Osteosarcoma that has spread from the initially affected bone to one or more sites in the body, distant from the site of origin, is called metastatic. The most common site to which osteosarcoma spreads, or metastasizes, is the lungs. Metastatic osteosarcoma is typically difficult to control, though patients with lung metastases have a better prognosis than patients with distant metastases. Historically, less than 20% of patients with metastatic osteosarcoma survived without recurrence of their cancer. However, survival has improved with the development of more effective chemotherapy.
The following is a general overview of treatment for metastatic osteosarcoma. Treatment may consist of surgery, radiation, chemotherapy, biological therapy, or a combination of these treatment techniques. Multi-modality treatment, which is treatment using two or more techniques, is increasingly recognized as an important approach for increasing a patient’s chance of cure or prolonging survival. In some cases, participation in a clinical trial utilizing new, innovative therapies may provide the most promising treatment. Circumstances unique to each patient’s situation may influence how these general treatment principles are applied and whether the patient decides to receive treatment. The potential benefits of multi-modality care, participation in a clinical trial, or standard treatment must be carefully balanced with the potential risks. The information on this website is intended to help educate patients about their treatment options and to facilitate a mutual or shared decision-making process with their treating cancer physician.
Chemotherapy for Metastatic Osteosarcoma
The main improvement in the treatment of osteosarcoma over the past 30 years has been the development of chemotherapy. Historically, chemotherapy was administered as an adjuvant, or after surgery. Clinical trials have shown that treatment of osteosarcoma with adjuvant chemotherapy improves the patient’s chance of survival and decreases the risk of cancer recurrence compared to local therapy alone. More recently, neoadjuvant chemotherapy has been developed. This is the administration of chemotherapy before surgery in order to shrink the cancer.
Chemotherapy using multiple drugs, called combined chemotherapy, followed by surgery to remove as much of both the primary and metastatic cancer as possible, may be the most promising treatment for metastatic osteosarcoma. However, three studies conducted by the Pediatric Oncology Study Group suggest that further research is needed to identify the optimal chemotherapy combination for patients with metastatic osteosarcoma. The three chemotherapy combinations evaluated were an Ifex®-based treatment, high dose Ifex® supported by Neupogen®, and neoadjuvant Paraplatin® with adjuvant high-dose methotrexate, Ifex®, doxorubicin, and Platinol®. Surgery was performed in all three studies.
Of the three chemotherapy combinations evaluated, the Ifex®-based treatment was considered tolerable and provided the longest survival among patients. Approximately 53% of the patients lived 5 years or more after treatment and approximately 47% did not experience a recurrence of their cancer for 5 years or longer. Patients with fewer metastases in their lungs, or metastases in only one lung, lived longer after treatment.1 High-dose Ifex® chemotherapy supported by Neupogen® was more effective, resulting in a partial response in 49% of the 43 patients treated, and a complete response in 10%.2
The third treatment evaluated was neoadjuvant Paraplatin® chemotherapy followed by surgery, when feasible, and then 40 weeks of adjuvant chemotherapy. This combination appears to be less effective than the Ifex®–based treatment. Of the 37 patients treated, approximately 32% lived more than 3 years or more and 24% did not experience a recurrence of their cancer for more than 3 years.
Researchers from St Jude Children’s Research Hospital reported outcomes of 29 patients with metastatic osteosarcoma treated between 1986 and 1997 with ifosfamide, cisplatin, doxorubicin and high-dose methotrexate.3 The five-year survival for patients with lung metastases only was 46% with the better results in those with unilateral lung metastases (metastases in only one lung), no more than three nodules and those in surgical remission. They also concluded that cisplatin was probably superior to carboplatin.
Researchers from Italy treated 57 patients with metastatic osteosarcoma between 1995 and 2000 with neoadjuvant (before surgery) chemotherapy.4 These patients were treated with primary chemotherapy, restaging, simultaneous surgical removal of the primary tumor and metastatic lesions and maintenance chemotherapy after recovery from surgery. Thirty-five of the 57 patients achieved remission after neoadjuvant chemotherapy. The two year event-free survival was 21% and overall survival was 55%.
Researchers from France have reviewed their experience with treating 78 pediatric patients with metastatic osteosarcoma.5 These patients were treated between 1987 and 200. Fifty-nine percent of patients had only one metastatic site with 35 being in the lung. After combination chemotherapy 36% of patients were in a complete remission. Event-free survival at five years was 14% and the overall survival was 19%. Patients who had more than one metastatic site had a worse outcome.
Role of Surgery
As a generality, patients with metastatic osteosarcoma have the same primary surgery performed as patients with localized disease. It is important to gain local control in order to better treat metastatic disease. Every attempt is made to perform limb sparing surgery but this is not always possible. In addition all accessible metastatic lesions are usually surgically removed after neoadjuvant (before surgery) chemotherapy.
Role of Radiation Therapy
Radiation therapy has a limited role in the treatment of metastatic osteosarcoma. The standards and options for use of radiation therapy in the management of patients with osteosarcoma have been reviewed.6 Radiation therapy may be indicated for relief of symptoms in patients with inoperable lesions. There is no apparent benefit from whole lung radiation in patients with lung metastases.
Strategies to Improve Treatment
The development of more effective cancer treatments requires that new and innovative therapies be evaluated with cancer patients. Clinical trials are studies that evaluate the effectiveness of new drugs or treatment strategies. Future progress in the treatment of metastatic osteosarcoma will result from the continued evaluation of new treatments in clinical trials. Participation in a clinical trial may offer patients access to better treatments and advance the existing knowledge about treatment of this cancer. Patients who are interested in participating in a clinical trial should discuss the risks and benefits of clinical trials with their physician. Areas of active exploration to improve the treatment of metastatic osteosarcoma include the following:
High-Dose Chemotherapy with Autologous Stem Cell Transplantation: High-dose chemotherapy is an intensive treatment that can kill more cancer cells than traditional chemotherapy. However, healthy cells are also destroyed, especially the blood producing stem cells located in the bone marrow. Damage to the bone marrow compromises blood cell production resulting in: 1) neutropenia (low white blood cell count), 2) anemia (low red blood cell count), and 3) thrombocytopenia (low platelet count). Neutropenia results in low immune function, making the patient susceptible to infections. Anemia makes it more difficult for the body to deliver oxygen and critical nutrients to the tissues of the body. Thrombocytopenia compromises the body’s ability to form blood clots in order to stop bleeding.
A treatment that has been developed to help restore blood cell production in damaged bone marrow is autologous stem cell transplantation. This procedure involves the infusion of stem cells, which are precursor cells that can develop into more specific cells such as white blood cells, red blood cells, and platelets. In an autologous transplantation, the stem cells are obtained from the patient before high-dose chemotherapy treatment. The cells are collected from the bone marrow or peripheral blood, processed, frozen, and stored.
Several small pilot studies have evaluated the use of high-dose chemotherapy with autologous stem cell transplantation in patients with advanced osteosarcoma. The results of these studies suggest that this treatment may be an effective treatment for selected patients with metastatic osteosarcoma.
An Italian study suggests that the patients who responded best to high-dose chemotherapy were those who had a significant anti-cancer response following initial therapy. This study involved 32 patients with metastatic osteosarcoma, most of whom had relapsed from prior therapies. At the end of the high-dose treatment, 25 patients were in complete remission, and 6 were alive with disease progression. Overall, 20% of patients survived 3 years or more following treatment.7
In a small study conducted by Italian and Scandinavian researchers, 6 children with metastatic or recurrent metastatic osteosarcoma were treated with two high-dose chemotherapy cycles supported by autologous peripheral blood stem cells. Both of the patients who received this treatment as initial therapy were alive and disease free 3 and 7 months from the time of transplant. Of the 4 patients treated for recurrent disease, 2 were alive and disease free at 9 months after transplant.8
Bone-seeking Radiation Treatment with Autologous Stem Cell Transplant: Although osteosarcoma is typically resistant to radiation therapy, the total dose of radiation delivered to the cancer through bone-seeking radiation may delay progression or even achieve permanent control in some patients with inoperable or relapsed cancer. Samarium-153-EDTMP is a radioactive isotope that localizes radiation to bone. In a small study, all 6 patients experienced significant improvement in quality of life after treatment with this type of radiation followed by an autologous stem cell infusion. One patient was a long-term survivor. Based on these results, researchers concluded that high-dose bone-seeking radiation therapy appears feasible and warrants further evaluation in clinical trials.9
Gene Therapy: Currently, there are no gene therapies approved for the treatment of osteosarcoma. Gene therapy consists of transferring new genetic material into a cell for therapeutic benefit. This can be accomplished by replacing or inactivating a dysfunctional gene, or replacing or adding a functional gene into a cell to make it function normally. Gene therapy has been directed towards the control of rapid growth in cancer cells, control of cancer death, or efforts to make the immune system kill cancer cells. A few gene therapy studies are being carried out in patients with osteosarcoma. There are a number of preclinical studies and one phase I study planned which suggests that gene therapies will be tested in patients with osteosarcoma in the near future.10,11,12,13
Hyperthermia: Applying heat to the blood supply of an extremity affected by osteosarcoma has been utilized to increase the effectiveness of cancer chemotherapy drugs. In this procedure, the blood supply to the affected limb is isolated and heated before returning it to the body. This treatment is usually accompanied by intra-arterial infusion of chemotherapy. The theory underlying this treatment is sound, and encouraging results have been reported. However, the technique is difficult to perform and there have been no randomized trials comparing the effectiveness of hyperthermia and chemotherapy to conventional chemotherapy treatment. Heat can also be applied directly to cancer with the use of microwaves, but the advantages of this approach are not clear.
Japanese researchers have shown that hyperthermia may help to control cancer locally, resulting in a more limited surgical procedure. These researchers treated 20 patients with osteosarcoma of the lower limb with preoperative hyperthermia applied by isolating and heating the blood in conjunction with Platinol®-based chemotherapy. More than half of the patients experienced a significant reduction in their cancer following the preoperative treatment with hyperthermia.14,15
Intraoperative Radiation Therapy (IORT): IORT consists of a single dose of radiation therapy that is delivered directly to the area of cancer during surgery. IORT is performed in specially-equipped operating rooms. Because of the advantage of being able to see the area being treated, the radiation doctor can protect sensitive structures, such as nerves and blood vessels, by moving them away from the radiation beam.
Results from one study evaluating IORT indicate that cancer may recur less often in the area of the surgery. In this study, very high-dose IORT was used in combination with chemotherapy with the aim of saving an affected limb. However, the cancer may still recur in surrounding tissue that is not radiated.
In osteosarcoma, IORT is often used in an attempt to save an affected limb. IORT, combined with preventive stabilization of the bone with metal rods and chemotherapy, appears to improve quality of life in patients with osteosarcomas in the extremities. In one study, 39 patients with osteosarcoma of the extremity were treated with very high doses of IORT. Following treatment, local recurrences occurred in 19 of these patients and 23 had distant metastasis.
1 Harris MB, Gieser P, Goorin AM, et al. Treatment of metastatic osteosarcoma at diagnosis: a Pediatric Oncology Group Study. Journal of Clinical Oncology 1998;16: 3641-3648.
2 Goorin AM, Harris MB, Bernstein M, et al. Phase II/III Trial of Etoposide and High-Dose Ifosfamide in Newly Diagnosed Metastatic Osteosarcoma: A Pediatric Oncology Group Trial. Journal of Clinical Oncology 2002;20: 426-433.
3 Daw NC, Billups CA, Rodriquez-Galindo C, et al. Metastatic osteosarcoma. Cancer 2006;106:403-412.
4 Bacci G, Briocoli M et al, Neoadjuvant chemotherapy for osteosarcoma of the extremities with metastases at presentation: recent experience at the Rizzoli Institute in 57 patients treated with cisplatin, doxorubicin, and a high dose of methotrexate and ifosfamide. Annals of Oncology 2003;14:1126-1134.
5 Metastatic osteosarcoma at diagnosis: Prognostic factors and long-term outcome-The French pediatric experience. Cancer 2005;104:11001109.
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9 Franzius C, Bielack S, Flege S, et al. High-activity samarium-153-EDTMP therapy followed by autologous peripheral blood stem cell support in unresectable osteosarcoma. Nuklearmedizin 2001;40:215-20.
10 Liebau C, Merk H, Roesel C, et al. rIL-18 triggered gene therapy based on a transduction with the IL-12 plasmid: a new option as immuno-therapy for osteosarcoma? Anticancer Res 2002;22:2559-65.
11 Witlox MA, Van Beusechem VW, Grill J. Epidermal growth factor receptor targeting enhances adenoviral vector based suicide gene therapy of osteosarcoma. J Gene Med 2002;4:510-6.
12 Jia SF, Worth LL, Densmore CL. Eradication of osteosarcoma lung metastases following intranasal interleukin-12 gene therapy using a nonviral polyethylenimine vector. Cancer Gene Ther 2002;9:260-6.
13 Benjamin R, Helman L, Meyers P, A phase I/II dose escalation and activity study of intravenous injections of OCaP1 for subjects with refractory osteosarcoma metastatic to lung. Hum Gene Ther 2001;12:1591-3.
14 Nakano H, Tateishi A, Miki H, et al. Hyperthermic isolated regional perfusion for the treatment of osteosarcoma in the lower extremity. Am J Surg 1999;178:27-32.
15 Fan Q, Ma B, Guo A. Surgical treatment of bone tumors in conjunction with microwave-induced hyperthermia and adjuvant immunotherapy. A preliminary report Chin Med J (Engl) 1996;109:425-31.
16 Oya N, Kokubo M, Mizowaki T, et al. Definitive intraoperative very high-dose radiotherapy for localized osteosarcoma in the extremities. Int J Radiat Oncol Biol Phys 2001;51:87-93.
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