Increased Cancer Death Risk After Solid Organ Transplant

Alexander M. Castellino, PhD

January 07, 2016

Now that they are living longer, solid organ transplant recipients (SOTRs) face an increased risk of dying from cancer.

The incidence of cancer deaths in SORTs is 2.84 times higher than that of the general population, according to a study published online January 7 in JAMA Oncology.

"Our study represents, to our knowledge, the largest population-based study evaluating cancer mortality from post-transplant de novo and recurrent malignant neoplasms in all SOTRs," the researchers write in their discussion.

"With advances in immunosuppression, SOTRs are doing well with their transplants and living longer. However, other issues are emerging," corresponding author Nancy N. Baxter, MD, PhD, from the division of general surgery at St. Michael's Hospital in Toronto, told Medscape Medical News.

"Our study shows that cancer mortality is the second most common cause of death in SOTRs," she added.

This analysis shows that SOTRs are at an increased risk for cancer-specific death, regardless of age, sex, organ transplanted, and transplant period, write the authors of an accompanying editorial.

The editorial was coauthored by Marianne Schmid, MD, and Felix K.-H. Chun MD, from the Department of Urology at the University Medical Center Hamburg-Eppendorf in Germany, and Quoc-Dien Trinh, MD, from Brigham and Women's Hospital and Harvard Medical School in Boston.

Our study shows that cancer mortality is the second most common cause of death in SOTRs.

"The relationship between transplantation and cancer death has been previously described. The novelty of this study is that it is the most comprehensive effort to date, and circumvents many of the limitations from previous studies," editorialist Dr Trinh told Medscape Medical News.

The Retrospective Population-Based Study

For their study, Dr Baxter and colleagues used an SOTR cohort (n = 11,061) that spanned 20 years, from January 1991 to December 2010, and was assembled from the Canadian Organ Replacement Register — a national registry harboring information on approximately 98% of all Canadian SOTRs since 1981. Non-Ontario SOTRs were excluded from the study, as were SOTRs who died in the 30 days after transplantation.

SOTRs were linked to the Ontario Cancer Registry, which contains information on all incident cancers other than nonmelanoma skin cancers. Mortality was determined from death certificates from the Office of the Registrar General of Ontario death database (ORGD), with verification from the Ontario Cancer Registry. An ICD-9 code of 140 to 239 determined that death was related to cancer.

Cancer mortality rates from the SOTR cohort were compared with those in the general population, which were determined from ORGD and population estimates from Statistics Canada.

Cancer mortality site information was obtained from the ORGD cause of death field.

This robust methodology circumvented a previous population-based analysis on the same topic, the editorialists explain.

"The ability to ascertain the type of cancer death allows us to differentiate between (1) recurrence and death from a pretransplant neoplasm and (2) death from a de novo malignant neoplasm," the editorialists write.

"This is an important distinction because many liver and lung transplant recipients ultimately die of the same disease that was the indication for the transplantation," they further explain.

More Cancer Deaths in SOTRs

Median age of the 11,061 SOTRs was 49 years, 4004 (36.2%) were women, 1124 (10%) had a history of cancer before transplantation. In 442 (39%) of these patients, cancer was the reason for transplantation.

Post-transplant cancer was reported in 1267 (11%) patients, and median time from transplantation to post-transplant cancer diagnosis was 5.16 years.

In the SOTR cohort, 3068 (28%) deaths were recorded, 603 (20%) of which were related to cancer.

With respect to patients with a history of pretransplant cancer, most cancer deaths were associated with the same cancer for which the transplant was indicated. Of the 127 cases of recurrent cancer, 98 (77%) were associated with the very same reason for undergoing transplantation.

Regardless of age and sex, with a standardized mortality ratio (SMR) of 2.84, SOTRs had a 2.84 higher risk of dying from cancer than those in the general population in Ontario.

When patients with a pretransplant cancer history were excluded from the analysis, SOTRs still had a 1.93 higher risk of dying from cancer than those in the general Ontario population.

SMR for skin cancer was the highest (29.82), followed by non-Hodgkin's lymphoma (SMR, 9.76). Although SMR for liver cancer was high (12.72), much of the risk could be attributed to those having a transplant for liver cancer. After the exclusion of these patients, risk was greatly reduced (SMR, 2.28).

Although the overall SMR for cancer was higher for SOTRs than for the general population across all ages, pediatric SOTRs were at a higher risk for cancer (SMR, 84.61) than adults older than 60 years (SMR, 1.88).

"Pediatric SOTRs have a heightened risk of lymphoma, especially non-Hodgkin's lymphoma, which is transplant-related," Dr Baxter told Medscape Medical News.

When cancer deaths were examined by cancer site and transplanted organ, no specific pattern emerged.

All patients were reported to be at increased risk for non-Hodgkin's lymphoma mortality, with cardiothoracic SOTRs having the highest risk. Liver transplant recipients were at increased risk of dying from liver cancer, but kidney transplant recipients were at increased risk of dying from leukemia, melanoma, colorectal cancer, oral cavity/pharyngeal cancer, and prostate cancer. Liver, heart, and lung cancer recipients were at an increased risk of dying from esophageal cancer.

Regarding the generalizability of these data from the Ontario population to SOTRs in the United States, Dr Trinh responded: "On the one hand, Ontario is an ethnically diverse population that in many ways compares to the US; on the other hand, the Canadian healthcare system is vastly different from US healthcare with regard to equal access to care, costs, etc."

Why is Cancer Mortality Increased?

"The increase in cancer mortality is multifactorial," Dr Baxter told Medscape Medical News.

When the immune system is dampened with effective immune suppression to facilitate graft acceptance, immune surveillance decreases, she explained. In addition, with immune suppression, patients are unable to fight infections, which may be associated with some cancers, Dr Baxter indicated.

The editorialists agree. "Immunosuppression induces a chronic immune disturbance, which predisposes the patients to infections and inflammation. This may be important, as certain viruses are known to be involved in the development of malignant neoplasms," they write.

"There are two leading theories why SOTRs are at risk of cancer death," Dr Trinh said.

"For one, cancer arising in an immunosuppressed environment may be more biologically aggressive. Secondly, patients may receive less aggressive cancer treatment due to comorbidities and the fear that transplant rejection may occur," he added.

For example, oncologists may not, justifiably, be willing to give a full-dose regimen of life-saving chemotherapy to a transplant recipient, Dr Trinh explained.

"There are several institutional series that have described the care of bladder cancer in transplant recipients, and these show that providers treat these individuals less aggressively, which is understandable, given the risks of some of the recommended treatments," Dr Trinh told Medscape Medical News.

What Can Be Done?

Although provocative, the study does not establish what needs to be done for SOTRs at risk for cancer death, the editorialists indicate.

"Despite the fact that SOTRs have shorter life expectancies and a higher risk of dying of non-cancer-related causes, these patients have an elevated risk of cancer death as compared with the general population. Addressing the cancer burden in SOTRs is critical to improving the survival of these patients," the study authors conclude.

"We have made significant advances in transplant outcomes; now, the focus needs to shift to trying to reduce the burden of cancer in these patients," Dr Baxter said.

Several measures may be important for SOTRs. Faced with longer survival from transplant and significant risk for mortality from cancer, aggressive treatment needs to be considered for these patients, Dr Baxter indicated.

Prevention and screening should also be areas of focus, she said. For example, patients at risk for lung cancer should undergo lung cancer screening, Dr Baxter suggested.

Dr Trinh agrees. Patients should be encouraged to seek guideline-compliant preventive care, which would include lifestyle recommendations (such as discontinuing tobacco smoking) and cancer screening, Dr Trinh proposed.

Dr Baxter also noted that transplant physicians and oncologists typically do not have much in common, and it is important to bring them together. "It's certainly possible to bring them together, but the incentives have to be there in order to get everyone to the table," Dr Trinh told Medscape Medical News.

Finally, Dr Trinh said: "We can generate hypotheses, but ultimately, more studies are needed to fully understand how to 'fix' the problem."

"Do we need to treat transplant recipients with cancer more aggressively? Are immunosuppressive drugs at fault?" he asked.

Dr Baxter reports receiving research funding from Pfizer. The editorialists have disclosed no relevant financial relationships.

JAMA Oncol. Published online January 7, 2016. Abstract, Editorial


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