The Role of Anti–Tumor Necrosis Factor Receptor Agents in Cancer Survivors: Does the Risk Justify the Benefit?

Article Outline

• The Problem
  • Case Report
• Rheumatologist's Opinion
• Medical Oncologist's Opinion
• Medical Oncologist's Opinion
• Epidemiologists' Opinion
• Dermatologist's Opinion
• Summary and Assessment
• References
• Copyright

Anti-tumor necrosis factor (TNF) receptor therapeutics, such as entanercept (Enbrel; Amgen, Thousand Oaks, CA), infliximab (Remicade; Centocor, Malvern, PA), adalimumab (Humira; Abbott, North Chicago, IL), and likely others, have revolutionized the treatment of rheumatoid arthritis. Their use has been successfully extended to other rheumatologic diseases, plaque psoriasis, and most recently inflammatory bowel disease. The full spectrum of the utility of these immunosuppressive agents for the treatment of inflammatory/autoimmune diseases remains to be defined. The number of patients under chronic treatment with these immunosuppressive agents will continue to expand exponentially.

The association between chronic immunosuppression, whether it be treatment (eg, organ transplantation) or disease (eg, human immunodeficiency virus [HIV] infection, chronic lymphocytic leukemia [CLL]) related, and malignancy has been amply documented. Chronically immunosuppressed patients are at greatest risk for developing lymphoma¹, ², ³ and skin malignancies, especially squamous cell cancer⁴ and more recently melanoma. Although less well described, the course of cancer in the immunosuppressed patient seems accelerated.⁵ Discontinuing immunosuppression is not a realistic option for organ transplant patients. Rather these patients are surveilled for malignancy and problems are dealt with as they arise. Despite great advances in organ transplantation, the limited availability of donor organs keeps the number of patients at risk relatively small. Although HIV infection is considerably more common, advances in the treatment of the underlying condition should reduce the risk of secondary malignancies.

Anti-TNF receptor therapy likewise has been associated with the development of malignancy and offers several unique challenges. The mechanism of immunosuppression is unique in that it is the consequence of targeting a specific signal transduction pathway. At present one can only speculate as to whether or not this will alter the pattern (frequency, time course, histological types) of second malignancies. The number of patients in harm's way is vast and rapidly expanding. The risk to these patients goes well beyond that of developing a new primary malignancy, as many individuals will have had a prior cancer and, although seemingly disease-free, will harbor a variably definable likelihood of recurrence. These patients also will be at risk for developing a second cancer of the same histology or an associated malignancy (eg, breast and ovarian cancers). Since anti-TNF receptor therapy can be considered “optional,” oncologists are being asked to approve such therapy in cancer survivors.

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The Problem 

Case Report 

A 52-year-old woman (DOB 1955) underwent excision of a deeply pigmented mid-sternal skin lesion on May 26, 1998 (her age 43), which was interpreted as a superficial spreading melanoma of Clark's level II invasion and a Breslow thickness of 0.3 mm (Figure 1). On June 12, 1998, the area was more widely re-excised and the surgical defect was closed primarily. There was no residual disease in the biopsy specimen. She was followed on a regular basis since that time primarily for the development of a second primary cutaneous melanoma. The patient had multiple clinically dysplastic nevi. An excisional biopsy of single dysplastic nevi was performed in May 1998 and in May 2001, and another two dysplastic nevi were removed on December 15, 2005. Her last routine visit was in September 2007, at which time a hemogram, liver function chemistries, lactate dehydrogenase, and chest x-ray failed to indicate any evidence of metastatic melanoma.

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• Figure 1. 

  Superficial spreading melanoma. Clark's level II, Breslow thickness 0.3 mm with melanophages and a patchy lymphocyte infiltrate in the dermis (hematoxylin & eosin stain) (A) Low-power overview; (B) higher power.

In 1978 (age 23) the patient was diagnosed with antinuclear antibody (ANA)-positive rheumatoid arthritis during her first pregnancy. The disease was controlled initially with prednisone, hydroxychloroquine sulfate, and minocycline. In 1999, one year after the diagnosis of melanoma, she experienced a flare-up of her rheumatoid arthritis. A discussion ensued regarding the safety of initiating therapy with an anti-TNF receptor medication. Because of concern regarding the possible exacerbation of her melanoma, parenteral gold therapy was initiated instead. Because of persistent symptoms, anti-TNF receptor therapy was started in 2001. She achieved an excellent and durable remission.

The patient did well until she developed what clinically appeared to be a sinusitis that failed to respond to conservative therapy. A chest x-ray performed on January 8, 2008 revealed a right hilar mass and suggested multiple lung nodules (Figure 2). A computed tomography scan confirmed the presence of the right hilar mass and more clearly defined multiple pulmonary nodules suggestive of lung cancer. On February 8, 2008, the patient underwent a left upper lobe wedge resection that revealed three foci of adenocarcinoma of the lung (Figure 3). Systemic therapy was initiated.

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• Figure 2. 

  Chest x-ray. Posteroanterior view showing a right hilar mass and probable pulmonary nodules suggestive of lung cancer.

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• Figure 3. 

  Histopathology of a lung nodule. (A) High power—gland formation and mucin production (hematoxylin & eosin stain). (B) Immunohistology—positive for thyroid transcription factor 1 (TTF1).

This patient with dysplastic nevi was diagnosed with rheumatoid arthritis well before the diagnosis of a low-risk melanoma. She was under oncologic surveillance primarily for the development of a second primary cutaneous melanoma, as well as for the unlikely recurrence of the original melanoma. With the development of disabling and otherwise unmanageable symptoms of rheumatoid arthritis, the patient's oncologist was asked if anti-TNF receptor therapy was permissible. The oncologist agreed to treatment and intensified surveillance for possible recurrence of the melanoma, as well as for lymphoma and a second cutaneous malignancy. The rheumatoid arthritis promptly remitted. More than 5 years elapsed without problems with lymphoma or with her melanoma. Several months after a routine check up (to include a normal chest x-ray), the patient developed a cough unresponsive to conservative therapy. A chest x-ray revealed findings consistent with a primary lung cancer widely metastatic within the lungs. Biopsy confirmed the presence of adenocarcinoma of the lung.

Various experts were asked to opine on the management of this patient, and where appropriate comment on the following issues:

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Rheumatologist's Opinion 

With regard to the case report, the onset of rheumatoid arthritis during pregnancy is unusual. It was stated that she was ANA-positive, but no mention is made of the presence of rheumatoid factor or, more recently anti-cyclic citrullinated peptide (anti-CCP) antibodies. The disease was initially controlled with prednisone, hydroxychloroquine sulfate, and minocycline.

In May 1998 she had an excision of a melanoma and subsequently has had very careful follow-up. In 1999, she had a flare-up of her rheumatoid arthritis. A discussion ensued regarding the safety of the TNF blockers and she was given a trial of gold therapy. With failure of gold treatment, she was then given a TNF blocker and she achieved an excellent and durable remission. Unfortunately, 8 years later she developed the explosive onset of adenocarcinoma of the lung.

I cannot proffer an opinion as to whether the “explosive” development of adenocarcinoma of the lung was consequent to the anti-TNF therapy or simply a known pattern of presentation of the disease.

Approval of the use of anti-TNF therapy in this patient involves obtaining more information than is available in the case report. Obviously her physicians were reluctant to use this therapy since a course of gold therapy was administered initially. Had she been off all medication when she developed an exacerbation of her disease, I would have given her prednisone, hydroxychloroquine sulfate, and possibly minocycline (along with osteoporosis therapy) for 4 to 6 months with careful follow-up. With no improvement, I would have added methotrexate. With no improvement on methotrexate, I would have added an anti-TNF drug therapy. I would try to stretch out the therapy and attempt to interrupt treatment after several months. If my concerns were met, I would not hesitate to use the anti-TNFs in the above situation.

As regards monitoring the patient for malignancy, I would have done nothing beyond what was done in the report.

Finally, uncontrolled rheumatoid arthritis is a terrible problem. I would explore treatments that were compatible with optimal treatment for her life-limiting lung cancer.

John R. Patterson, MD

Department of Medicine

Jefferson Medical College

Philadelphia, PA

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Medical Oncologist's Opinion 

Anti-TNF antibodies have become widely used for rheumatoid arthritis and other serious autoimmune conditions. Data from cohort studies as well as meta-analyses of randomized trials suggest that anti-TNF antibodies are associated with an increased risk of malignancies. There is some uncertainty as to which malignancies may be more commonly associated with these agents; reports have indicated increased rates of hematological and solid tumors. In the current case report, a woman being treated for rheumatoid arthritis developed metastatic non-small cell lung cancer despite no previous history of smoking. If I had been consulted on this case, I would have concurred with the use of the anti-TNF therapy given the severity of the rheumatoid arthritis. Given that the absolute increase in malignancies associated with treatment with anti-TNF drugs appears to be relatively low, and the fact that non-small cell lung cancer can arise in nonsmokers, there is no way to determine whether the anti-TNF therapy contributed to the lung cancer in this particular case. I think it would be hard to justify aggressive screening for malignancies in patients receiving anti-TNF therapy given how low the absolute risk is and given that there is no consensus as to which type of malignancies should be targeted for screening.

In this particular case, in the setting of metastatic lung cancer, I would seriously consider discontinuing the anti-TNF treatment. Mouse models have suggested that tumors arising in severely immunosuppressed hosts failed to be “immuno-edited” by the immune system.⁶ As a result, these tumors can potentially be recognized and rejected by a normal immune system. This is in contrast to tumors that arise in immunocompetent mice that have been immuno-edited and are ignored by the immune system. In the current case report, the lung cancer arose in the setting of immunosuppression due to the anti-TNF antibody treatment. It is possible that this lung tumor is unedited by the immune system and that removing the immunosuppression could result in tumor regression. I believe it would certainly be worth a try.

Paul Chapman, MD

Department of Medicine

Memorial Sloan-Kettering Cancer Center

New York, NY

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Medical Oncologist's Opinion 

The index patient had a history of a stage I melanoma on the sternum excised in 1998. She also had a long history of rheumatoid arthritis, eventually requiring therapy with an anti- TNF antibody. TNF blockade yielded a substantial improvement for the patient after initiation in 2001. Unfortunately, she developed multifocal non-small cell lung cancer in 2008, requiring systemic therapy.

This case highlights a number of issues faced by practicing oncologists relating to anti-TNF therapy, and more generally by the class of agents referred to as biological response modifiers. Three very clinical questions are raised by this case: (1) What is the risk of using these agents in a patient with a prior diagnosis of cancer, in this case, melanoma; (2) What is the overall cancer risk associated with anti-TNF agents in patients without a prior cancer history; and (3) What is the impact of these agents on the course of cancer once it subsequently develops?

To reliably assess and balance these risks, both the severity and likelihood of the risk must be known. While some estimate of the severity of risks can be undertaken, almost no reliable data exist regarding the likelihood of the risks. Therefore, recommendations regarding anti-TNF use at the present must rely on clinical judgment.

We have faced the first issue, regarding the advisability of anti-TNF use for rheumatoid arthritis in patients with a prior melanoma history, in our Cutaneous Oncology Program Clinic. Typically, patients are referred to us by rheumatologists for oncologic “clearance” prior to receiving anti-TNF therapy. The competing risks to be weighed are the risk of recurrent melanoma versus the risk of inadequately controlled rheumatoid arthritis. While oncologists may tend to focus on the consequences of recurrent melanoma, one must not discount the severe consequences of progressive rheumatoid arthritis: severe chronic pain, debility due to joint destruction, and even mortality due to side effects of alternative medications and secondary effects of rheumatoid arthritis itself.

At present, data regarding the risk of reactivation of melanoma in anti-TNF–treated patients consists of several case reports.⁷ Assuming melanoma in reported cases reflects reactivation of known previously treated melanoma and not an occult primary lesion, the reference melanoma lesion had not been cured by initial surgical treatment. Whether it would have recurred when it did, irrespective of anti-TNF therapy, is unknown. While there are biologically plausible reasons that reactivation of melanoma could occur under the immunological influence of anti-TNF therapy, this remains a hypothesis.

Clinically, the likelihood of a given patient's melanoma recurring must be balanced against the severity of disease warranting anti-TNF blockade. Perhaps the most important component is educational: the patients must be aware of the limitations of our available data and the potential risks associated with melanoma recurrence, including the possibility of death due to metastatic melanoma. Patients with stage III melanoma and a high recurrence risk may weigh the risks differently than those with a low, but not zero, recurrence risk. Similarly, those with severe advanced rheumatoid arthritis or other diseases responsive to anti-TNF therapy may be more inclined to accept a higher theoretical risk of melanoma recurrence versus patients with less aggressive disease and perhaps unexplored therapeutic alternatives. The key point is that adequate patient education (and, for medico-legal purposes, documentation of that education) is critical to allow the patient to make an informed decision regarding the use of these remarkable therapies.

The US Food and Drug Administration has recognized that TNF blockade is associated with increased risk of malignancy (see package inserts for entanercept, dated April 2009; infliximab, dated April 2009; and adalimumab, dated March 2009). However, the absolute risks are actually very small. For example, in randomized controlled trials of infliximab, 14 patients were diagnosed with malignancies, the most common of which were breast, colorectal, and melanoma, among 4,019 infliximab-treated patients versus one among 1,597 controls (0.52/100 patient-years among infliximab-treated v 0.11/100 patient-years among controls). Median follow-up period was about 0.5 years and thus the malignancy risk may increase over time. Similar data are presented for entanercept and adalimumab. These data suggest that some cancer cases are probably associated with anti-TNF therapy, but the absolute risk is low.

Complicating this discussion in regards to melanoma is the potential melanoma risk associated with alternative therapies for rheumatologic conditions. Methotrexate is commonly prescribed for rheumatoid arthritis. As it has been in use for decades, methotrexate is unlikely to be subjected to large-scale controlled assessment, preventing the acquisition of safety data comparable to that for anti-TNF antibodies. Several retrospective studies of the cancer risk of methotrexate have been undertaken. A study from Australia indicated a 1.5-fold increased risk of malignancy, and a threefold increase in risk of melanoma among methotrexate-treated rheumatoid arthritis patients versus the general population.⁸ Another retrospective study compared risk of malignancy in rheumatoid arthritis patients treated with methotrexate versus those treated with biological response modifiers, including etanercept, infliximab, or adalimumab.⁹ The study examined 7,306 patients receiving methotrexate and 1,152 receiving biological response modifiers. The risk of hematologic and solid malignancies, including melanoma, was statistically indistinguishable. Again, the absolute risk was small: for solid tumors, the risk was 1.6 malignancies per 100 person-years of use among those treated with biological response modifiers versus 1.8 per 100 person-years for methotrexate-treated patients. In general, the risk of melanoma or other solid tumors should not prevent use of anti-TNF therapy, if it is likely to be beneficial. An exception might be patients with a known syndrome increasing melanoma or cancer risk, such as a family with known p16 mutations associated with melanoma.

Finally, what is the course of a malignancy, such as melanoma, once it develops in patients actively treated with anti-TNF blockade? We are again faced with lack of reliable data. Given the association with disease development, it would be prudent to discontinue anti-TNF therapy in such patients. Further therapy should be undertaken according to established oncologic principles, based on the type of malignancy, its stage, and the patient's general medical condition.

The index patient under discussion had a low risk of melanoma recurrence after primary treatment. The patient had progressive rheumatoid arthritis and even underwent a therapeutic trial of an alternative, parenteral gold, prior to using anti-TNF therapy. Other than the presence of dysplastic nevi, she has no history suggesting an underlying syndrome of markedly increased melanoma risk. We would thus advise her that her prior melanoma history was not a contraindication to anti-TNF therapy. Ongoing monitoring in this patient would have involved screening related to her melanoma history (periodic skin examinations, directed history and physical examinations, chest-x-ray) and age/sex-appropriate cancer screening (breast examination, possibly mammography, cervical cancer screening).

This nonsmoking patient developed non-small cell lung cancer. Interestingly, this was detected on a chest x-ray in January 2008, and had not been present on a prior study of September 2007. By the time of histologic diagnosis in February 2008, the disease was apparently unresectable, requiring systemic therapy. Whether this aggressive disease course was related to anti-TNF therapy or coincidental is unknown, but it would be prudent to discontinue anti-TNF therapy after the diagnosis of metastatic disease.

In conclusion, this case illustrates important issues for oncologists in advising patients about the use of biological response modifiers. Definitive data regarding the oncologic risks of these therapies are lacking, especially in those with a prior history of curatively treated cancer and in those suffering a disease recurrence. More reliable data may be acquired by the institution of prospective patient registries composed of those being treated with anti-TNF therapy. As new immune-modifying agents are added to the pharmacopoeia, these questions will continue to face oncologists in their clinical practices.

Lee D. Cranmer, MD/PhD

Skin Cancer Institute

Arizona Cancer Center

University of Arizona

Tucson, AZ

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Epidemiologists' Opinion 

This case report provokes many interesting questions. Is the risk of melanoma increased in patients with rheumatoid arthritis? If so, what is the relative contribution of the disease itself and its immunosuppressive treatments? What is the influence of anti-TNF therapy upon cancer incidence? More specifically, does anti-TNF therapy increase the risk of new incident malignancy (including recurrence and metastasis) in patients who have a prior treated malignancy? And can anti-TNF therapy be continued safety in patients who develop an incident malignancy? The first two questions have an existing evidence base, reviewed elsewhere.¹⁰ The third question is amassing more literature.¹¹ Conversely, the evidence base for the remaining questions is scarce. Nonetheless, clinicians repeatedly wrestle with similar clinical scenarios and must make treatment decisions despite the paucity of evidence.

Is it even possible to determine the influence of anti-TNF therapy upon the risk of malignancy in patients with rheumatoid arthritis who have a prior malignancy? When anti-TNF therapy was tested in phase III randomized controlled trials (RCTs), prior malignancy was often an exclusion criterion.¹², ¹³, ¹⁴ Such RCT data cannot therefore address this question. British Society for Rheumatology (BSR) guidelines for the use of anti-TNF therapy in the United Kingdom were necessarily based upon expert opinion rather than clinical evidence. The theoretical potential for anti-TNF therapy to increase the risk of malignancy¹⁵ and the absence of any relevant data from the RCTs led to the advice that: “caution should be exercised in the use of anti-TNF therapies in patients with previous malignancy. The potential benefits of treatment need to be considered against the risks related to potential recurrence of the specific malignancy. If patients have been free of any recurrence of their malignancy for 10 years there is no evidence for a contraindication to anti-TNF therapy.”¹⁶ Similar guidelines were adopted in other countries. Thus any observational study conducted after the introduction of these guidelines can only address the question by analyzing patients with prior malignancy who, despite the guidelines, have been treated with anti-TNF therapy.

Several European academic rheumatology biologics registers were established since 2001 with the primary aim of addressing the safety of biologic therapy in rheumatic diseases.¹⁷ The findings of these studies, with respect to the above scientific question, have so far only been published in abstract form.¹⁸, ¹⁹ The early findings appear reassuring: the rate of new or recurrent malignancy in patients with prior malignancy is not higher in patients treated with anti-TNF therapy compared to traditional disease-modifying anti-rheumatic drugs (DMARDs). It is imperative that these results are interpreted with great caution, evaluating the potential biases and confounders of observational studies. Patients with prior malignancy selected to receive anti-TNF treatment may be systematically different in their risk of new or recurrent malignancy than patients selected not to receive anti-TNF therapy, introducing a selection bias. Second, results cannot be extrapolated to inform treatment decisions about patients with prior malignancy that clinicians would not previously have considered treating. Such patients are not represented in the study, and may behave differently from those included. Third, the average follow-up time is still short in these studies. Reassuring findings after only a few years may not hold true after longer follow-up, particularly given the long latency of some malignancies.

Bearing in mind these limitations, we can be relatively reassuring that, assuming the clinician has carefully weighed up the risk and the benefit in the individual patient, anti-TNF therapy may be given to some patients with prior malignancy. Unfortunately, there is a signal that patients with prior melanoma have a poorer outcome when treated with anti-TNF therapy. The BSR Biologics Register reported 17 patients with prior melanoma who received anti-TNF therapy. Three of 17 patients developed incident cancers after an average follow-up time of 3 years. This compared to no incident malignancies in 10 patients with prior melanomas treated with traditional DMARD therapy after an average of 2 years' follow-up.¹⁹ The possibility of a causal relationship is supported by the finding that anti-TNF therapy might increase the risk of de novo melanoma,²⁰ and that supraphysiological doses of TNF have been used with melphalan for the treatment of melanoma.²¹ This emerging signal suggests that particular caution is necessary for patients with prior melanoma considering anti-TNF therapy.

There is no existing literature about the safety of continuing anti-TNF therapy in patients with rheumatoid arthritis who develop a malignancy while on treatment. However, chemotherapy for malignancy often obviates the need for ongoing anti-TNF therapy, where control of active rheumatoid arthritis is a byproduct of the cancer immunosuppression. Beyond the rheumatology literature, studies examining the benefit of anti-TNF therapy in patients with cancer-associated anorexia may also provide some reassurance for continuing treatment in patients with rheumatic disease who develop malignancies while on therapy.

William G. Dixon, MRCP, PhD

Kimme L. Hyrich, MD, PhD, FRCPC

Deborah P.M. Symmons, MD, FFPH, FRCP

Epidemiology Unit

The University of Manchester

Manchester, UK

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Dermatologist's Opinion 

I believe all dermatologists and rheumatologists would agree that inhibition of the immune response to improve the signs and symptoms of an autoimmune disease also decreases the body's ability to combat certain types of malignancies.

In my 20 years of dermatology practice, now focusing primarily on cutaneous oncology, the frequency with which I encounter the devastating effects of immunosuppression has increased dramatically. It is clear that immunosuppression, whether it is disease- (HIV, CLL), drug- (anti-rejection agents, chemotherapeutic agents) or radiation-related, may cause profound progression of cutaneous malignancies. In addition, treatment of a primary malignancy may result in the development of a secondary malignancy. For example, secondary leukemias may occur as a result of the therapy for breast carcinoma, ovarian carcinoma, and lymphomas. Therefore, a notable increase in clinical response rates with newer immunosuppressive treatment regimens is not without its risks. This dilemma is succinctly demonstrated in the present case report. At this time, there is no reasonable explanation for the “explosive” development of adenocarcinoma of the lung in this patient, a nonsmoker not exposed to second-hand smoke.

Although difficult to assign an exact cause–effect relationship to the anti-TNF receptor therapy, one certainly must maintain a heightened awareness to this probability. We know that TNF is essential in the causation of vascular necrosis, in turn causing an ischemic insult to tumor cells. Likewise, TNF-α has direct cytotoxic effects mediated by the apoptosis pathway on susceptible tumor cells. It may stimulate innate immunity, induce inflammation, inhibit tumorogenesis and viral replication, and also increase tumor concentrations of coadministered antineoplastic drugs. A recent study on aging and decreased cutaneous immunity²² suggests insufficient TNF-α as one possible mechanism.

How do clinicians manage patients today, with the uncertainty of the role of TNF-α in each individual cancer? I would also have approved the use of an anti-TNF receptor blocker as therapy for a young (age 54), otherwise healthy (thin melanoma 9 years prior, nonsmoker, ardent follower of good health maintenance and prevention) female with an almost 30-year history of a debilitating autoimmune disorder who had tried and failed many standard first-, second-, and third-line treatments. The use of an approved and available TNF-α blocking agent improves quality of life. She achieved an excellent and durable remission but 7 years later developed a life-threatening malignancy. Of course there is cause for concern that her drug therapy promoted a secondary malignancy. These concerns are outlined in the discussion on the biology of TNF-α above. The true dilemma is not whether she required this course of therapy, but was there a “safer” alternative? If the answer is “no” then we, as physicians, must assist our patients with “the hands they are dealt.” I would not have seen this particular patient for skin screening more frequently than every 6 months, unless there was an urgent concern. After 10 years disease-free, she would receive yearly total body skin checks based on her melanoma history. At this time, I do not monitor nonmelanoma or melanoma patients at shorter intervals based on their use of biological agents. Standard screening for thin melanoma (< 1 mm in thickness) survivors does not dictate yearly chest x-ray studies. A normal chest x-ray in September 2007 and the development of an explosive cancer in January 2008 signal both physicians and patients with the reality that secondary malignancies may occur and they can be very aggressive. I do not subscribe to the use of an unnecessary immunosuppressive agent in a patient with a life-threatening malignancy, until I am certain that the patient will survive for at least 2 years and more conservatively, 5 years. If they do survive, reintroduction of a TNF-α blocker needs to be a mutual agreement between doctor and patient if no alternative acceptable therapies are available at that time.

The truth remains that cancer is a complex disease. We must weight the risks of cancer recurrence, development of secondary malignancy, and severity of the underlying illness before utilizing immunosuppressive agents in our treatment armamentarium.

Mary Toporcer, MD

Dermatology and Dermatologic Surgery

Doylestown, PA

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Summary and Assessment 

The introduction of anti-TNF agents into the therapeutic armamentarium for a variety of “autoimmune” diseases seemingly has resulted in a dramatic improvement in symptoms and arrest of disease progression. This impressive clinical benefit has fueled the use of these agents placing a vast population at risk for toxicity. Concurrent increases in the incidences of many types of cancer and in the number of cancer survivors make it inevitable that questions will be asked of oncologists regarding the advisability of using of anti-TNF agents in these patients who also have clinically significant autoimmune disease. In the absence of adequate data, clinicians will have to rely on their experience and their judgment to inform and advise patients.

This case typifies the patient about whom oncologists will be consulted: a cancer survivor with a debilitating autoimmune disease resistant to conventional therapy but predictably highly responsive to anti-TNF therapy. Of the multiple factors to be considered, the one of greatest concern and the simplest to define is the risk of recurrence of the previously treated cancer in the absence of immunosuppressive therapy. Also assessable, albeit much less precisely so, is the risk of developing a second but unrelated cancer. However, in almost all cases this risk will be substantially less than that of recurrence. Even less well defined is the impact of anti-TNF therapy on these risks. As cited by Cranmer and by Dixon et al above, this risk, although imprecisely defined seems none the less minimal. Also to be considered are the severity of the autoimmune disease, alternative therapies if any, and the anticipated duration of treatment, which is usually chronic. These factors are similar to those employed by the US Food and Drug Administration in their Risk Evaluation and Mitigation Strategy (REMS) for postmarketing surveillance of drugs and biologicals to assure that the agent's benefits outweigh the risks.²³ Anti-TNF agents are among the drugs with approved REMS programs.

Typically, anti-TNF therapy controls the symptoms but does not cure the disease. Thus treatment tends to be chronic. In the cancer survivor, the goal is to achieve reasonable control of the autoimmune disease with the least immunosuppression (lowest dose and shortest duration of treatment). When treatment is protracted, the interspersion of drug-free intervals should be considered. The patient is monitored for the anticipated cancer-related risks. In patients under active treatment for cancer, the need for anti-TNF therapy may be obviated by the immunosuppressive effects of that therapy. When that does not occur, perhaps the decision to re-introduce anti-TNF therapy is best left to the informed patient.

Michael Mastrangelo, MD

Department of Medical Oncology

Jefferson Medical College

Philadelphia, PA

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References 

1. Wolfe F, Michaud K. Lymphoma in rheumatoid arthritis (The effect of methotrexate and anti-tumor necrosis factor therapy in 18,572 patients). Arthritis Rheum. 2004;50:1740–1751
   • View In Article
   • MEDLINE
   • CrossRef
2. Weyad CM, Goronzy JJ, Kurtin PJ. Editorial—lymphoma in rheumatoid arthritis (An immune sysem set up for failure). Arthritis Rheum. 2006;54:685–689
   • View In Article
   • MEDLINE
   • CrossRef
3. Van Vollenhoven RF. Benefits and risks of biological agents (Lymphoma). Clin Exp Rheumatol. 2004;22(suppl 35):S122–s125
   • View In Article
   • MEDLINE
4. Setoguchi S, Solomon DH, Weinblatt ME, et al. Tumor necrosis factor alpha antagonist use and cancer in patients with rheumatoid arthritis. Arthritis Rheum. 2006;54:2757–2764
   • View In Article
   • MEDLINE
   • CrossRef
5. Fulchiero GJ, Salvaggio H, Drabick JJ, et al. Eruptive latent metastatic melanomas after initiation of antitumor necrosis factor therapies. J Am Acad Dermatol. 2007;56:S65–S67
   • View In Article
   • Abstract
   • Full Text
   • Full-Text PDF (283 KB)
   • CrossRef
6. Dunn GP, Old LJ, Schreiber RD. The immunobiology of cancer immunosurveillance and immunoediting. Immunity. 2004;21:137–148
   • View In Article
   • MEDLINE
   • CrossRef
7. Fulchiero GJ, Salvaggio H, Drabick JJ, et al. Eruptive latent metastatic melanomas after initiation of antitumor necrosis factor therapies. J Am Acad Dermatol. 2007;56(Suppl):S65–S67
   • View In Article
   • Abstract
   • Full Text
   • Full-Text PDF (283 KB)
   • CrossRef
8. Buchbinder R, Barber M, Huezenroeder L, et al. Incidence of melanoma and other malignancies among rheumatoid arthritis patients treated with methotrexate. Arthritis Rheum. 2008;59:794–799
   • View In Article
   • CrossRef
9. Setoguchi S, Solomon DH, Weinblatt ME, et al. Tumor necrosis factor alpha antagonist use and cancer in patients with rheumatoid arthritis. Arthritis Rheum. 2006;54:2757–2764
   • View In Article
   • MEDLINE
   • CrossRef
10. Chakravarty EF, Farmer ER. Risk of skin cancer in the drug treatment of rheumatoid arthritis. Expert Opin Drug Safety. 2008;7:539–546
    • View In Article
11. Askling J, Bongartz T. Malignancy and biologic therapy in rheumatoid arthritis. Curr Opin Rheumatol. 2008;20:334–339
    • View In Article
    • CrossRef
12. Maini R, St Clair EW, Breedveld F, et al. Infliximab (chimeric anti-tumour necrosis factor alpha monoclonal antibody) versus placebo in rheumatoid arthritis patients receiving concomitant methotrexate: a randomised phase III trial (ATTRACT Study Group). Lancet. 1999;354:1932–1939
    • View In Article
    • Abstract
    • Full Text
    • Full-Text PDF (133 KB)
    • CrossRef
13. Bathon JM, Martin RW, Fleischmann RM, et al. A comparison of etanercept and methotrexate in patients with early rheumatoid arthritis. N Engl J Med. 2000;343:1586–1593
    • View In Article
    • MEDLINE
    • CrossRef
14. Keystone EC, Kavanaugh AF, Sharp JT, et al. Radiographic, clinical, and functional outcomes of treatment with adalimumab (a human anti-tumor necrosis factor monoclonal antibody) in patients with active rheumatoid arthritis receiving concomitant methotrexate therapy: a randomized, placebo-controlled, 52-week trial. Arthritis Rheum. 2004;50:1400–1411
    • View In Article
    • MEDLINE
    • CrossRef
15. Balkwill F. Tumor necrosis factor or tumor promoting factor?. Cytokine Growth Factor Rev. 2002;13:135–141
    • View In Article
    • Full Text
    • Full-Text PDF (69 KB)
    • CrossRef
16. Ledingham J, Deighton C. Update on the British Society for Rheumatology guidelines for prescribing TNFalpha blockers in adults with rheumatoid arthritis (update of previous guidelines of April 2001). Rheumatology (Oxford). 2005;44:157–163
    • View In Article
    • MEDLINE
    • CrossRef
17. Zink A, Askling J, Dixon WG, Klareskog L, Silman AJ, Symmons DP. European Biologics Registers—methodology, selected results, and perspectives. Ann Rheum Dis. 2009;68:1240–1246
    • View In Article
    • CrossRef
18. Strangfeld A, Listing J, Herzer P, et al. RA patients with prior malignancy under treatment with biologics. [abstract] Ann Rheum Dis. 2008;67(Suppl II):
    • View In Article
19. Dixon WG, Watson KD, Lunt M, et al. The influence of anti-TNF therapy upon cancer incidence in patients with rheumatoid arthritis (RA) who have had prior malignancy: results from the BSRBR [abstract]. Arthritis Rheum. 2008;58(Suppl):S638–S639
    • View In Article
20. Wolfe F, Michaud K. Biologic treatment of rheumatoid arthritis and the risk of malignancy: analyses from a large US observational study. Arthritis Rheum. 2007;56:2886–2895
    • View In Article
    • CrossRef
21. Eggermont AM, ten Hagen TL. Tumor necrosis factor-based isolated limb perfusion for soft tissue sarcoma and melanoma: ten years of successful antivascular therapy. Curr Oncol Rep. 2003;5:79–80
    • View In Article
    • MEDLINE
    • CrossRef
22. Agius E, Lacy KE, Vukmanovic-Stejic M, et al. Decreased TNF-α synthesis by macrophages restricts cutaneous immunosurveillance by memory CD4⁺ T cells during aging. J Exp Med. 2009;206:1929–1940
    • View In Article
    • CrossRef
23. Food and Drug Administration. Food and Drug Administration Amendments Act of 2007. Public Law 110-85. September 27, 2007;
    • View In Article