In addition to that, what about neoadjuvant chemotherapy? At the same time that these studies were being done, we had the development of prostheses and these prostheses took about 2-3 months to initially obtain from the companies. So Dr. Rosen, who was at Memorial Hospital at times, decided, “Well, if we are waiting this long for the prostheses and we are considering doing a limb-sparing procedure, maybe instead of waiting for the tumor to grow more, we should be giving some chemotherapy.” So he developed several protocols giving induction neoadjuvant chemotherapy for early treatment to possibly reduce tumor size, to facilitate the limb-sparing procedure and, as we talked about before, giving us an in vivo chemosensitivity test. Now there have been multiple institution studies done in institutions around the country looking at neoadjuvant chemotherapy with results that are at least as good for relapse free survival compared to adjuvant chemotherapy. There has been no definite randomized trial confirming that patients do any better, but I can tell you now that most orthopedic surgeons will not operate on a patient without the patient receiving induction chemotherapy first. The only randomized trial was done by the Pediatric Oncology Group and this is just to show you that in our adjuvant studies, which are mostly multi-institutional and cooperative groups, five year disease free survivals were between 46-61%. In single institution studies with neoadjuvant they were a little bit higher, but we know usually that single institution studies there is patient selection, so it could be a little bit higher. But in a randomized trial there was no difference between adjuvant or neoadjuvant plus adjuvant chemotherapy.

Here is the data. In 100 patients, again a small study – because these are rare tumors and the study took quite a long time – there was no difference in disease free or overall survival. So several oncologists in the community took this study to say that there is no benefit in neoadjuvant chemotherapy and you shouldn’t give it. Adjuvant chemotherapy is enough. But I think you really need to decide whether the cup is half full or the cup is empty. Another way of looking at this study is, yes there is no difference in survival but you have the benefit that you may be able to do much more limb-sparing surgery. So you could look at this study and say, “There are more patients who have had limb-sparing surgery and there has been no detriment in terms of survival in doing the limb-sparing surgery.”

Well, as part of Rosen’s study of giving induction chemotherapy, he also wanted to evaluate whether you could tailor chemotherapy afterwards. In other words, the in vivo chemosensitivity test. In other words, giving induction chemotherapy then looking at histologic necrosis and then, based on whether the patient had a good response – greater than 90% necrosis or less than 90% necrosis – either giving the same chemotherapy or if there was a very poor response to chemotherapy, giving other active drugs. In his initial studies, specifically protocol called the T-10 protocol, there appeared to be initial favorable outcome by changing the chemotherapy, giving a lesser chemotherapy preoperatively and then giving more aggressive chemotherapy postoperatively for those patients who were poor responders. Unfortunately, this concept has been tested in the Children’s Cancer Study Group, the German Group, the Italian Group, and they failed to confirm this concept. Other researchers at Memorial, Dr. Meyers, presented Dr. Rosen’s data with longer follow-up and it hasn’t held up. So I think what’s really important, in terms of induction chemotherapy, is that you need to use more intensive chemotherapy up front. That for the most part giving more intensive therapy postoperatively is not going to bail you out.