In a randomized study there is no benefit for low grade soft tissue sarcomas. So if you have a patient who has a recurrence or who has positive margins, or close margins, with a low grade soft tissue sarcoma, they need external beam radiation therapy. They should not receive brachytherapy. What has been tried at the NCI and at Howard University, where there is a radiation therapy unit in the OR specifically for retroperitoneal tumors. It’s intraoperative radiation and the problem with that is that there is increased neuropathy with this, despite the fact that you get decreased GI toxicity and local recurrence. In terms of survival, it has not made much of a difference. It’s also extremely expensive to have a unit in the OR. So this really hasn’t fully caught on. This is just a comparison of studies looking at preoperative, postoperative and brachytherapy. As you can see, with limb-sparing surgery that the recurrence rates are from about 5-15%. There can be problems with radiation therapy; severe fibrosis, lymphedema, fracture of the bones, ulceration, poor wound healing, ileus requiring surgery, nerve palsies, loss of functional capacity, decreased fertility if it’s a medial thigh lesion, and development of secondary malignancies – leukemia and lymphomas.

The NCI a couple of years ago did a randomized study of 91 patients who were randomized to adjuvant radiation therapy or no adjuvant radiation therapy after surgery, and the median follow-up is almost ten years. They found that adjuvant radiation therapy did reduce the local recurrence rate significantly, but there was no difference in overall survival. And it’s not surprising because this is a local treatment, not a systemic treatment. In terms of quality of life; there was significantly worse limb strength and edema and range of motion but there were few effects on daily activities or global quality of life. What they have suggested now; there probably are a selected group of patients, even with sarcomas – maybe more superficial high grade sarcomas – that have a low risk of local recurrence and do not require radiation therapy. If you look at this month’s JCO, the October issue, there is another article from the Dana Farber group emphasizing this as well, in a small group of patients who also just had limb-sparing surgery without radiation and had a very low recurrence rate of approximately 7%. The problem is to figure out specifically which group of patients that is.

Our next modality is chemotherapy and our three most active drugs are Adriamycin, dacarbazine and ifosfamide. Adriamycin is the active standard. It has a steep dose response, so those patients who have received 40 mg per meter squared versus 50, versus 70 or 75, those patients who received 75 mg per meter squared have a higher response rate. There is dose-limiting cardiotoxicity but this can be decreased if you give it as a continuous infusion over 2-3 days. Dacarbazine has severe GI toxicity but this can be reduced also by giving it as a continuous infusion, and it has significant activity in both extremity and specifically uterine leiomyosarcomas, not GI leiomyosarcomas. Ifosfamide is the new kid on the block. It has at least equivalent activity to Adriamycin. It is superior to Cytoxan. There is no cross resistance so those patients who received Cytoxan can respond to ifosfamide. Those patients who have failed other regimens have about a 25% response rate. There is also a dose-response curve for ifosfamide, and you want to give at least the minimum of around 8-9 gm per meter squared. If given alone, we usually give about 12-14 and those patients who have received around anywhere from 6-10 gm per meter squared in a regimen where they have received chemo along with the ifosfamide, can then respond afterwards approximately, about 20-30% of these patients, to higher dose single dose ifosfamide at a dose of 14 gm per meter squared. It is schedule-dependent, and the group at M.D. Anderson has felt and shown that giving it as a bolus of 2-4 hour infusion appears to have a higher response rate than giving it as a continuous infusion. There is significant activity for synovial cell. You need to be aware that there are not only problems with myelosuppression but you also need to watch the kidneys well because the patients, some of these patients, can develop RTA and you also have to be aware of the encephalopathy, which can sometimes be very concerning for the patient, the family and the physician. But it usually goes away in about 3-4 days. We can treat it with either methylene blue or Valium. If you are going to treat it with methylene blue you want to make sure that the patient is not G6PD deficient or else you will have a severe hemolytic anemia on your hands.