Other chemotherapies have been looked at. Suffice it to say that all these really do not have much activity except cisplatin, and I’ll show you a recent study that suggests that there is synergism with Adriamycin. Other drugs, actinomycin-B, vincristine, VP-16, are really used more for the small round cell sarcomas, Ewings sarcoma and rhabdomyosarcoma, which we see more in kids. Now this is a recent study out of Czechoslovakia which was randomized, looking at the use of epirubicin and Adriamycin derivative, versus epirubicin and platinum and as you can see, looking at the response rates, there are almost double for platinum and epirubicin.
So you are going to see, in the next few years, in addition to ifosfamide and Adriamycin being used, sometimes having cisplatin incorporated in the studies as well. There are many new agents. Most of these agents have not panned out. We do have the liposomal doxorubicin compounds. The initial studies have shown very low response rates, but they were all done in patients who were treated with many other treatments. There has been a randomized study done by the ERTC recently which suggests that it may have equivalent activity to Adriamycin, but it had a very low response rate. I think the jury is still out as to whether liposomal doxorubicin can be substituted. So I would, at this point in time, use either Adriamycin or epirubicin, but not one of the liposomal compounds as a standard treatment. Two newer drugs, gemcitabine, appears to have some activity of about 15-20% and there is one single study from the Dana Farber that was presented at ASCO that suggests that Navelbine may have a small amount of activity, specifically in angiosarcomas.
When we combine treatment; an older study from intergroup comparing Adriamycin/DTIC to the MAID regimen, which was the standard regimen in the 80’s and early 90’s. As you can see, the response rate was higher but there was no difference in survival. This study sort of suggested that in older patients and those patients with low to intermediate grade tumors, you are probably just as well off to use Adriamycin and DTIC, which is less toxic and you can always give ifosfamide afterwards rather than combining all three drugs.
The ERTC did a study comparing Adriamycin, Adriamycin/ifosfamide to the old 5A/DIC regimen of M.D. Anderson. Again, no difference in response rates, survival is the same. They then increased the dose of Adriamycin up to 75 and added a growth factor and showed an increase in the response rate. More recently they did a randomized study of this dosage versus this dosage, where there was an increase in the Adriamycin alone but a very low dose of ifosfamide, and showed no difference in survival. The group at M.D. Anderson has then given much higher doses of Adriamycin and ifosfamide, and you can see here that the dose of Adriamycin is up to 75 mg per meter squared, but ifosfamide is given at 10 gm per meter squared.
They have really obtained the highest response rates for the treatment of sarcoma. Many institutions now, including our own, tend to use this A/I regimen at a dosage of either 9-10 gm per meter squared of the ifosfamide plus Adriamycin with growth factors. In terms of our feeling that these two drugs are the two most active and that adding dacarbazine only adds toxicity without benefit and compromises then the dosages of Adriamycin and ifosfamide that you can use. This is a fairly tough regimen and this was in a group of selected patients with good performance status, under 65 and have had radiation to less than 20% of their marrows. Otherwise the patient is going to get marked myelosuppression.