Dr. Jason Chien was not happy with the answers he could give his patients. Chien, an investigator in the Clinical Research Division's Pulmonary/Critical Care Section at the Hutchinson Center, knew there was a connection between a patient's lung function and risks of long-term complications or death after stem-cell transplantation. But nobody had shown how extensive that link was.
"When I was asked to give my opinion regarding a patient's poor lung function prior to transplant, I didn't feel like the information we had access to was consistent with our clinical observations," said Chien, who also runs a pulmonary clinic at Seattle Cancer Care Alliance (SCCA) for long-term survivors of stem-cell transplants. "That's really what drove me to conducting these studies — so we can provide a better answer to the patients and their oncologists."
Recently, Chien and other Hutchinson Center researchers have published several papers relating lung-function tests to transplant outcomes. One of the papers related poor pretransplant lung function to heightened risks of respiratory failure and death after transplant. Another paper assessed the lung function of pediatric patients who survived five or more years after transplantation.
Ultimately, the research will provide better answers for patients — and for other doctors — about the risks of respiratory failure and death after stem-cell transplantations.
Before and after
Stem-cell transplantation refers to the process by which diseased blood cells are removed by chemotherapy and/or radiation, and then replaced with donor stem cells. When successful, the stem cells regenerate into a normal blood and immune system. But the process — which has been used with increasing success in recent years to treat numerous cancers — can have treatment-related pulmonary complications. Thus the need for continued research.
Although much of Chien's work focuses on the care of survivors after transplantation, his group's recent studies have taken a step back to assess what the pulmonary function tests taken before transplants indicated about the risks for respiratory failure and death occurring after transplant.
Chien is senior author of a paper published in the May 2005 issue of the American Journal of Respiratory and Critical Care Medicine. In this paper, the researchers examined lung-function tests from 2,852 patients who received transplants between 1990 and 2001. While they stopped short of ascribing actual predictive powers to the lung-function tests, the researchers found that poor lung function prior to transplantation is closely associated with higher risks of early respiratory failure and death.
Lead author Tanyalak Parimon, who is currently in a residency in Boise, Idaho, analyzed data for the article while at the Hutchinson Center.
"What's really novel about this study is that for the first time ever we found that for every aspect of lung function measured by a pulmonary function test, the lower your lung function, the higher your risk for these two outcomes [early respiratory failure and death]," Chien said. Earlier studies, including one conducted at the Hutchinson Center in the early 1990s, had shown — in a more limited way — that only some aspects of poor lung function were associated with risks.
The new study also took measurements from the lung-function tests and developed a "lung-function score" that boiled down the many pulmonary function test variables to estimate each patient's lung function-related risks before transplant. "We found that this score actually performed better than the individual parameters measured by lung-function tests," Chien said.
However, Chien stresses that the prediction of a transplant patient's risk for death should involve more than just measurement of baseline-lung function. There are clearly other pretransplant risk factors for death that should be considered, he says, such as a patient's age and the extent of their disease. Chien and colleagues plan to publish further research that takes other pretransplant risk factors into account.
Meanwhile, Chien said that the findings about pretransplant lung tests have already led to some clinical changes. Locally, the SCCA has adapted its protocol for tests prior to stem-cell transplants. "Our center has eliminated a particularly painful arterial blood test because it provided no more information than a lung-function test," he said. "That, I think, has benefited patients, not to mention that it has reduced costs."
Dr. Mary Flowers, medical director for the SCCA's Long-Term Follow-Up Clinic (LTFU) also sees promise in the work associating lung function to respiratory failure and mortality risks. "The first step to improve outcomes in transplants is to be able to identify the risk factors associated with those outcomes," she said. "Moreover, by establishing a pulmonary clinic at the SCCA, Dr. Chien has played an important role in the management of late lung complications after transplantation of LTFU patients."
Standardized pretransplant tests
Both Flowers and Chien agree that, for a further test of the link between pretransplant lung tests and outcomes, it would help for all transplant centers to conduct testing in a standardized way, follow patients long-term, and track these data in a centralized database. Currently, only some of the largest transplant centers record pretransplant pulmonary function data, and no centers are tracking these data for research purposes. "Clinically, my goal is to urge all transplant centers to obtain pretransplant pulmonary function tests and incorporate them into the mortality risk assessment," Chien said. "From a research perspective, I hope these data encourage registries, such as the Center for International Bone Marrow Transplantation Registry (CIBMTR) and the National Marrow Donor Program (NMDP), to include the reporting of pretransplant pulmonary function tests in their research databases."
While Chien's group has been looking retrospectively at lung-function tests conducted before transplants in adult patients, Dr. Jean Sanders, who directs the Hutchinson Center's pediatric stem-cell transplantation program, has been using lung-function tests to assess the status of long-term transplant survivors who were children at the time of their transplants.
Publishing results in the June 2005 issue of the journal Pediatric Blood and Cancer, Sanders found that 55 percent of long-term survivors had pulmonary dysfunction of some kind, primarily restrictive lung disease, a condition in which the volume of air in the lungs is decreased. The study represented the largest-ever analysis of pulmonary function in pediatric transplant survivors taken at a point in time. The 215 patients analyzed had all survived at least five years after transplantation.
"The purpose of doing this research was to answer the question, 'Do we have a problem?'" Sanders said. "The answer is, 'Yes, these children do have problems five or more years after their transplants.'"
Sanders knew of a number of long-term patients who had died of pulmonary disease and felt that the problem needed to be studied: "Physicians taking care of these patients must be alert to studying them long-term, not just saying, 'You're cured.'"
"I think most doctors would have guessed that 20 percent of patients have dysfunction," said Paul Hoffmeister, the paper's lead author and project coordinator in the Pediatric Transplantation program. "Finding that more than 50 percent had dysfunction was pretty astounding."
The research points up the importance of following transplant patients long-term with lung-function testing.
Sanders said that further studies are necessary to see if the lung dysfunction in the patients gets worse or stays the same. Meanwhile, the pulmonary tests proved their worth for identifying the problems in long-term survivors.
"It's gratifying to identify what problems long-term survivors are having, both to help them deal with these problems and also to try to prevent these problems for future transplant patients," Hoffmeister said.