What is the skinny on tandem tranplants in neuroblastoma?

I have been receiving a lot of email lately regarding the tandem transplant question in high risk neuroblastoma. While I can't blame anyone for having fear related to one transplant, much less two, I am seeing a higher degree of concern than I have in years past. Most of these discussions have focused on the toxicity related to the transplants. Parents often feel that if you have double the transplant you must also have double the risk. Fortunately, from published papers, that has not necessarily been the case. Regardless, I thought a more thorough discussion of why the COG is asking the tandem transplant question was worthwhile. There is a fairly large amount of science in this area. What does the research seem to indicate?

Not surprisingly there is actually some pretty strong data supporting the idea behind tandem transplants. First, the published data seems to indicate that the toxicity is tolerable. In other words, it does not seem to be adding much more toxicity than a single transplant. In fact, there is at least one study that actually seems to indicate that there is less toxicity. Go figure? While there is some somewhat long term data, a tandem transplant's effect in the long term (10, 20, 50 years) is relatively unknown. For that, we will have to wait and see. The main point to gain from all of the research is that while there is toxicity related to the second transplant it does not appear to double your risk.

From the standpoint of an increase in survival, the published studies seem to show a significant increase in survival. Now please realize that I say this also knowing that institutions like TXCCC went from tandem transplants back to single transplants because they did not see a difference in survival and, in their experience, saw an increase in toxicity. I have not seen that data published and only know that from personal communication. With that being said, the strongest published data still seems to indicate that a tandem transplant will increase survival. We just don't know if that will still hold true in a large randomized phase 3 trial such as the one being offered in the COG.

There have been some fairly decent sized studies that have looked into tandem transplants. While none are directly comparable to the current study offered by the COG they do offer some insight into the impact of the tandem transplant. In most cases the studies have included differing induction chemotherapy regimens, total body irradiation, and a difference in timing of local irradiation. However, one can make a strong argument that the difference in survival seen in these studies in probably due to the tandem transplant itself.

There are 3 published studies regarding tandem transplants that appear to be the most referenced. These are:

• High-risk neuroblastoma treated with tandem autologous peripheral-blood stem cell-supported transplantation: long-term survival update. J Clin Oncol. 2006 Jun 20;24(18):2891-6.
• Tandem high-dose chemotherapy and autologous stem cell rescue in patients over 1 year of age with stage 4 neuroblastoma. Bone Marrow Transplant. 2007 Jul;40(1):37-45.
• Treatment of high-risk neuroblastoma with triple-tandem high-dose therapy and stem-cell rescue: results of the Chicago Pilot II Study.J Clin Oncol. 2002 May 1;20(9):2284-92.

The earliest work attempting to answer the question of whether a double transplant might improve survival used a double harvest/double graft approach with purged bone marrow support, with an OS rate of 32% at 5 years in a high-risk group of patients. In an analysis of 546 patients with advanced neuroblastoma from the European Bone Marrow Transplantation Solid Tumor Registry, a 5-year progression free survival (PFS) rate of 24% was reported for 436 patients who underwent a single procedure compared with 33% for 110 patients who underwent double mega-therapy. In the Chicago Pilot II study (mentioned above) in which 17 high-risk neuroblastoma patients were treated with triple-tandem cycles of high-dose therapy with peripheral blood stem cell rescue (PBSCR) and local irradiation, the 3-year PFS rate was 57%. In the long term survival study mentioned above, patients who underwent double high-dose therapy had a 3-year PFS rate from time of first transplantation of 61%, and 5- and 7-year PFS rates of 54% and 52%, respectively. For reference, the 3 year PFS for a single transplant was 34% in a large randomized phase 3 study in the COG. While a tandem transplant certainly appears to be better than the results of a single transplant, the question as to whether or not two transplants is significantly better than single transplant regimens still requires a larger, phase III randomized study to prove. This is the rationale behind this COG's randomized tandem transplant trial.

From the standpoint of these studies it certainly appears that a tandem transplant would be the way to go. However, it isn't as clear as it may seem. As I pointed out, there are some differences in the studies. Secondly, in these smaller studies with single institutions or small groups of hospitals it is impossible to rule out patient bias and other factors. Many of these studies were completed at institutions known for their superior patient care and expertise in this area. Could the quality of care provided at these institutions impact survival - possibly? All of these are reasons why it is important to ask the tandem transplant question in a randomized phase 3 trial. We simply do not know the answer for sure. We certainly hope it significantly increases survival but the bottom line is that we do not know. It could go either way.

Many parents ask - "If it were you, what would you want?" My answer is no different than theirs. I want my child to live. There is no answer. That is what is so important about this trial. Frankly, if my child were randomized to a single transplant I would be very happy that we would not have to subject her to the added risk of a second transplant. If she were randomized to 2 transplants I would be happy that she had a chance at increased survival. No matter which way we went you could bet that I would be able to find an adequate amount of research supporting our direction.

We don't know the answer. But, it is because of our children that others will.

I wish there was an answer for all of our purpii but, as of this point in time, either side of the coin could be a winner.