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Ann Thorac Surg 1995;60:584-585
© 1995 The Society of Thoracic Surgeons
DR JOEL D. COOPER (St. Louis, MO): I congratulate Dr Keenan and his colleagues on their excellent work, and I appreciate the opportunity to review the manuscript. I cannot recall another so well constructed randomized, prospective clinical trial of immunotherapy after lung transplantation, and I think this is absolutely the way to do it. This type of trial is the only way to answer some of the very pressing questions directed at the currently biggest obstacle to long-term survival after lung transplantation. The early results seem encouraging, perhaps less so than many of us would have hoped, given the urgency of this problem. I also congratulate Dr Keenan and colleagues on their restraint in interpreting their intermediate results.
In my comments I will focus on clinical trials in general, particularly some of the pitfalls of clinical trials, as they may apply to this particular study.
One pitfall is the timing of the evaluation. Most of these patients had a follow-up of less than 2 years after transplantation and the mean follow-up was less than 2 years. My colleague, Dr Sundaresan, reported our own analysis of this problem yesterday by dividing our overall experience with 187 patients into four quartiles: the most recent group of patients, the second most recent, the third most recent, and the most remote group. In the first quartile, our initial experience, the patients all have more than 4 years' follow-up; in the next quartile, the patients have more than 2 
years' follow-up; and the first two groups, the most recent patients, represent those with less follow-up.
As Dr Sundaresan pointed out, the incidence or the prevalence of bronchiolitis oblitereus syndrome rises significantly after the 2 -year mark compared with the early results. So again I emphasize that these are early results and that they are results that have been analyzed at a rather critical time, namely, at a follow-up of 2 years or less. I will be anxious to hear the results after a follow-up of another year or 2.
The second potential pitfall of a clinical trial is to compare a new therapy versus an old therapy and to draw the conclusion that there is a significant difference when, in fact, the flow in the trial is that the control arm has less than the usual expected results and the new therapy, showing better results, in fact has results that are the same as might be expected with traditional therapy. There have been many such trials in which this flow has led to a faulty conclusion.
Our own survival curve showed that with a cyclosporine-based protocol, our 1-, 2-, and 3-year survival curve is virtually identical, just a couple of points higher than the survival curve you showed with tacrolimus. Your 1-year and 2-year survival rates were 83% and 76%, respectively, and ours were 85% and 80%. I would argue that perhaps the 71% and 66% 1-year and 2-year survival rates, respectively, in your cyclosporine-treated control group were, for some reason, less than one would expect, thus creating the impression that the tacrolimus group represents an advance in therapy.
Finally, you indicated that the diagnosis used for this analysis was confirmation by histology of obliterative bronchiolitis (OB). Dr Sundaresan's presentation yesterday indicated that using physiologic criteria when the patients are first seen with what we believe is the bronchiolitis obliterans syndrome, we found the vast majority showed only the physiologic derangement, the loss of forced expiratory volume in 1 second, and not the histologic changes. Even after a longer follow-up, the vast proportion still showed only physiologic, not histologic, confirmation. I wonder if your experience has been the same.
Please construe my comments as caveats, not criticisms. I very much enjoyed the manuscript and your presentation.
DR HANI SHENNIB (Montreal, PQ Canada): I enjoyed your paper very much and congratulate you on doing this study. I think it would have been very difficult for one center to do alone, and it is a credit to the Pittsburgh group that they have a large enough number of patients to be able to undertake such a study. However, despite the large number of patients you have accrued, I believe that you could not disprove a potential disadvantage of a type II error with the number of patients you have. To conclude that both groups are equal in many aspects may not necessarily be correct, and the FK 506 may still have an unrecognized advantage.
I have two concerns. One relates not only to the overall incidence of acute rejection and infection but also to management issues. For example, in the cyclosporine group, I noticed that the levels were around 700 to 1,000 ng. I think many other centers would not go to that level, and I wonder if you see problems with kidney function, not to the extent of a requirement of dialysis but chronic renal dysfunction.
The second concern has to do with age advantages for FK 506 versus cyclosporine. When you analyzed your data, did you find that the younger age group benefit more with FK 506 than with cyclosporine?
DR HANS-JOACHIM SCHÄFERS (Hannover, Germany): I congratulate the authors on an extremely well designed study protocol and an excellent presentation. It is very difficult to compare immunosuppression protocols, even with one immunosuppressive agent, between centers, especially in view of the fact that there is no clear correlation between certain drug levels and the direct immunosuppressive effect. Given this fact, I think the comparison is even more difficult if it involves two immunosuppressive agents. This is where I have trouble interpreting the data.
You quoted cyclosporine levels of 750 to 1,000 ng/mL. This appears to be within the range that formerly was used for nonspecific radioimmunoassay whole-blood levels. For most centers that use specific radioimmunoassay whole-blood determinations, a range of 100 to 400 ng/mL is currently used, which weakens your argument of a narrow therapeutic window for cyclosporine. My question is, what type of levels did you choose?
My second question refers to the neurotoxicity of FK 506. In hepatic transplantation, a significant incidence of neurotoxicity in the early postoperative phase has been observed. Have you seen anything similar in your experience?
DR PAULO F. G. CARDOSO (Porto Alegre, Brazil): Congratulations, Dr Keenan, for such outstanding work in this clinical area. All of us involved in transplantation know that immunosuppression is still a problem.
I have two questions. The first concerns the cost of tacrolimus. I remember that FK 506 was quite an expensive drug a couple of years ago, and I wonder how much it costs today.
The second question is about tolerance. Did you notice some degree of induction of tolerance over the course of immunosuppressive treatment with the drug? I realize that your follow-up is still short, but this issue has also been addressed experimentally by others, such as Dr Hirai in Japan, and it seems very important if it can be translated to the clinical setting. Therefore, I am interested in hearing something about the induction of tolerance you may have noticed.
DR KEENAN: I thank Dr Cooper for discussing our paper and acknowledge the fact that his leadership role in the field of lung transplantation sets a standard to which we all need to aspire. His brief discussion about the 1-year, 2-year, and even 3-year survival rates at Barnes Hospital, being clearly much better than registry data and much better than the majority of lung transplant centers around the world, means that many of us still have some lessons to learn about how to manage these patients to improve their survival.
In regard to the question of whether or not our follow-up is short, I agree that it is at this point probably the earliest that we could legitimately even start to look at the issue of OB. As I said in the presentation, the average time of presentation of OB was about a year or a little less than a year. Clearly, as we follow these patients, there are going to be individuals in whom it will develop more than 2 years postoperatively. However, if I look back at our experience since 1986 with the isolated lung transplantations we have performed, OB developed in the vast majority of those patients within the 2- to 2 -year period. I think we have probably now captured the majority of patients who are at risk for developing OB. There will continue to be some as time goes on, but I think that the ability to analyze the issue of OB is fundamentally available now and will change only somewhat modestly over time.
As for the diagnosis of OB, clearly the frustration with using histology alone is what led many of us to adopt the physiologic approach to bronchiolitis obliterans syndrome. I think the experience in many centers is still not good enough to rely completely on that as the way to go, and for the purposes of this trial, we thought that relying on histology, an accepted gold standard, if you will, was appropriate. Perhaps by reanalysis we will find other patients later who will show this syndrome, but I am not convinced that it will make the analysis any different.
In regard to the comments of Dr Shennib and Dr Schäfers about the cyclosporine level being between 750 and 1,000 ng, you are quite right that that represents a nonspecific TDX, a method that we use clinically at the University of Pittsburgh. Perhaps by using the more specific radioimmunoassay analyses, we could tighten our therapeutic window. In all instances we try to push the level of immunosuppression, whether it is FK 506 or cyclosporine, to what is considered a somewhat toxic level, whether by the nonspecific or the specific technique, and we use rises in serum creatinine and decline in creatinine clearance as the measures for this. Approximately 40% to 50% of the patients in each arm have some major degree of renal dysfunction with a doubling of the serum creatinine levels from preoperative levels.
As for Dr Shennib's other question about whether younger patients do better, frankly we have not analyzed that. I think that the fact that overall, irrespective of age, the tacrolimus-treated patients did better speaks for itself.
In regard to Dr Cardoso's comments, throughout much of this trial, tacrolimus, or FK 506, was an experimental drug, and therefore it was provided free to the patients. Subsequent to the Food and Drug Administration approval of tacrolimus, which is why it has its new name and the trade name Prograf, it is now commercially available and has been priced to compete with cyclosporine at virtually the same cost to the patient. I think that only now will we be able to look seriously at the induction of tolerance and the presence potentially of microchimerism through peripheral blood analysis. We have not done that yet but will over the next couple of years.
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