The AJT Report: News and issues that affect organ and tissue transplantation

Abstract

This month, The AJT Report explores new efforts to assess cancer risk in transplant patients, including a multinational study underway to better understand skin cancer in the post-transplant population.

The Cancer Connection

Over the past several years, the transplant community has learned about skin cancer and post-transplant lymphoproliferative disease in transplant recipients, but little is known about other types of cancer in transplant patients. “We need to figure out whether transplant patients are getting more of certain types of cancer, when the cancer is being diagnosed relative to the time of transplant and the stage of the tumor and if the outcome is different for transplant patients compared with non-transplant patients,” says Sandy Feng, MD, transplant surgeon at the University of California, San Francisco. But, it's been difficult for the transplant community to gather this information. “We're transplant, not part of the cancer community,” says Dr. Feng. “It's like we're two different worlds trying to merge, so it's not easy to get the data.”

That may be changing. This summer, Eric Engels, MD, a senior investigator at the National Cancer Institute (NCI), and colleagues from the Health Resources and Services Administration (HRSA) and the Scientific Registry of Transplant Recipients (SRTR) are analyzing data from a comprehensive national Transplant Cancer Match Study. The collaborative effort is matching SRTR data on 150,000 U.S. transplant recipients with information from 12 state or regional cancer registries. The researchers hope to publish their findings later this year. “We're all very excited about this study and we've had a lot of enthusiasm from the cancer registries,” says Dr. Engels. “It's a challenge to do these studies because U.S. cancer data are collected separately in each state. But once we've shown how powerful this approach is, we expect additional registries to be interested in future collaboration.”

The team wants to characterize cancer risk among transplant recipients as well as determine the types of cancer these patients get. “One of the cancers we've been especially interested in is lung cancer,” says Dr. Engels. The risk of lung cancer appears to be elevated in transplant recipients, while their rate of smoking is about the same as the general population. This suggests that there might be something else going on, he says.

Epidemiology of Cancer in Immunosuppressed Individuals

Since 1998, Dr. Engels has studied cancer in immunosuppressed individuals, primarily those with HIV/AIDS. About five years ago, he began research on cancer in solid organ transplant recipients, including epidemiologic studies of risk factors for transplant-associated Kaposi sarcoma and hepatocellular carcinoma using SRTR data.^1,2 In addition, he recently used Medicare data to write about skin cancer in transplant patients, including information on a rare skin cancer called Merkel cell carcinoma, which also has a higher incidence in transplant recipients than in the general population.³

Dr. Engels has found that having a weakened immune system increases the risk for a number of cancers, but probably not all cancers. “That's what we want to look at in this new study,” he notes. “It may be that having a weak immune system predisposes people, in particular, to viruses. But we don't expect the risk will be greatly elevated for some of the common cancers like colon, breast or prostate.”

E. Steve Woodle, MD, chief of the division of transplant surgery at the University of Cincinnati, and colleagues have recently published stage-specific comparisons between de novo cancers (lung, breast, prostate, colon, bladder, renal cell and melanoma) occurring in transplant patients and those in the general population.⁴ The researchers compared data in 635 adult transplant recipients from the Israel Penn International Transplant Registry with that of about 1.2 million adults from the general population in the Surveillance, Epidemiology and End Results (SEER) database. These studies demonstrated that cancers in transplant recipients often present at more advanced stages, but that this varies based on the type of cancer. Cancer-specific survival was evaluated and revealed that transplant recipients had poorer survival for some stages in most of the cancer types studied. Dr. Woodle and his team also demonstrated that transplantation confers a relative risk comparable with that of the cancer stage in terms of its effect on disease-specific survival.

However, all potential risk factors that influence disease-specific survival were not determined, says Dr. Woodle. The Cincinnati group is currently conducting a more detailed analysis that includes multiple risk factors in transplant and general population patients. In collaboration with Joseph Kim, MD, PhD, assistant professor of medicine at the University of Toronto, Dr. Woodle's team is conducting an epidemiologic analysis of this “very robust” data set to examine the effect of transplantation on cancer risk and outcomes. “We think this particular project provides a highly controlled study structure to get at the issue of the effect of immunosuppression on cancer behavior and outcomes,” says Dr. Woodle.

KEY POINTS

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  A collaborative effort is under way to match SRTR data with information from cancer registries to characterize cancer risk among transplant recipients.
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  Patients with weakened immune systems may have increased risk for some, but not all, cancers.
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  More frequent and detailed cancer surveillance check-ups among transplant recipients may catch the disease earlier.

More Frequent Cancer Check-Ups?

Dr. Woodle's team suggests that more frequent and detailed checkups may catch cancer in its earliest stages. A similar argument was made by Spanish researcher J. Ignacio Herrero, MD, a hepatologist who is on the Transplant Committee of the University of Navarra Hospital in Pamplona, Spain, and his team: They called for a close surveillance protocol for the diagnosis of malignancy.⁵ When asked whether his studies have encouraged his European colleagues to increase cancer surveillance, he says “most European liver transplant programs do not have a program of neoplasia surveillance for their patients, but the increasing numbers of patients dying of neoplasia with a functioning graft is moving some of them to surveillance.”

The risk of lung cancer is elevated in transplant recipients, while their rate of smoking is about the same as the general population. This suggests there might be something else going on.—Eric Engels, MD

Dr. Feng is impressed with the intensive screening program. “It's important to demonstrate that screening has benefited their population because they've been able to identify cancers early, and that's improved the outcome of those patients. But the next questions are, 'Is it cost effective? How much screening should you do? Should everybody be getting mammograms or is there a subset of patients who should be getting mammograms, or subsets getting colonoscopies, or a subset at risk for head and neck cancer because of alcoholism?' None of that is yet known.”

Switch to an mTOR inhibitor?

Some of the latest work in transplant patient skin cancer involves viruses, says Hans H. Hirsch, MD, from the Division of Infectious Diseases, University Hospitals Basel, Switzerland, who also notes that it is possible that, as the risk for cancer increases with long-term immunosuppression, certain immunosuppressive drugs (such as mammalian target of rapamycin [mTOR]) might protect or delay cancers.¹ For example, a recent study in AJT showed that a switch to an mTOR inhibitor (sirolimus) reduced premalignancies.²

However, Fiona Zwald, MD, transplant dermatologist at Emory University in Atlanta, cautions that–due to adverse effects–sirolimus is not for everyone, adding that she'd like to see a study that compares cyclosporine or tacrolimus with sirolimus to see which patients do better from the standpoint of skin cancer.

A Global Effort

To better understand skin cancer in the post-transplant population, researchers have conducted a number of international studies on the topic, and more are currently under way. Skin Care in Organ Transplant Patients, Europe (SCOPE) is an interdisciplinary network of dermatologists, transplant physicians, patient support groups and basic researchers brought together to meet the increasing need for qualified dermatological aftercare in transplant patients who develop skin cancer. Developed in 2000, the organization works closely with the North American and Australian International Transplant Skin Cancer Collaborative (ITSCC). According to SCOPE president Jan Nico Bouwes Bavinck, MD, PhD, the strength of the European network is its large number of participating patients, which allows the study of less-common skin cancers.

SCOPE is now working on a study about pain as a possible signal of skin cancers, and members have joined forces in a multinational trial to study afamelanotide as a systemic photoprotective agent against actinic keratosis and squamous cell carcinoma in solid organ transplant recipients.

In 2006, the ITSCC was one of three organizations that created an education and awareness program. Called the After Transplantation-Reduce Incidence of Skin Cancer (AT-RISC) Alliance, it's a cross-disciplinary collaboration between ITSCC, the International Transplant Nurses Society (ITNS) and the Transplant Recipients International Organization (TRIO).

ITSCC board member and Emory University transplant dermatologist Fiona Zwald, MD, recently collaborated with ITSCC colleagues in an AJT article about melanoma in solid organ transplant recipients in which she outlines the clinical course of pre-transplant melanoma, donor-transmitted melanoma and de novo melanoma post transplant.¹