Seminars in Oncology
Volume 37, Issue 3 , Pages 188-189, June 2010

The Role of Anti-Tumor Necrosis Factor Receptor Agents in Cancer Survivors Revisited

Article Outline

 

At times we encounter clinical problems for which there are no directly applicable evidence-based solutions, but we are compelled by circumstances to act. When doing so we rely on related evidence, general principles of best medical practice, and our experience. Each ”Current Clinical Practice” feature article in Seminars in Oncology describes such a challenging presentation and offers treatment approaches from selected specialists. We invite readers' comments and questions, which, with your approval, will be published in subsequent issues of the Journal. It is hoped that sharing our views and experiences will better inform our management decisions when we next encounter similar challenging patients. Please send your comments on the articles, your challenging cases, and your treatment successes to me at Gloria.Morris@hemonc1.com. I look forward to a lively discussion.

Gloria J. Morris, MD, PhD

Current Clinical Practice Feature Editor

The management of a cancer survivor with disabling rheumatoid arthritis effectively treated only with an anti-tumor necrosis factor receptor agent1 presents an interesting dilemma for the physician and raises many issues, both theoretical and practical. From a theoretical perspective, it points out the important relationship between a properly functioning immune system and cancer development. The practical aspects of managing patients on these potent immunosuppressive agents are highlighted by the devastating course of events in this patient previously presented.1 Was the adenocarcinoma of the lung simply coincidental in this nonsmoker from a nonsmoking household or was it causally related to the treatment for her arthritis? In any given patient one can never know.

Historically, there has been controversy over the interaction between the immune system and the development of cancer. The early concept of “immune surveillance” proposed that the development of cancer cells in humans was a frequent occurrence.2 The reason cancer was not more prevalent was that immune regulatory cells were capable of identifying and eradicating malignant cells. The successful malignant cell was explained, at least to some degree, by the concept of “low zone tolerance.”3, 4, 5 In this scenario, minimally antigenic malignant cells are present for a long period of time in low numbers, favoring the development of suppressor T cells. These T cells actively prevent an immunologic response against the malignant clone. Initially referred to as suppressor T cells, in today's nomenclature they are referred to as “T-Regs.”6

The development of an aggressive malignancy in this pharmacologically immunosuppressed patient adds to a growing body of evidence that chronically immunosuppressed individuals, whether the result of disease or iatrogenic intervention, are at increased risk for the development of malignancies. There have been several clinical situations associated with immunosuppression, the most recent and dramatic of which has been the development of the acquired immune deficiency syndrome (AIDS). Early, as this disease spread, it became obvious that the development of AIDS was associated with malignancy, most commonly non-Hodgkin lymphoma (NHL) and Kaposi sarcoma (KS).7 In fact, these diseases were ultimately included as AIDS-defining. Treatment was limited and patients typically died early. With the advent of highly active antiretroviral therapy (HAART) treatments, patients are now living much longer and the incidence of both NHL and KS has decreased significantly within this setting.8 In contrast, we are now observing an increase in solid tumors, including anal, colorectal, lung, liver, oro-pharyngeal, renal, and vaginal cancers, as well as Hodgkin lymphoma, leukemia, and melanoma.9, 10 The incidence of the above malignancies is in excess of what would be otherwise expected in the general population.

In the context of the above, we address several issues related to the present patient. Fortunately, we have two points in time to evaluate the aggressive growth of this lung cancer. In September of 2007, she had a chest x-ray that is interpreted as normal. A short 3 months later, there is evidence of a dominant right hilar lung mass along with multiple lung metastases. Pathologic evaluation documents that this is an adenocarcinoma. While we readily associate small cell lung cancer as a tumor with rapid growth, adenocarcinomas are not typically associated with this characteristic.

To appreciate the aggressiveness of this tumor, consider the following: the growth of any tumor is the sum of the number of cells produced versus those that are lost for any number of reasons. It is estimated that most solid tumors have somewhere in the range of 10% to 30% of cells in the cell cycle at any given time. With a cell cycle time on average of 2.5 days, and a cell loss of somewhere between 80% and 90%,11 starting from a single cell, it would take somewhere between 12 and 24 months to achieve a size of 1 cm. In light of this, one can quickly appreciate the incredible aggressiveness of this tumor. There are many factors that have a role in controlling the growth of malignant cells. The rapid growth of tumor in this patient supports the importance of an effective immune system as an integral part of this control.

As there is growing evidence of an increased risk of cancer development in patients with any form of immunosuppression, it seems clear that we will continue to encounter patients for whom immunosuppressive compounds offer the best opportunity for control of otherwise uncontrolled disabling symptoms. I would agree that at the outset, treatment with anti-TNF therapy was a reasonable recommendation for this patient. There were no other predisposing risk factors and the patient actually did well for 5 years. However, in light of the development of this aggressive malignancy, I would recommend discontinuation of all immunosuppressive agents at this time.

Continued study to define the risks of these compounds will allow us to develop a set of guidelines for monitoring patients over time. In the meantime, it would seem prudent to consider diagnostic computed tomography or positron emission tomography scans on a 6- to 12-month basis for patients who are treated with one of these compounds for more than 12 months. Potentially, the use of intermittent schedules of administration will decrease the cancer risk. Until we have a better sense of these risks, we should have a high index of suspicion for aggressive investigation of all new unexplained symptoms.

Edward F. McClay, MD

Director

Institute for Melanoma Research & Education

Encinitas, CA

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References 

  1. Chapman P, Cranmer L, Dixon WG, et al. The role of anti-tumor necrosis factor receptor agents in cancer survivors: does the risk justify the benefit?. Semin Oncol. 2010;37:11–19
  2. Leone G. The relationship between immunological defence and the development of tumours. Arch Sci Med (Torino). 1973;130:273–282
  3. Kölsch E, Stumpf R, Weber G. Low zone tolerance and suppressor T cells. Transplant Rev. 1975;26:56–86
  4. Stumpf R, Heuer J, Kölsch E. Suppressor T cells in low zone tolerance (I. Mode of action of suppressor cells). Eur J Immunol. 1977;7:74–85
  5. Heuer J, Stumpf R, Kölsch E, Shen FW, Hämmerling GJ. Suppressor T cells in low zone tolerance (II. Characterization of suppressor T and amplifier cells by physical and serological methods). Eur J Immunol. 1977;7:769–775
  6. Ribas A. Overcoming immunologic tolerance to melanoma: targeting CTLA-4 with tremelimumab (CP-675,206). Oncologist. 2008;13(Suppl 4):10–15
  7. Eltom MA, Jemal A, Mbulaiteye SM, Devesa SS, Biggar RJ. Trends in Kaposi's sarcoma and non-Hodgkin's lymphoma incidence in the United States from 1973 through 1998. J Natl Cancer Inst. 2002;94:1204–1210
  8. Brodt HR, Kamps BS, Gute P, Knupp B, Staszweski S, Helm EB. Changing incidence of AIDS-defining illnesses in the era of antiretroviral combination therapy. Aids. 1997;11:1731–1738
  9. Patel P, Hanson DL, Sullivan PS, et al. Incidence of types of cancer among HIV-infected persons compared with the general population in the United States, 1992-2003. Ann Intern Med. 2008;148:728–736
  10. Mitsuyasu RT. Non–AIDS-defining malignancies in HIV. Top HIV Med. 2008;16:117–121
  11. Tannock I. Cell kinetics and chemotherapy: a critical review. Cancer Treat Rep. 1978;62:1117–1133

 Address correspondence to Gloria J. Morris, MD, PhD, Editor, Current Clinical Practice, Hematology and Oncology Associates of Northeastern PA, PC, 1100 Meade St, Dunmore, PA 18512. E-mail: dr.morris@hemonc1.com

PII: S0093-7754(10)00089-8

doi:10.1053/j.seminoncol.2010.06.010

Refers to article:

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

    Paul Chapman, Lee Cranmer, W.G. Dixon, K.L. Hyrich, John R. Patterson, D.P.M. Symmons, Mary Toporcer, Michael J. Mastrangelo
    Seminars in Oncology February 2010 (Vol. 37, Issue 1, Pages 11-19)

Seminars in Oncology
Volume 37, Issue 3 , Pages 188-189, June 2010

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