Okay, what about treatment now, in terms of surgery? There has been a marked transition. If you remember Edward Kennedy’s son. He had an osteogenic sarcoma about 20 years ago. He had an amputation. It is rare now for a patient to require an amputation. About 80% of the time now limb-sparing surgery is done. It is probably based on improved diagnostic imaging. Also, it’s based on our orthopedic musculoskeletal surgeons having refined reconstructive techniques, with many new types of prostheses with better function and better materials that last longer. We now have intensive multi-agent chemotherapy which we can give beforehand to try to shrink these tumors down. And it’s been shown that with limb-sparing surgery and with a prosthesis there’s an improved quality of life, and probably it’s cost-effective as well.

When do we still have to do amputation? If there is neurovascular compromise, significant, where there’s really marked loss of limb function already. If it’s a very very young patient – although some of these prostheses now, you can go back in a change the size and stretch them out. If there is a pathologic fracture it’s somewhat of a contraindication, although at some centers now we do give induction chemotherapy. If you then have marked destruction of tumor – which sometimes you have – and you can then develop a new rim of bone, of new bone, around the tumor you can do a successful limb-sparing resection. If there is an improper biopsy site or a local infection, or an inadequate extremity function to begin with, then those would all be indications for doing amputation.

In terms of radiation; we use radiation much less often for osteogenic sarcoma. It’s usually for palliation and an unresectable pelvic lesion or an unresectable vertebral lesion. Occasionally we also use it if there is a tumor of the maxilla or the mandible where you can’t get very good margins. Now our active chemotherapeutic drugs are Adriamycin, high dose methotrexate, platinum and ifosfamide. There is a dose response for all these active agents. You need to be aware that for methotrexate that you need to give industrial strength methotrexate, 8-12 gm per meter squared. You want to achieve serum concentrations of greater than 10 micro-molar. You want, for the first 24 hours, to limit the initial hydration so that the urine output is less than 1400 cc per meter squared for the first 24 hours, so that you can obtain these concentrations. Because if you don’t obtain these concentrations the response rates are much lower. In the past we used a combination of bleomycin, Cytoxan and actinomycin-C in some of the earlier regimens that were used in induction chemotherapy later on. Its use for metastatic disease was looked at again and really this regimen does not have much activity for osteogenic.

Okay, what about adjuvant chemotherapy for osteogenic sarcoma? Well, between the 1940’s and the 1970’s pretty much only surgery or radiation therapy was done and the survival was approximately 20%. There were then uncontrolled trials, single institution studies of adjuvant chemotherapy in the 1970’s which showed a relapse free survival of 35-60%. It appeared then people were starting to use adjuvant chemotherapy. The Mayo Clinic then in the 1970’s looked at a group of patients with osteogenic sarcoma that just had surgery alone and they appeared to have a survival of 42% and they felt that this was related to better diagnostic imaging and better surgery. They then performed a study at their institution looking at adjuvant chemotherapy versus surgery alone, and there was no difference in survival. But the dose of methotrexate that they used at that time was much much less than 8-12 gm per meter squared that we now recommend. So after that study was done, the multi-institutional osteosarcoma group and UCLA performed two randomized studies looking at the use of surgery alone versus surgery plus adjuvant chemotherapy. Both relapse free survival and overall survival they showed significant benefit for adjuvant chemotherapy.