Well, where are we going in the future? I think where we are going in the future for sarcomas is further dose intensification with growth factor and stem cell support. Possibly reversing multi-drug resistance, like for Adriamycin, with PSC-833 and Incel. Possibly angiogenesis inhibitors to reduce the chances of metastasis. New work done in hormonal growth manipulation, one out of the Dana Farber. Dr. Dimitri looking at the peroxisome proliferator activating receptor gammon. It’s a ligand. Troglitazone is a ligand for this receptor which is an antidiabetic drug. Stimulating this receptor causes terminal differentiation of lipocytes and it may be helpful in inducing adipose differentiation. At the NCI a somatostatin analog, somatuline, is being looked at. This blocks the release of growth hormone which decreases the production of insulin-like growth factor 1, which is a growth factor for osteogenic sarcoma, and which is being looked at in the adjuvant setting. Also, as I mentioned, the work at Memorial with the possible use now of Herceptin in those osteogenic sarcoma patients who are HER2/neu positive, to possibly use in conjunction with platinum. Immune-modulation; worked on by Dr. Kleineman at the M.D. Anderson. LMTPE is one of the smallest components of the microbacterium and this causes stimulation of the pulmonary macrophages and in both a murine and a human model has … she has shown that there has been a reduction in the incidence of lung metastasis and a decrease in lung metastasis. So the intergroup, pediatric group now – which is the CCSG plus POG – is looking at the use of this agent after the patients have received adjuvant chemotherapy in osteogenic sarcoma. Possible use of immunotoxins. Our group and the NIHLBI are looking at the use of non-myeloablative allogeneic transplant. In other words, giving a somewhat lower dose chemotherapy regimen of Cytoxan and fludarabine in those patients who have a relative who is an HLA match. And in terms of giving them then their relative’s marrow, and in hopes of in addition to giving their relative’s stem cells back to them, also lymphocytes and in hopes of inducing a graft-versus-tumor response. This has already been tried now in renal cell and has been presented at the ASCO and they have some very high quality responses, specifically for renal cell. We have chosen sarcomas as well because they appear to have MHC class I and II antigens and HLA antigens where you may be able to induce an immune response.

Also utilizing oncogene products, modifying tumor suppresser genes, antisense oligonucleotides, using the fusion genes that I showed you earlier as molecular markers and possibly developing vaccines to some of these tumor-specific fusion peptides. And that’s work that’s being done at the pediatric branch at the NCI.

Well, in conclusion I want to emphasize that in order to advance the goals of local tumor control, limb-salvage with optimal function, to minimize treatment morbidity, and also to improve long term survival with the goal of maximum cure; that for the sarcomas because they are so rare and because they involve so many different disciplines, it’s really important if possible to have a multi-disciplinary team approach to treat these patients.

Two studies now, which have incorporated not only Adriamycin, methotrexate and cisplatin, but also looking at the use of higher doses of ifosfamide, one by Dr. Meiser where ifosfamide was incorporated with Adriamycin and high dose methotrexate, gave a very high limb-sparing surgery rate, very high tumor necrosis rate and very good relapse free and overall survival. Another institution, the Rizzoli Institute in Italy looking at two different studies. This was not prospectively randomized but retrospective, but in one where ifosfamide was given postoperatively and another where ifosfamide was given preoperatively. You can see that in the study where it was given preoperatively there is a much higher limb-salvage rate, much higher amount of tumor necrosis, local recurrence is the same and disease free survival is better.

So now for osteogenic sarcoma, I think what I’ve tried to show you is that in the 70’s and before the 70’s for historical controls, those patients who just received surgery or radiation, about 20% of patients survived. With the benefit of adjuvant and neoadjuvant chemotherapy with agents like platinum, Adriamycin and high dose methotrexate, that’s increased to about 60%. With ifosfamide now added to the regimens there is about another 10-20% benefit, but still approximately 30%, 20-30% of our patients, those with chondroblastic osteogenic sarcomas, those with metastasis on presentation still do very poorly. So we need new approaches.

So in overview now of osteosarcoma; a core or incisional biopsy, surgery – limb-sparing if possible – metastasectomy beneficial in select patients. In terms of chemotherapy, adjuvant is the standard. That’s been shown in two prospective studies of significant benefit, so that is the standard and has definite survival benefit. Whether tailoring is beneficial, the studies do not pan that out. It’s probably more important to give more aggressive chemotherapy as induction. Neoadjuvant, although there has been no study to show any definite improvement, it appears to be at least equivalent with probably more patients having limb-sparing surgery. This is favored, as I said, by most orthopedic oncologists and should include at least platinum and Adriamycin. Some regimens also include high dose methotrexate, but that has to be given properly. And probably now also to include higher doses of ifosfamide.

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.