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.

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.

What about the bone sarcomas? Even rarer than the soft tissue sarcomas, and the only one I’m going to talk about today is osteosarcoma. It’s about 35%. It’s usually a disease of the second decade, similar to Ewings sarcoma. Chondrosarcoma and malignant fibrocystic sarcoma are in older age group. It’s usually a tumor of the metaphyseal area of the bone, usually the distal femur as opposed to Ewings sarcoma which usually is a disease of the shaft or the diaphyseal portion of the bone. This is the most common primary bone tumor, excluding myeloma. There are about 1,000 new patients per year. Somewhat of an increased incidence in males versus females. There is a biphasic occurrence, mostly in adolescents with the growth spurt, but also in the elderly associated with Paget’s disease and previous radiation therapy. What you are looking for when you look at the pathology is malignant sarcomatous stroma, associated with the production of osteoid and immature bone. As I said, it involves the metaphyseal portion of bone and it usually either metastasizes to lung or other bone, again avoiding the liver. In about 15-20% of the time patients present with metastasis. So you want to see here abnormal-looking osteoblasts and osteocytes in a sea of osteoid. If you don’t see osteoid then you can’t call this an osteogenic sarcoma. There are multiple different types of osteogenic sarcomas. I don’t want you to memorize the slide. I just want you to be aware that of the conventional type, chondroblastic usually has somewhat of a worse prognosis, don’t respond as well to chemo. There are some clinical variants. Osteosarcoma of the jaw, mandible maxillary area where again you may not be able to achieve very wide margins, and here you may use radiation therapy. Postradiation osteosarcoma, which connotes somewhat of a worse prognosis. They are older patients as well as Paget’s disease being older patients as well. A variant, telangiectatic where when you cut through the bone of a telangiectatic sarcoma it’s markedly vascular. This used to have a much worse prognosis. With our newer forms of chemotherapy they respond very well.

A paraostial and periosteal sarcoma, which are the surface variants, which I’ll show you. And paraostial you want to be aware of because this really just occurs on the surface of the bone. It does not elevate the periosteum like periosteal. These are usually very low grade and although these can appear somewhat large, they are low grade and usually you can just treat them with surgery alone. The periosteal sort of have a mixed prognosis, and some of these are treated with chemotherapy.

What about prognostic factors for osteogenic sarcoma? I talked about the classification subtypes. Again, location; distal tumors do better than proximal. Extremities do better than axial or involvement of the pelvis or the vertebrae, and that’s because you can obtain better wide margins. Size becomes important, especially if it’s over 15 cm. Again, it’s going to be harder to achieve good margins and usually the tumor has been around for a longer time, possibility of metastasis. So they have a worse prognosis. Symptom duration; those patients who have a long symptom duration usually do better than short because it’s slower growing. Those very young patients or those patients older than 20 have a somewhat worse prognosis. Again, females do somewhat better than males, and there have been some studies to suggest that those patients who have very elevated alkaline phosphatases and LDH levels have a worse prognosis. But that’s probably more to connote what the tumor bulk is. If patients have skip lesions, they do worse. If they have a pathologic fracture they do worse. There is some evidence now to suggest that if those patients received induction neoadjuvant chemotherapy first that they can do well, and that not all these patients have to receive an amputation. Like soft tissue sarcoma, if you have lymph node involvement – which is extremely rare – it’s a very very poor prognosis. Or if there is extra-skeletal disease, there’s usually a worse prognosis. And those patients who have metastasis at presentation, specifically if there is metastasis to other bone, do much worse.

Histologic grade is important. We usually treat intermediate and high grade tumors. If it’s a low grade periosteal, as I mentioned, the patient usually just has surgery. The Italian group has shown that loss of heterozygosity of the retinal blastoma gene, also P-glycoprotein, connotes somewhat of a worse prognosis. Ploidy; the jury is still out, and recently reported at ASCO this year, approximately 30-40% of the patients are HER2/neu positive. Those patients that are HER2/neu positive have a worse prognosis, and when you give them neoadjuvant chemotherapy they have a worse response, in terms of histologic necrosis. Because of the availability now of Herceptin and because we know that there may be some synergy or added effect of Herceptin with cisplatin, you are going to see in the next few years, new studies looking at the use of cisplatin with Herceptin in osteogenic sarcoma in those patients who are HER2/neu positive.

Well, what about neoadjuvant chemotherapy? Neoadjuvant chemotherapy has the benefit of eradicating possible micro-metastases and decreasing the emergence of drug resistant cells. You are perfusing a tumor that is intact with an intact blood supply, you are reducing possible tumor size and neovascularity for possibly facilitating a resection with better surgical margins and more limb salvage, and it also may have the benefit of giving you an in vivo evaluation of chemotherapy. Chemotherapy neoadjuvantly has been given multiple ways; IV, continuous IV infusion, intra-arterial with or without radiation, tourniquet IM infusion, and isolated limb perfusion. Most of these studies have been small. They have been single institution with a short duration of follow-up. Three of the major studies have been at UCLA using very high doses of ifosfamide, 14 gm per meter squared, with radiation followed by platinum and Adriamycin, and then operating. At Mass. General using the MAID regimen with radiation therapy interdigitated, in between the chemotherapy. Our institution using Adriamycin/ifosfamide as well as intra-arterial platinum with Adriamycin. What these studies suggest is that there is improved local control, there appears to be an increase in the histologic necrosis when you sample the tumor. The limb salvage rate appears to be very good when compared to studies at these institutions previously. So they are retrospective rather than prospective. And survival appears to be somewhat better.
Cancer
So based on this now, several of the groups are looking at neoadjuvant chemotherapy, and one of them being done by the intergroup is looking at this MAID plus RT. But there are other groups considering using the Adriamycin/ifosfamide regimen.

So as an overview for neoadjuvant, I would consider this for patients who are at high risk for local recurrence and mets, those with large high grade inadequately resected tumors. I would tend to use a more aggressive regimen, which appears to reduce local recurrence and has a higher complete pathologic response rate. This may convert more patients from an amputation to a limb-sparing surgical option. There is less normal tissue removed, preserving extremity function. Single institution studies show that this is feasible and safe. I can’t tell you at this point which is the best regimen. We are going to need more multi-center prospectively randomized studies and probably more and better chemotherapy.

Now what about the patient who recurs after receiving adjuvant chemotherapy or who recurs just after having surgery and radiation therapy? There are some patients who will just have recurrences in the lung, with a small number of lesions. If the primary tumor has been eradicated, there is no extrapulmonary metastasis, the patient is a good surgical risk, the patient is deemed to be fully resectable by a thoracic surgeon who does a lot of these, they may be eligible for a metastasectomy and we usually do a median sternotomy unless the patient has a left posterior lower lobe which can’t be visualized well. It’s usually a clam-shell median sternotomy. In multiple studies – and these are in your handout – the five year survival for the patient receiving a metastasectomy – which we normally don’t think about for a patient who has a solid tumor with metastasis – for soft tissue sarcoma there’s a five year survival of 25-30%. For osteogenic sarcoma there is 35-40%. So this is something to consider for your patient. Whether you should give chemotherapy before the metastasectomy or whether chemotherapy after the metastasectomy in terms of further increasing survival, whether this will be of benefit is unknown. There is a study being done by the EORTC which is also involved with our intergroup here, which is looking at that, in terms of at least adjuvant chemotherapy.

What about adjuvant chemotherapy now? There were twelve studies looking at the role of adjuvant chemotherapy. As you can see, these were all Adriamycin-based. The majority have shown a significance of benefit in disease free survival. Only two small studies showed a benefit in overall survival. There were many problems with these studies. They were very small, there was variable patient inclusion criteria, differences in grade. There were low grade tumors in here, the anatomic sites were all over, there were different histologic subtypes, there were problems in terms of the chemotherapy that was given in terms of the doses. Some of them had some suboptimal delivery and a delayed start, a delayed start in some studies of up to three months. A short duration of follow-up. Some of these studies had good risk factor patients with small, less than 5 cm or low grade tumors, and some of them had preoperative chemotherapy or resection of pulmonary mets which could have affected survival. So Dr. Turney in 2006 reported at ASCO and then an article came out in the Lancet, of doing an individual patient data metaanalysis. In other words, collecting all the data from the institutions, rather than just obtaining raw data from the articles in the literature. She had almost 1600 patients from 14 randomized trials, and these were all Adriamycin alone regimens and all regimens where patients had not received growth factors in order to maintain dose intensity. She found, in this metaanalysis, that there was a benefit, a significant benefit, for relapse free survival but no benefit for overall survival. After the study she then … or as part of the study after the data was in, she did a subset analysis and she did show that for extremity sarcomas there appeared to be a possible significant benefit of adjuvant chemotherapy.
Cancer information and treatment
Then more recently, the Italian group has looked at this higher dose regimen; ifosfamide at 9 gm per meter squared and a dose of epirubicin of 120 mg per meter squared, which is equivalent to at least Adriamycin 75 mg per meter squared, plus growth factors. They started out doing a study that was supposed to involve 250 patients, but after the first 104 patients were randomized – and these were extremity lesions greater than 5 cm, high grade, deep spindle cell – at a median follow-up of 24 months, which was reported in 2006, there was a significant difference in both, for benefit of adjuvant chemotherapy for both disease free survival and overall survival. More recently, last May, they now have 36 month follow-up and this benefit persists. They stopped the study after 104 patients because of the fact that they didn’t think they could continue this study knowing this marked difference. So now there are several centers around the country specifically for extremity sarcomas that are large, high grade, and deep, who feel that adjuvant chemotherapy is of benefit.

Well just to conclude on this, Adriamycin regimens appear to increase disease free survival, but there is no clear benefit for overall survival, except for this new study that I showed you. There is a significant risk of cardiotoxicity if you give the Adriamycin push as opposed to a continuous infusion. The role of adjuvant chemotherapy remains unproven. I think we need new trials. Unfortunately, some trials have been closed prematurely. Many people now feel that Adriamycin/ifosfamide for high risk patients with large, deep, high grade extremity lesions is of benefit, and certainly for Ewings, PNET, and rhabdomyosarcoma – the small cell sarcomas which we usually see mostly in children – there is definite proven benefit of adjuvant chemotherapy.