What Are the Cancer Risks Following Long-Term Immunosuppressive Treatment?

Immunosuppression is the suppression of the body's immune system and its ability to fight infections and other diseases. Certain diseases are known to suppress the body’s immune system. For example, “primary immune-deficiencies” are inherited. Secondary immune-deficiencies such as diabetes, undernutrition, and HIV infection are acquired.[1] However, the most common cause of immunosuppression today is the widespread use of immunosuppressant drugs. Immunosuppressant drugs are used after organ transplant and autoimmune diseases.

Organ Transplant

Almost everyone who receives an organ transplant is required to take immunosuppressant drugs. This is because the body recognises a transplanted organ as a foreign mass which triggers a response by the body’s immune system to attack it. By weakening the immune system, immunosuppressant drugs decrease the body’s reaction to the foreign organ. The drugs allow the transplanted organ to remain healthy and free from damage. The immunosuppressant drugs in a patient’s regimen are adjusted and may eventually be reduced as the risk of organ rejection lessens over time. However, most people who have had a transplant will need to take at least one immunosuppressant drug for their lifetime.[2] 

Autoimmune diseases

Immunosuppressant drugs also are used to treat autoimmune diseases. An autoimmune disorder is a disease process where the body attacks its own tissue. For example lupus (SLE) results from a misdirected activity of the body’s own immune system. By suppressing this reaction, immunosuppressant drugs can help control the impact of the disease on the body.

Other diseases treated with immunosuppressant drugs include:

• Psoriasis
• Rheumatoid arthritis
• Crohn’s disease, a chronic inflammation of the digestive tract
• Multiple sclerosis
• Alopecia areata (patchy hair loss) [2]

In the past, radiation therapy was used to decrease the strength of the immune system, but now immunosuppressant drugs are used to inhibit the reaction of the immune system. The downside is that with such a deactivated immune system, the body is very vulnerable to opportunistic infections, even those usually considered harmless. Also, prolonged use of immunosuppressant drugs increases the risk of cancer.[3]

Cortisone was the first immunosuppressant identified, but its wide range of side effects limited its use. The more specific azathioprine was identified in 1959, but it was the discovery of cyclosporine in 1970 that allowed for significant expansion of kidney transplantation to less well-matched donor-recipient pairs as well as broad application of liver transplantation, lung transplantation, pancreas transplantation, and heart transplantation.[3]

Benefits of Organ Transplantation?

Australia has a world class reputation for successful transplant outcomes, both in terms of survival rates of the recipients and in the number of organs that are able to be transplanted from each donor.[4]

• In 2015, 435 organ donors gave 1,241 Australians a new chance in life!
• One organ and tissue donor can transform the lives of 10 or more people!
• Transplantation can dramatically improve the life of the recipient and enable them to live an active, healthy life.
• ​​There are significant cost benefits to organ transplantation when compared to the ongoing cost of treatment for people requiring transplants. 

Risks versus benefits of Organ Transplantation

While transplantation is a life-saving therapy for patients with end-stage organ disease, it also puts recipients at an increased risk for developing cancer, in part because of medications administered to suppress the immune system and prevent rejection of the organ. In large part due to this immunosuppression, previous studies have demonstrated an elevated risk of cancer that is 2-4 times higher in transplant recipients than the risk seen in the general population.[5-13] In spite of the elevated cancer risk in transplant recipients, the benefits of organ transplantation for people with end-stage organ disease far outweigh this risk.[4]

Past studies of cancer risk in transplant recipients focused mainly on those who received kidney transplants, and other studies were too small to accurately estimate risk for all but the most common cancer types. In order to better identify and define cancer risk in solid organ transplant recipients, the National Cancer Institute in collaboration with the U.S. Health Resources and Services Administration initiated the Transplant Cancer Match Study (TCM).[14]

What Types of Cancer areTransplant Recipients at Risk of?

In the United States organ transplant recipients have a high risk of developing 32 different types of cancer. Some are related to known infections (e.g. anal cancer, Kaposi sarcoma) and others unrelated (e.g. melanoma, thyroid and lip cancers). The most common malignancies with elevated risk are non-Hodgkin lymphoma and cancers of the lung, liver, and kidney.

Kidney cancer risk was elevated and bimodal in onset time and also was increased in liver recipients and heart recipients. [14]

Lung cancer risk was most elevated in lung recipients but also increased among other recipients (kidney, liver, and heart).

Liver cancer risk was elevated only among liver recipients in the first 6 months and a 2-fold excess risk for 10 to 15 years thereafter. 

Cancers caused by viral infections

Much of this increased cancer risk is related cancers caused by viral infections. The most common of these virus-related cancers is non-Hodgkin lymphoma, which is frequently caused by Epstein Barr virus. Other virus-related cancers include Kaposi sarcoma (caused by human herpes virus 8), cancers of the cervix, vagina, vulva, penis, anus, and oral cavity (caused by human papillomavirus), and liver cancer (caused by hepatitis C and B viruses).

Transplant recipients also showed an increase in malignancies of the lung, kidney, and thyroid. Skin cancers (especially squamous cell and basal cell carcinomas, but also melanoma) occur at an elevated frequency. In contrast, risk was decreased for breast cancer and, to a lesser extent, prostate cancer. [14] Additional analyses were undertaken for the four most common malignancies with elevated risk: non-Hodgkin lymphoma, lung, liver, and kidney.

Non-Hodgkin lymphoma, liver cancer, and kidney cancer were especially elevated for the youngest recipients, reflecting large increases relative to the general population. The incidence of non-Hodgkin lymphoma was highest in lung recipients, intermediate in liver and heart recipients, and lowest in kidney recipients. [14]

Lung cancer, the elevated risk was greatest among lung recipients, but was also present for recipients of other organs. Risk for lung recipients was especially high in the first 6 months after transplant.

Liver cancer, liver recipients had a strongly elevated risk compared to the general population. Among liver recipients, 95.4% of liver cancers were diagnosed in the first 6 months after transplant, leading to remarkable risk during this interval.

Kidney cancer risk was highest in kidney recipients, but was also elevated among liver and heart recipients. Non-Hodgkin lymphoma and cancers corresponding to three commonly transplanted organs (kidney, liver, lung) together comprised 43% of all cancer cases in recipients, compared with 21% in the U.S. general population. {15}

References

1. Fernandez J. Overview of immunodeficiency disorders. Merck Manuals. https://www.merckmanuals.com/professional/immunology-allergic-disorders/immunodeficiency-disorders/overview-of-immunodeficiency-disorders Updated Feb 2013. Accessed 11 Feb 2016.
2. Giorgi A. Immunosuppressant drugs. Healthline. http://www.healthline.com/health/immunosuppressant-drugs#Overview1 Updated 20 June 2013. Accessed 11 Feb 2016.
3. Immunosuppression. Wikipedia. https://en.wikipedia.org/wiki/Immunosuppression Updated 26 Nov 2015. Accessed 11 Feb 2015. Accessed 11 Feb 2016.
4. Facts and statistics. Australian Government Organ and Tissue Authority. http://www.donatelife.gov.au/discover/facts-and-statistics Updated 2015. Accessed 11 Feb 2016.
5. Engels EA, Pfeiffer RM, Fraumeni JF, et al. Spectrum of Cancer Risk among U.S. Solid Organ Transplant Recipients: The Transplant Cancer Match Study. JAMA. 2011;306 (17):1891-1901.
6. Birkeland SA, Storm HH, Lamm LU, et al. Cancer risk after renal transplantation in the Nordic countries, 1964–1986. Int J Cancer. 1995; 60:183–189.