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.

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.

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.