© 2008 American Thoracic Society doi: 10.1164/rccm.200801-019ED
Lung Transplantation in Children with Cystic FibrosisA View from Europe
Great Ormond Street Hospital for Children
Great Ormond Street Hospital for Children
Hospital Vall d'Hebron Epidemiologic studies do not usually receive extensive coverage in the lay press. Nonetheless, this was the response to Liou and colleagues' results concerning post–lung transplant survival that were published in The New England Journal of Medicine last year (1). According to the authors, only 5 of 514 children with cystic fibrosis (CF) listed for transplantation in the United States would have received survival benefit from the procedure. Many of the news sources reporting on this study mentioned the authors' conclusion that a prospective randomized trial is now required. However, closer examination of the data reveals a more complex picture concerning the utility of lung transplantation in children with CF. Liou and colleagues identified children by retrieving data from the U.S. CF Foundation Patient Registry and the Organ Procurement and Transplantation Network. Of the 514 children listed, 141 died prior to transplantation, at a median time of 223 days after listing; and 248 underwent transplantation, with a median post-transplant survival of 1,037 days. A simple reading of these figures suggests that children who received transplants lived much longer than those who did not. However, such a conclusion is unreliable, as it may be that children with poorer life expectancy died on the list, whereas those with better prognosis survived to transplantation. In 1977, Crowley and Hu (2) described a modification of Cox proportional hazards modeling (3) designed to answer exactly this question. In this analysis, patients' life expectancy from the time of listing is modeled from prognostic variables, and transplantation then entered as a time-dependent covariate. A partial hazard ratio for transplantation is thus calculated that applies at the time of surgery. Importantly, this method assumes that the other variables entered into the model are accurate predictors of survival. Using this method, Liou and colleagues calculated that only 5 of 514 children listed for transplantation were likely to have received a survival benefit from the procedure, 315 were unlikely to have received a survival benefit, and for the remaining patients the benefit was unclear. The findings of this study are dramatically at odds with previous work. A number of reports have now calculated a significant survival benefit for lung transplantation in adults (4–9). The one previous pediatric study, of 124 children with CF from Great Ormond Street Hospital for Children in London (10), calculated a highly significant survival benefit associated with lung transplantation (partial hazard ratio for transplantation, 0.31; 95% confidence interval, 0.13–0.72; P = 0.007). In their discussion, Liou and colleagues imply that the discrepancy between their study and the previous one from London is because the London study was underpowered. We suggest that a closer comparison of the London study with that of Liou and colleagues provides important insights into the potential utility of lung transplantation for CF. First, the survival advantage reported by the London group was clear cut and highly statistically significant. Second, there is a discrepancy between the post-transplant survival figures reported in the two studies, with the London group reporting a median survival of approximately 3.5 years, while Liou and colleagues report median post-transplant survival of 2.84 years during a later era. This result is surprisingly poor, as the International Society of Heart and Lung Transplantation now reports a median post–lung transplant survival of just under 5 years for children (11), with most larger centers reporting even better results (personal communication, O. Elidemir, Texas Children's Hospital, on behalf of the International Pediatric Lung Transplant Collaboration). The third discrepancy between the two studies is even more striking. While the great majority of children listed in the London study had a predicted survival without transplant of less than 2 years, Liou and colleagues estimate that 57% of the children listed in the United States had a predicted survival of 5 years or greater. If Liou and coworkers' prognostic model is accurate, then it is not surprising that many of these children had their lives shortened by transplantation. Is that assumption true? Although Liou and colleagues studied a number of predictive variables in constructing their survival model, many physiological markers that transplant centers use for making prognostic and listing decisions were not available for their analysis. Our concern is heightened by comparing the raw data with the model predictions. Of the 266 children who did not undergo transplantation, 151 (57%) were predicted by the model to have survival without transplant of 5 years or greater. However, 141 (53%) of these children then died on the list—the majority within 8 months. Of the remainder, 40 (15%) were lost to follow-up, and only 85 (32%) were still known to be alive at the end of the study. It is not for Europeans to tell physicians in the United States how to treat their patients, but we can report our own practice. In London and Barcelona, it is very rare for children with CF to be considered for lung transplantation unless they are already on full medical therapy and, despite that, they have a predicted life expectancy of 2 years or less. To our knowledge, most of our European colleagues apply similar protocols. The benefit of this approach is that most children who receive transplants will have their lives extended as a result. The disadvantages are that many children die while waiting for organs, and a few die without ever being listed when the assessment of prognosis is inaccurate. These are not small issues, and decisions on listing are not taken lightly. The most important point about this controversy is that the United States is currently in a position to apply many of the advantages of the European listing model while minimizing the disadvantages. The Lung Allocation Score (LAS) was introduced in 2005 for all patients listed for lung transplantation aged 12 years or older (12). This score aims to direct organs to those patients who have the potential for greatest survival benefit (i.e., those who have the poorest predicted survival without transplant and the best predicted post-transplant survival). Even the first attempt at the LAS uses prognostic data of higher quality than that used by Liou and colleagues (12). The aim, however, is to regularly update the LAS model in an attempt to improve reliability. Given this scenario, we believe that a call that this system should be halted and substituted with a randomized controlled trial is incorrect. We hope instead that the current controversy will stimulate rigorous study of how effectively the LAS achieves its objectives, and hopefully encourage its extension to younger children. In conclusion, we see no justification for stopping transplanting lungs into children with CF. FOOTNOTES Conflict of Interest Statement: None of the authors has a financial relationship with a commercial entity that has an interest in the subject of this manuscript. REFERENCES
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