Osteosarcoma that has not responded to treatment or has returned after an initial response to treatment is considered recurrent. Recurrent osteosarcoma occurs in 30-50% of patients with initial localized disease and 80% of patients presenting with metastatic disease. The most common site to which osteosarcoma spreads, or metastasizes, is the lungs. The most common site of recurrence is also the lungs.1 A long interval between the primary diagnosis and the appearance of recurrent disease is associated with a better prognosis. Also, patients with recurrence of their disease in the lung have a better prognosis than patients with other distant metastases because they may sometimes be cured if the cancer can be completely removed with surgery, followed by chemotherapy.
The following is a general overview of treatment for recurrent osteosarcoma. Treatment may consist of surgery, chemotherapy, or a combination of the two. 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.
Treatment of Recurrent Osteosarcoma
Effective treatment of recurrent osteosarcoma requires both local and systemic therapy. Local therapy consists of surgery and is directed at removing the primary osteosarcoma. Systemic therapy is treatment directed at eliminating cancer cells throughout the body, and usually consists of chemotherapy.
The delivery of systemic therapy in addition to local treatment is necessary to maximize a patient’s chance of cure. Most patients with recurrent osteosarcoma actually have micrometastases that are undetectable using current procedures. Micrometastases are cancer cells that have spread beyond the area of the original cancer. The presence of micrometastases may cause osteosarcoma recurrence following local treatment with surgery alone. Thus, systemic therapy is often needed to treat undetectable micrometastases. Typically, patients undergo chemotherapy followed by surgery and then additional chemotherapy after the surgery.
The multi-modality approach to treatment for osteosarcoma requires that patients be treated by a multi-disciplinary team that may consist of a primary care physician, an orthopedic surgeon experienced in bone tumors, a pathologist, radiation oncologists, pediatric oncologists, rehabilitation specialists, pediatric nurse specialists, social workers, and others. An experienced team is best found in a specialty cancer center that treats many patients with osteosarcoma. Engaging a multidisciplinary team at one of these centers helps ensure that the patient receives treatment, supportive care, and rehabilitation that will achieve optimal survival and quality of life. The primary cooperative group evaluating osteosarcoma treatment in the U.S. is the Children’s Cancer Study Group.
Treatment of Local Recurrences
A small fraction of patients with recurrent disease will have only local disease and no evidence of metastatic disease. The first line of therapy is surgical removal or amputation. If surgery is not feasible then local radiation therapy is probably the best therapy. Researchers from the UK reported that the survival of 57 patients with local recurrences only was 41% at five years. These patients were treated with excision, radiotherapy or amputation.2 The role of adjuvant chemotherapy in these patients has not been thoroughly explored. However, since most of these patients develop distant metastatic disease adjuvant (after surgery) or neoadjuvant chemotherapy is probably indicated.
Treatment for Metastatic Disease with or without Local Recurrences
Surgery for Recurrent Osteosarcoma
The ability to completely remove the cancer with surgery is the most important factor that determines prognosis for patients with recurrent disease. For patients who have a recurrence of their osteosarcoma in the bone, the approach to surgery is the same as patients with localized osteosarcoma: removal of the cancer without amputation. Patients who have had a recurrence of their osteosarcoma in the lungs should be carefully assessed to determine whether their cancer can be removed surgically because some may be successfully treated with aggressive surgical removal with or without chemotherapy.
Results from a clinical trial evaluating surgical treatment of patients with osteosarcoma of the extremity indicate that complete removal of osteosarcoma in the lung is effective following intensive chemotherapy.3 Of 111 patients, 36 had surgical removal of recurrent cancer in their lungs. Following the surgical procedure, 23% of the patients survived five years or more compared to no long-term survivors among patients whose cancer recurred in their bones. Researchers from Germany reported a five-year survival of 34% after complete surgical removal of lung metastases from osteosarcoma.4 Researchers from Italy have suggested that patients can benefit from second, third or fourth surgeries for lung metastases if the primary tumor is controlled.5
Chemotherapy for Recurrent 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.
Patients who have recurrent osteosarcoma have usually not responded to treatment with multi-agent chemotherapy or have relapsed after a response. Regimens for the treatment of recurrent disease usually use different chemotherapy agents that have different mechanisms of action than those used for initial treatment. Clinical trials have shown that some patients with recurrent osteosarcoma responded to the combination cyclophosphamide and etoposide,6 or Ifex® (ifosfamide).
When compared to other chemotherapy combinations, Ifex®-based treatment was considered tolerable and provided the longest survival among patients with metastatic osteosarcoma. Approximately 53% of the patients lived five years or more after treatment and approximately 47% did not experience a recurrence of their cancer for five years or longer.7 However, two studies have shown that treatment with Ifex® resulted in only a limited response (approximately 6%8 and 10%9) in patients with recurrent osteosarcoma. High-dose Ifex® chemotherapy supported by Neupogen® (filgrastim; a white blood cell booster) was more effective. In patients with metastatic osteosarcoma, this treatment resulted in a partial response in 49% of the 43 patients treated, and a complete response in 10%.10 Researchers from Turkey have reported that high-dose Ifex resulted in disease control in 5 of 16 patients with recurrent osteosarcoma.11
Researchers from Italy have reported outcome of 162 patients with osteosarcoma of the extremities who had recurrent disease.12 These authors reported that patients who had complete surgical resection of recurrent disease had a five-year survival of 39% while those who had incomplete surgery had a three-year post-relapse survival of 0%. However, chemotherapy helped to relieve symptoms and prolong survival. Researchers from the Mayo Clinic reported a 7% survival rate in 30 patients who achieved a complete remission from surgery or surgery plus chemotherapy for lung metastases.13
Researchers from Germany have reported the outcomes of 501 patients with recurrent metastases and 51 with local recurrences.14 They reported survivals of at two, five and ten years of 38%, 23% and 18%, respectively. They observed a five-year overall survival 39% for those patients who had a surgical complete remission and 0% survival for those without a surgical remission.
Researchers from Memorial Sloan-Kettering treated 31 patients at first recurrence and 22 achieved a complete remission after surgery and chemotherapy.15 However, at the time of this report only 29% were alive and in remission.
Researchers from the Istituto Ortopedico, Rizzoli in Bologna reported at 28% five-year post-relapse event-free survival for 235 patients with recurrent osteosarcoma.16
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 recurrent 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 recurrent osteosarcoma include the following:
New Chemotherapy Regimens
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 platelets. Neutropenia results in low immune function, making the patient susceptible to opportunistic 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 which had relapsed from prior therapies. At the end of the high-dose treatment, 25 patients were in complete remission, and six were alive with disease progression. Overall, 20% of patients survived three years or more following treatment.17
In a small study conducted by Italian and Scandinavian researchers, six 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 three and seven months from the time of transplant. Of the four patients treated for recurrent disease, two were alive and disease free at nine months after transplant.18
Intra-arterial Chemotherapy: The administration of chemotherapy into a selected artery that delivers blood directly to the cancer has been evaluated as a treatment option for patients with different types of cancer, particularly abdominal cancers. This technique is now being refined and evaluated as a possible new treatment option for patients with osteosarcoma. This strategy increases the anti-cancer effects of chemotherapy in several ways:
- The chemotherapy agent does not become diluted by mixing with the entire blood supply prior to reaching the cancer.
- The chemotherapy agent is not broken down in the body through biochemical processes prior to reaching the cancer.
- Larger amounts of the chemotherapy agent can reach the cancer with fewer associated systemic side effects.
Although the theory behind intra-arterial chemotherapy is sound, Italian researchers have demonstrated that it did not appear to offer any significant advantage over standard chemotherapy to patients with osteosarcoma. These researchers compared intra-arterial to standard intravenous infusions of a combination chemotherapy including Platinol® in 221 patients with osteosarcoma of the extremity.19 Both a three-drug and a four-drug regimen were evaluated. In the three-drug regimen, there was a better response rate to intra-arterial chemotherapy compared to standard intravenous infusion, but no difference was noted in the four-drug regimen.
Another study from Italy demonstrated that, although a better response was observed in patients receiving intra-arterial Platinol®, the benefits of this approach did not appear to outweigh the disadvantages of cost and patient discomfort, especially since additional treatment is available for patients who do not respond well to intravenous Platinol®. This study included 95 patients with localized osteosarcoma. In patients receiving intra-arterial Platinol®, 64% showed good responses compared to 43% receiving intravenous Platinol®.20
New Radiation Treatments
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 six 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.21
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 one 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. Local recurrences occurred in 19 of these patients and 23 had distant metastases.22
Other Novel Treatments
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.23,24,25,26
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 conservative 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.27,28
1 Tabone MD, Kalifa C, Rodary C, et al. Osteosarcoma recurrences in pediatric patients previously treated with intensive chemotherapy. J Clin Oncol 1994;12:2614-20.
2 Grimer RJ, Sommerville S, Warnock D, et al. Management and outcome after local recurrence of osteosarcoma. European Journal of Cancer 2005;41:578-583.
3 Ward WG, Mikaelian K, Dorey F, et al. Pulmonary metastases of stage IIB extremity osteosarcoma and subsequent pulmonary metastases. J Clin Oncol 1994;12:1849-58.
4 Pfannschmidt J, Klade J, Muley T, et al. Pulmonary resection for metastatic osteosarcomas: a retrospective analysis of 21 patients. Thoracic Cardiovascular Surgery 2006;54:120-123.
5 Briccoli A, Rocca M, Salone M, et al. Resection of recurrent pulmonary metastases in patients with osteosarcoma. Cancer 2005;104:1721-1725.
6 Rodriguez-Galindo C, Daw NC, Kaste SC, et al. Treatment of refractory osteosarcoma with fractionated cyclophosphamide and etoposide. J Pediatr Hematol Oncol 2002;24:250-5.
7 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.
8 Miser JS, Kinsella TJ, Triche TJ. Ifosfamide with mesna uroprotection and etoposide: an effective regimen in the treatment of recurrent sarcomas and other tumors of children and young adults. J Clin Oncol 1987;5:1191-8.
9 Harris MB, Cantor AB, Goorin AM, et al. Treatment of osteosarcoma with ifosfamide: comparison of response in pediatric patients with recurrent disease versus patients previously untreated: a Pediatric Oncology Group study. Med Pediatr Oncol 1995;24:87-92.
10 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.
11 Berrak SG, Pearson M, Berberoglu S, et al. High-dose ifosfamide in relapsed pediatric osteosarcoma: therapeutic effects and renal toxicity. Pediatric Blood Cancer 2005;44:215-219.
12 Ferrari S, Briccoli A, Mercuri M, et al. Postrelapse survival in osteosarcoma of the extremities: prognostic factors for long-term survival. Journal ofClinical Oncology 2003;21:710-715.
13 Hawkins DS, Arndt CA. Pattern of disease recurrences and prognostic factors in patients with osteosarcoma treated with contemporary chemotherapy. Cancer 2003;98:2447-2456.
14 Kempf-Bielack B, Bielack SS, Jurgens H, et al. Osteosarcoma relapse after combined modality: an analysis of unselected patients in the Cooperative Osteosarcoma Study Group (COSS). Journal of Clinical Oncology 2005;23:559-568.
15 Chou AJ, Merola PR, Wexler LH et al. Treatment of osteosarcoma at first recurrence after contemporary therapy: The Memorial Sloan-Kettering experience. Cancer 2005;104:2214-2221.
16 Bacci G, Briccoli A, Longhl A, et al. Treatment and outcome of recurrent osteosarcoma: experience at Rizzoli in 235 patients initially treated with neoadjuvant chemotherapy. Acta Oncol. 2005;44:748-755.
17 Fagioli F, Aglietta M, Tienghi A, et al. High-dose chemotherapy in the treatment of relapsed osteosarcoma: an Italian sarcoma group study. J Clin Oncol 2002;20:2150-6.
18 Miniero R, Brach del Prever A, Vassallo E, et al. Feasibility of high-dose chemotherapy and autologous peripheral blood stem cell transplantation in children with high grade osteosarcoma. Bone Marrow Transplant 1998;22 Suppl 5:S37-40.
19 Bacci G, Ferrari S, Tienghi A, et al, A comparison of methods of loco-regional chemotherapy combined with systemic chemotherapy as neo-adjuvant treatment of osteosarcoma of the extremity. Eur J Surg Oncol 2001;27:98-104.
20 Ferrari S, Mercuri M, Picci P, et al. Nonmetastatic osteosarcoma of the extremity: results of a neoadjuvant chemotherapy protocol (IOR/OS-3) with high-dose methotrexate, intraarterial or intravenous Platinol®, doxorubicin, and salvage chemotherapy based on histologic tumor response. Tumori 1999;85:458-64.
21 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.
22 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.
23 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.
24 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.
25 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.
26 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.
27 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.
28 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.