lymphoma and some skin cancers in patients with RA. Reports of a potential increase in some solid tumors and lymphoma in juvenile idiopathic arthritis (JIA) and IBD emphasizes that there may be differences between diseases.

A US Food and Drug Administration (FDA) analysis identified 48 cases over a 10-year period (1998 to 2008) of malignancies in children and adolescents who received TNF-alpha inhibitor therapy for JIA or IBD [25,26]. Approximately one-half of these cases were Hodgkin and non-Hodgkin lymphomas, including 10 cases of hepatosplenic T-cell lymphoma in patients with IBD who had also received thiopurines (6-mercaptopurine or azathioprine); others included leukemia, melanoma, and solid organ cancers. Warnings about the use of TNF inhibitors in children and adolescents were issued based upon this analysis [25]; however, a 2018 analysis of a United States administrative database of 15,598 children treated with TNF inhibitor therapy and 73,839 children never treated with TNF inhibitor therapy (with JIA, IBD, or psoriasis) did not find a statistically significant increased risk of cancer (hazard ratio [HR] 1.58, 95% CI 0.88-2.85) associated with TNF inhibitor exposure [27]. When limited to children with IBD, the study did find a higher standardized incidence ratio (SIR) of malignancy compared with the general population among children who received TNF inhibitor in combination with a thiopurine compared with children who only received a TNF inhibitor, suggesting this may be a group of patients at higher risk. However, the absolute risk of cancer across all groups was extremely low (TNF inhibitor with thiopurine: three malignancies in 2977 person-years of follow-up; TNF inhibitor without thiopurine: four malignancies in 8913 person-years of follow-up) and adjustments for disease severity were not included in this part of the analysis, which could also influence risk. Nonetheless, clinicians should be aware of this higher risk in this population, regardless of the cause.

An early meta-analysis of the potential relationship between adalimumab or infliximab use and the development of malignancies, which included data from nine clinical trials involving 3493 patients with RA who received TNF inhibitors and 1512 patients who received placebo, found the following [13]:

The pooled OR for all malignancies among patients treated with TNF inhibitors was 3.3 (95% CI 1.2-9.1).

Malignancies were significantly more common in patients treated with higher doses compared with patients who received lower doses of the anti-TNF antibodies.

Among the 26 malignancies observed in the TNF inhibitor group, there were 15 solid malignancies. By contrast, only one solid malignancy was observed among patients in the comparison group.

For patients treated with the anti-TNF antibodies, the number needed to induce one additional malignancy of any type within a treatment period of 6 to 12 months was 154 (95% CI 91-500).

As shown earlier, most meta-analyses have not found this same association.

LYMPHOMA RISK — The majority of evidence available has not indicated a significant association between tumor necrosis factor (TNF) inhibitors and the development of lymphoma or has indicated, at most, a very small increased risk. (See 'Overall lymphoma risk likely not increased' below and 'Hepatosplenic T-cell lymphoma' below.)

The analysis of lymphoma risk in association with anti-TNF agents, particularly in patients with rheumatoid arthritis (RA), is confounded by the strong association between high cumulative disease activity and development of lymphoma [28]. As TNF inhibitor therapies are often reserved for those with the most severe disease, there is likely to be channeling of those patients at higher risk of lymphoma towards treatment with TNF inhibitors.

Overall lymphoma risk likely not increased — Multiple large well-done population- and registry-based studies from various countries, including the United States, United Kingdom, Sweden, Denmark, and France, have failed to demonstrate an increased risk of lymphoma among patients treated with TNF inhibitors compared with patients with the same disorder (most often RA) who were not treated with these agents [12,14,15,19,29-32]. Nonetheless, these analyses have the inherent limitations of observational studies (see 'Challenges in establishing malignancy risk' above and 'Studies of overall cancer risk' above). As examples:

A population-based study from Sweden was performed on patients with RA [14]. The study included a prevalent cohort (n = 53,067), an incident cohort (n = 3703), and a cohort treated with TNF inhibitors (n = 4160). Data from all three cohorts were linked to the Swedish Cancer Registry to ensure completeness in reporting. The study included almost 500 observed hematopoietic malignancies. The following findings were reported:

Prevalent and incident patients with RA were at increased risk for lymphoma (standardized incidence ratio [SIR] of 1.9 and 2, respectively) and leukemia (SIR of 2.1 and 2.2, respectively) compared with the general population.

RA patients treated with TNF inhibitors were at increased risk of lymphoma compared with the general population (SIR of 2.9). However, after adjustment for age, sex, and disease duration, the risk of lymphoma among patients in the cohort treated with TNF inhibitors was NOT higher than that among RA patients not treated with TNF inhibitors.

Further support for a lack of lymphoma risk associated with TNF inhibitors comes from the longitudinal study of long-term outcomes in RA performed in the United States using information from the National Data Bank for Rheumatic Diseases, for which patients completed questionnaires every six months [12]. The study included 19,591 participants and a total of 89,710 patient-years of follow-up [12]. Fifty-five percent of the patients received TNF inhibitors, and 68 percent received methotrexate (MTX) during the period of observation. The following findings were reported:

The incidence rate of lymphoma for the overall cohort was 106 per 100,000 person-years of exposure (95% CI 87-130).

The SIR for lymphoma was 1.8 (95% CI 1.5-2.2) among patients in this cohort compared with the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) database of individuals in the general population [2].

The odds ratio (OR) for lymphoma among RA patients who received a TNF inhibitor compared with RA patients who did not receive anti-TNF therapy was 1.0 (95% CI 0.6-1.8).

The OR for lymphoma in patients who received a TNF inhibitor plus MTX compared with patients who received MTX alone was 1.1 (95% CI 0.6-2.0).

When considered individually, neither infliximab nor etanercept was associated with an increased risk of lymphoma.

A subsequent analysis from the Database for Biological Therapies in Rheumatology (DANBIO) registry in Denmark has also reported no increase in the risk of non-Hodgkin lymphoma in patients with RA and other inflammatory arthritides treated with TNF inhibitor therapies (5345 patients over 15,592 person-years) compared with untreated patients (4351 patients over 9219 person-years) [19].

A 2017 report from the British Society for Rheumatology Biologics Register for Rheumatoid Arthritis (BSRBR-RA) compared the risk of lymphoma in RA between 11,931 TNF inhibitor-treated patients and 3367 biologic-naïve patients receiving DMARDs [30]. In total, 88 lymphomas were observed in TNF inhibitor-treated patients and 30 in the DMARD cohort. After adjusting for a number of potential confounding factors using propensity scores, no increased risk of lymphoma was observed in patients receiving TNF inhibitors.

Similar reassuring findings have been observed in patients with spondyloarthritis (SpA) to those seen in the more numerous studies of patients with RA. In a combined analysis of 8703 patients with SpA registered in either the Antirheumatic Therapies in Sweden (ARTIS) register or the DANBIO registry receiving TNF inhibitors who were compared with 28,164 TNF inhibitor-naïve patients with SpA, no increased risk of lymphoma was observed [32].

Only a few analyses, each with limitations, have suggested an increased risk of lymphoma from the use of TNF inhibitors.

Data presented to an advisory meeting of the US Food and Drug Administration (FDA) in 2003 included 70 cases of lymphoma among approximately 140,000 patients treated with etanercept [33]. Data on infliximab and adalimumab were also reviewed, although the clinical experience with these drugs was significantly smaller than with etanercept at that time. The following estimates were reported:

SIR for etanercept – 2.3 to 3.5

SIR for infliximab – 6.4

SIR for adalimumab – 5.5

The SIR of lymphoma among patients with RA in general, excluding those treated with TNF inhibitors, was estimated to be 2. However, a direct comparison between patients treated with and without TNF inhibitors, taking into consideration these differences, was not performed.

Data from a small regional patient registry in Sweden also suggested a possible increase in lymphoma among RA patients receiving TNF inhibitor therapies [34]. From this registry, 757 patients treated with etanercept or infliximab were identified and compared with a comparison group of 800 RA patients treated with conventional DMARDs drawn from a community-based cohort. The absolute risk of lymphoma in these groups was very low, with only five cases among the patients receiving etanercept or infliximab and two cases in the group treated with conventional DMARDs. Although the relative risk estimate was increased in the TNF inhibitor group, the very wide confidence intervals indicate that the risk estimates were very imprecise (SIR 11.5, 95% CI 3.7-26.9, versus 1.3, 95% CI 0.2-4.5), likely due to the small sample sizes analyzed. This increase in risk was not confirmed in subsequent larger studies with longer follow-up.

Hepatosplenic T-cell lymphoma — A small number of cases of hepatosplenic T-cell lymphoma (HSTCL), a very rare form of non-Hodgkin lymphoma, have been reported in association with the use of several monoclonal antibody TNF inhibitors. (See "Clinical manifestations, pathologic features, and diagnosis of hepatosplenic T cell lymphoma".)

Most, although not all, reports of HSTCL with TNF inhibitor use have involved adolescent or young adult males with inflammatory bowel disease (IBD), and a majority had also received thiopurines (azathioprine or 6-mercaptopurine) concomitantly with their TNF inhibitor [35].

A subsequent pooled analysis of lymphoma from 12 European biologic registries in more than 120,000 patients with RA, including 47,864 treated with TNF inhibitors, did not identify any modification in the distribution of lymphoma subtypes in RA patients treated with TNF inhibitors compared with biologic-naïve patients [36]. Specifically, no cases of HSTCL were identified among the 533 reports of lymphoma.

SOLID MALIGNANCY RISK — Data regarding the risk of solid malignancy as a complication of tumor necrosis factor (TNF) inhibitor use are generally favorable. (See 'Overall solid organ cancer risk' below and 'Cervical cancer' below and 'Cancer risk of cyclophosphamide and TNF inhibitor combination' below.)

Overall solid organ cancer risk — The potential relationship between TNF inhibitor therapies and increased risk for the development of solid organ malignancies was studied in a meta-analysis of 18 clinical trials including adalimumab, infliximab, and etanercept treatment, in which a statistically significant risk was not identified [37].

As examples of two registry-based studies that found no overall increase in risk of solid organ malignancies:

The Swedish rheumatoid arthritis (RA) registries concluded that the risk of solid malignancies among patients treated with TNF inhibitors is not higher than one would expect from the underlying disease [38]. This population-based study was composed of a prevalent RA cohort (n = 53,067), an incident cohort (n = 3703), and a cohort of patients treated with TNF inhibitors (n = 4160). Data from all three cohorts were linked to the Swedish Cancer Registry to ensure completeness in reporting. The risk of solid malignancies in this cohort was not greater than that of the general population in Sweden.

The British Society for Rheumatology Biologics Register for Rheumatoid Arthritis (BSRBR-RA) also reported no increased risk of new solid organ malignancies among patients with RA ever treated with a TNF inhibitor therapy, compared with those never treated with such agents [39]. Data on cancer occurrence were obtained through linkage of study patients with the United Kingdom national cancer register. In total, 11,767 patients treated with TNF inhibitor therapies (52,549 person-years) were compared with 3249 patients never treated with a TNF inhibitor (11,672 person-years).

The study also included analyses of site-specific solid cancers, including lung, breast, colorectal, and gastroesophageal cancers, none of which exhibited increased risk with TNF-inhibitor treatment.

Cervical cancer — Women with RA are at increased risk of cervical cancer, and based upon observations from one study, this risk might be slightly increased with use of TNF inhibitors (depending on the comparator group). This study from Sweden evaluated the pattern of cervical screening and cervical cancer risk among 9629 female patients receiving TNF inhibitors for RA compared with 34,984 biologic-naïve women with RA [40]. Patients receiving TNF inhibitors were not at an increased risk of low-grade cervical dysplasia (carcinoma in situ), termed cervical intraepithelial neoplasia (CIN) 1, but were at an increased risk of the more severe CIN 2 or higher-grade changes (relative risk [RR] 1.36, 95% CI 1.01-1.82) and invasive cervical cancer (RR 2.10, 95% CI 1.04-4.23), although the results were imprecise. (See "Cervical intraepithelial neoplasia: Terminology, incidence, pathogenesis, and prevention", section on 'Terminology'.)

The risk estimates with TNF inhibitors were lower (although still slightly elevated) when a stricter definition of a biologic-naïve patient was used (treated with two or more other disease-modifying antirheumatic drugs [DMARDs]). This likely represented a more closely matched population and suggests the initial risk observed with TNF inhibitors could be explained in part by higher severity of RA and past exposures to other immunosuppressive drugs, rather than a direct effect of TNF inhibitors themselves. There was no difference detected in screening patterns between women who were and were not receiving TNF inhibitors to account for the differences.

Cancer risk of cyclophosphamide and TNF inhibitor combination — The combination of TNF inhibition and cyclophosphamide heightens the risk of cancer beyond the risk observed with cyclophosphamide alone, and we do not use the combination of a TNF inhibitor together with cyclophosphamide. This is based upon findings from the Wegener's Granulomatosis Etanercept Trial (WGET), which was a randomized trial comparing the addition of etanercept or placebo to standard of care for the maintenance of remission in 180 patients with granulomatosis with polyangiitis [41]. Median follow-up was just over two years. The following findings were noted with respect to malignancy:

Six of the 89 patients (7 percent) assigned to etanercept developed solid malignancies compared with no solid malignancies in the standard therapy group. During the six-month observation period that followed the discontinuation of experimental treatment, two additional solid malignancies were diagnosed in patients who had received a TNF inhibitor, and one was observed in a patient who had not been treated with TNF inhibition.

All six of the patients with solid malignancies detected during the trial and seven of the nine patients overall were also treated with cyclophosphamide during the trial.

Based upon the age- and sex-specific incidence rate for solid malignancies from the Surveillance, Epidemiology, and End Results (SEER) database, the standardized incidence ratio (SIR) for solid malignancies among patients treated with the combination of cyclophosphamide and etanercept during the trial was 3.1 (95% CI 1.2-6.8).

Although the overall number of malignancies observed was small, the surprisingly high number of solid malignancies observed over a period of only two years suggested that the combination of TNF inhibition and cyclophosphamide heightens the risk of cancer beyond the risk observed with cyclophosphamide alone.

While additional studies are required, the manufacturer's labeling for etanercept states that use of etanercept (Enbrel) in patients receiving concurrent cyclophosphamide is not recommended due to an increased risk of developing cancer.

SKIN CANCER RISK

Nonmelanoma skin cancer — There has been evidence of an increased risk of nonmelanoma skin cancer among patients treated with tumor necrosis factor (TNF) inhibitors compared with those not receiving these agents, including meta-analyses of data from registries, prospective observational studies, and randomized trials [15,16,42,43]. However, two large observational studies have not confirmed these findings, showing an overall increased risk of nonmelanoma skin cancer in patients with rheumatoid arthritis (RA) regardless of whether they received treatment with TNF inhibitor therapies [19,44]. More limited studies have suggested a possible increased risk of malignant melanoma [15,42,45].

Thus, in all patients with RA, regardless of TNF inhibitor use, we advise routine skin cancer surveillance. Patients should also be educated regarding skin cancer prevention when starting treatment, including use of broad-spectrum sunscreens when in the sun, sun avoidance, and skin self-examination. (See "General principles and overview of management of rheumatoid arthritis in adults", section on 'Malignancy'.)

The range of evidence for increased risk of nonmelanoma skin cancer with use of TNF inhibitors is demonstrated by the following:

In a systematic review and meta-analysis of data from four observational studies involving over 28,000 patients, the risk of nonmelanoma skin cancer was significantly increased among patients exposed to TNF inhibitors compared with those who were not (relative risk [RR] 1.45, 95% CI 1.15-1.76) [15]. The risk of nonmelanoma skin cancer was significantly increased in patients treated with TNF inhibitors among a cohort of 20,648 patients with RA followed in the national administrative databases of the US Department of Veterans Affairs, compared with patients who had received nonbiologic disease-modifying antirheumatic drugs (DMARDs) (18.9 versus 12.7 per 1000 patient-years; hazard ratio [HR] 1.42, 95% CI 1.24-1.63) [43].

A meta-analysis of patient-level data from randomized trials of TNF inhibitor therapy, involving 15,418 patients, showed a significantly increased risk of nonmelanoma skin cancer among patients receiving TNF inhibitors (RR 2.02, 95% CI 1.11-3.95) [16].

By contrast, evidence of no increased risk in nonmelanoma skin cancer due to TNF inhibitor use includes the following:

The Danish Database for Biological Therapies in Rheumatology (DANBIO) registry found no increased risk of nonmelanoma skin cancer when comparing 3347 TNF inhibitor-treated patients with 3812 TNF inhibitor-untreated patients with RA [19].

The British Society for Rheumatology Biologics Register for Rheumatoid Arthritis (BSRBR-RA) also found no increased risk (eg, for basal cell carcinoma or squamous cell carcinoma) among 11,881 TNF inhibitor-treated patients compared with 3629 TNF inhibitor-untreated patients with RA [44].

The BSRBR-RA also studied the risk of recurrent skin cancer in 283 patients receiving either TNF inhibitors or conventional DMARDs with a past history of nonmelanoma skin cancer prior to starting therapy. The crude incidence rate of new skin cancer was almost 10-fold higher compared with those without a previous skin cancer; however, the risk was not increased in those receiving TNF inhibitor therapies compared with patients receiving nonbiologic therapies.

Both the Danish and British studies did find an increased risk of nonmelanoma skin cancer in patients with RA compared with the general population. This risk increase ranged from a 76 to 83 percent increase in patients with RA who were not treated with TNF inhibitors and a 72 to 92 percent increase among patients treated with TNF inhibitor therapies. This supports the view that all patients with RA should be screened for skin cancer, regardless of whether they are receiving TNF inhibitors.

Malignant melanoma — There are concerns about a possible association between TNF inhibitors and malignant melanoma, especially following reports of successful treatment of malignant melanoma with isolated limb perfusion with TNF-alpha in combination with melphalan [46] (see "Cutaneous melanoma: In-transit metastases" and "Overview of multimodality treatment for primary soft tissue sarcoma of the extremities and superficial trunk"). However, because malignant melanoma is a rare outcome, large studies are required to explore this risk among patients receiving TNF inhibitors for rheumatic diseases and uncertainty regarding this risk remains.

Two studies have suggested an increased risk:

In a population-based cohort study in Sweden of patients with RA who were either treated with a TNF inhibitor (n = 10,878) or were not treated with a biologic agent (n = 42,198) and of matched controls from the general population (n = 162,743), the risk of a first invasive melanoma was increased in patients receiving TNF inhibitors compared with patients with RA who were not treated with biologic agents (HR 1.5, 95% CI 1.0-2.2) [45]. This difference resulted in an absolute increase in risk for this population of 20 per 100,000 person-years. There was no significant increase in such risk for RA patients who were not treated with a biologic compared with the general population controls.

A pooled analysis of two observational studies identified in a 2011 systematic review found a trend suggesting an increased risk of melanoma, but the data were imprecise and did not achieve statistical significance (RR 1.79, 95% CI 0.92-2.67) [15].

An increased risk of melanoma was not proven among patients treated with TNF inhibitors in a 2016 meta-analysis involving patients from 11 European biologic registries [47]. In total, 130,315 patients with RA contributing 579,983 person-years of exposure were studied, including 48,304 patients never treated with TNF inhibitors. Overall, 287 first melanomas were recorded. Compared with the general population, the observed RR among patients treated with TNF inhibitors was 1.2 (95% CI 0.99-1.6). Compared with patients with RA who had never been exposed to biologic therapies, the RR was 1.14 (95% CI 0.8-1.6).

A large variation in risk was observed across the different countries, although this was felt to be explained largely by the low rates of melanoma within each registry. There were limitations to the study methods common to observational research, such as ascertainment bias, and individual variation of risk among populations with higher baseline risk, such as in Scandinavia; therefore, a small risk of melanoma cannot be excluded completely. However, the absolute risk is very low.

CANCER RISK IN PATIENTS WITH PRIOR MALIGNANCY — Somewhat limited studies have not found evidence for an increased risk of recurrent or new cancer in patients treated with a tumor necrosis factor (TNF) inhibitors who have a history of a prior malignancy. The paucity of data regarding this question has resulted from the exclusion of such patients from clinical trials with TNF inhibitors because of earlier concerns over such risk and from practice guidelines or drug labeling promoting caution in this population, given the lack of information to document safety.

Prior malignancy (all cancers combined) — Studies relying upon information from two large databases, one in Sweden and the other in the United Kingdom, have failed to demonstrate an association of TNF inhibitor use with an increased risk of solid, noncutaneous cancer in patients with a prior malignancy [48-50]:

Analyses of a Swedish population-based cohort using nationwide databases failed to demonstrate an increased risk of recurrent solid, noncutaneous cancer among 467 patients with rheumatoid arthritis starting a TNF inhibitor (between 2001 and 2015) after a diagnosis of cancer, compared with 2164 biologics-naïve patients matched for age, sex, year of diagnosis, and cancer type and stage (9.0 versus 7.2 percent; hazard ratio [HR] 1.06, 95% CI 0.73-1.54) [50]. Similar results were seen with other analyses of these data. While reassuring, the results were imprecise and an increased risk could not be entirely excluded, nor could the possibility of patients with a better cancer prognosis being more likely to have been chosen to receive TNF inhibitor therapy.

Analyses of data from the British Society for Rheumatology Biologics Register for Rheumatoid Arthritis (BSRBR-RA) involving over 18,000 patients with rheumatoid arthritis (RA) have not shown increased risk associated with a history of prior malignancy (all cancers combined) in patients treated with TNF inhibitors [48,49]. An earlier analysis was updated in 2016 and included 159 disease-modifying antirheumatic drug (DMARD)-treated and 243 TNF inhibitor-treated patients, with a median follow-up period of seven years (interquartile range [IQR] 3.5 to 8.8 years) following the start of TNF inhibitor therapy [49]. In this unmatched analysis, there was no increased risk seen in association with TNF inhibitor use (relative risk [RR] 0.56, 95% CI 0.36-0.88); notably, a higher proportion of patients experienced a recurrence of the same cancer in the nonbiologic DMARD-treated cohort compared with the TNF inhibitor-treated patients (17 versus 13 percent). The absolute risks were 54 and 33 events per 1000 patient-years, respectively.

A 2020 meta-analysis of 12 observational studies did not find any association with TNF inhibitors and an increased risk of cancer recurrence or new cancers in patients with prior cancers compared with conventional DMARDs (RR 0.95, 95% CI 0.83-1.09). Similar conclusions were drawn in subanalyses looking specifically at patients with a history of solid organ cancer, skin cancer, or breast cancer [51].

The lack of evidence for an overall difference in risk of malignancy between TNF inhibitors and conventional DMARDs should be interpreted with caution, as undefined criteria used in practice by rheumatologists for selecting therapy in patients with prior cancer, including the nature of the prior cancer and time since prior cancer, may have influenced the study outcomes.

History of malignant melanoma — In a 2016 report from the BSRBR-RA, a registry in the United Kingdom of over 18,000 RA patients, and updating a previous analysis from this registry, 15 traditional (nonbiologic) DMARD-treated and 23 TNF inhibitor-treated patients were reported to have a history of melanoma [48,49]. Of these, two DMARD patients and three patients in the TNF inhibitor group have been reported to have had a recurrence.

Whether melanoma conveys greater risk than other malignancies for disease recurrence following TNF inhibitor treatment remains to be determined by further study, but the successful use of immunotherapies for the treatment of melanoma underlines the role of the immune system in management of melanoma (see "Overview of the management of advanced cutaneous melanoma", section on 'Immunotherapy'). When a melanoma develops in a patient receiving TNF inhibitors, it would be the author's approach to discontinue the TNF inhibitor and consider alternative biologic DMARDs in consultation with the patient's oncologist. A similar approach is taken in patients with a prior history of melanoma. Whether this theoretical risk also extends to patients with a family history of melanoma or those at high risk due to geographic region or history of significant sun exposure is unknown.

History of head and neck cancer — No increase in the risk of recurrent head and neck cancer was detected in a retrospective cohort study that analyzed data from the US Department of Veterans Affairs administrative databases from 1998 to 2008 and a review of electronic medical records [52]. Among 180 patients with RA and a head and neck cancer, recurrence rates did not differ significantly between patients subsequently treated with TNF inhibitor therapy and those treated with nonbiologic DMARDs (5 of 31 [16 percent] versus 44 of 149 [30 percent], respectively). Although this is the largest study of head and neck cancer recurrence in patients with RA, it is limited by its observational nature, inevitable selection bias and unmeasured confounding variables, and the small number of cases.

History of breast cancer — At least two reports have described no increase in recurrent breast cancer in association with the use of TNF inhibitors [53,54].

An analysis of data from Sweden found no difference in the rate of recurrent breast cancer among a matched cohort of 120 women starting TNF inhibitor therapy and 120 biologic-naïve patients with RA, both with a history of past breast cancer, with nine women developing breast cancer recurrence in each group after a median of 4.9 years of follow-up [53]. The median time from the first breast cancer to the date of starting TNF inhibitor therapy or follow-up was 9.4 years. The generalizability of the results to women with more recent or poor-prognosis breast cancer is not known.

A second study set up with the United States Medicare database also did not confirm an increased risk of recurrent breast cancer among 291 women with either RA or inflammatory bowel disease (IBD) receiving TNF inhibitors over a median follow-up of 2.7 years, compared with 1164 matched nonusers [54]. A majority of women had had their initial breast cancer surgery one year prior to the start of study follow-up.

PROGNOSIS — Limited data indicate that treatment with tumor necrosis factor (TNF) inhibitors does not affect the prognosis of patients who develop cancer during or after treatment with these medications. An analysis of data from the Swedish clinical registries of rheumatoid arthritis (RA) patients, involving a total of 78,483 individuals, found that there were no differences between patients who had received TNF inhibitors and those who were naïve to biologic disease-modifying antirheumatic drugs (DMARDs) in the distributions of tumor stage or in the relative risk (RR) of death among patients diagnosed with cancer [55]. Similarly, there was no difference in the age- and sex-adjusted mortality rates following solid cancer diagnosis between "anti-TNF ever" and "anti-TNF never" -treated patients in the British Society for Rheumatology Biologics Register for Rheumatoid Arthritis (BSRBR-RA) [39].

SUMMARY AND RECOMMENDATIONS

General issues – The decision to use a tumor necrosis factor (TNF) inhibitor must be based upon the specific clinical features and unique risk profile of a given patient. The risks associated with TNF inhibitor use must be interpreted in the context of the potential benefits associated with these medications, as well as the adverse effects associated with conventional treatments for immune-mediated diseases. The adverse effects of untreated arthritis, including the risk of malignancy induction, are also significant in many cases. (See 'General issues' above.)

Studies of overall cancer risk – The evidence is generally reassuring with respect to the risk of lymphomas, leukemias, and solid malignancies, as well as the overall risk of malignancy stemming from the use of TNF inhibitors. A majority of observational studies have not confirmed an increased risk, despite the US Food and Drug Administration (FDA) having previously issued several warnings regarding such risk. (See 'Evidence of increased risk' above and 'Lymphoma risk' above and 'Solid malignancy risk' above.)

Challenges in establishing malignancy risk – Challenges in establishing the true magnitude of risk (if any) between TNF inhibitor use and the development of malignancy include:

Increased predisposition to cancer based upon the patient's underlying disorder. (See 'Challenges in establishing malignancy risk' above.)

Concomitant use of other medications that can heighten malignancy risk, particularly cyclophosphamide. Thus, TNF inhibitors should be avoided, if possible, in patients receiving cyclophosphamide. (See 'Cancer risk of cyclophosphamide and TNF inhibitor combination' above.)

A lack of data from randomized trials to address risk of new or recurrent malignancy in patients with a prior history of cancer. (See 'Cancer risk in patients with prior malignancy' above.)

Skin cancer risk – The risk of nonmelanoma skin cancer may be increased in patients who receive TNF inhibitors; however, the risk may be increased in all patients with rheumatoid arthritis (RA) regardless of treatment. Thus, general screening for skin cancer in patients with RA should be encouraged. The risk of melanoma is uncertain but may also be increased. (See 'Skin cancer risk' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges John Stone, MD, who contributed to an earlier version of this topic review.

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Topic 7975 Version 36.0

References

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