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.
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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.