Overview of Osteosarcoma

Symptoms and Diagnoses of Osteosarcoma

Osteosarcoma

Medically reviewed by Dr. C.H. Weaver M.D. Medical Editor (08/2018)

Osteosarcoma is the most common type of cancer of the bone. It is the third most common malignancy in children and adolescents, accounting for approximately 5% of all cancers in these age groups. In children and adolescents, 50% of osteosarcomas arise from the bones around the knee. The cause of most cases of osteosarcoma is unknown although a genetic predisposition is suspected. The main known cause of osteosarcoma is radiation therapy. Osteosarcoma is a relatively frequent complication in survivors of childhood cancers treated with radiation therapy with a latency period of 15-20 years.[1],[2]

Osteosarcoma originates most frequently in the thigh bone (distal femur), lower leg (proximal tibia) or upper arm (proximal humerus). Symptoms of osteosarcoma depend on the extent of disease, but may include pain, swelling, localized enlargement of the extremity and, occasionally, a bone fracture without trauma. At the time of diagnosis, approximately 80% of patients have localized osteosarcoma and the remainder have metastatic osteosarcoma.

Diagnostic Procedures

It is imperative that patients with diagnosed or suspected osteosarcoma undergo an evaluation by an orthopedic oncologist who is familiar with surgical management of this disease. Patients should undergo this evaluation prior to an initial biopsy, since an inappropriately performed biopsy may jeopardize a subsequent limb-sparing procedure.

There are several methods for diagnosing osteosarcoma. At this time, controversy exists over which of these methods is optimal.

Open Incisional Biopsy: An open incisional biopsy involves a wide incision through the skin in order to expose the suspicious mass so that a tissue sample can be removed and analyzed in a laboratory. Complications occur in approximately 16% of patients that receive this type of biopsy. In some cases, these complications could lead to unnecessary amputation.

Percutaneous Biopsy: A percutaneous biopsy, is an effective method for making a diagnosis before surgery. Since most patients are currently treated with neoadjuvant chemotherapy, it is important to make the diagnosis prior to surgery. A percutaneous core needle biopsy is a procedure in which a small needle with a hollow core is placed into the suspicious mass and a tissue sample is collected. This procedure uses computed tomography (CT) or fluoroscopy to help guide the biopsy needle.[3] In a recent study of 110 primary bone tumors, a percutaneous biopsy resulted in accurate diagnosis in all but 13 cases.

Fine Needle Aspiration Biopsy (FNAB): FNAB is another type of biopsy in which a very fine needle is placed into the mass for the collection of a cell sample, and is less invasive than the percutaneous biopsy. However, an adequate number of cells are difficult to obtain through FNAB, often times resulting in the need for a patient to undergo a repeat biopsy. One study using FNAB resulted in a conclusive diagnosis in only 65% of 40 patients.[4]

Other: Additional tests may help determine the extent or stage of osteosarcoma. X-ray examinations commonly detect bone destruction and increased bone formation caused by osteosarcoma. Computed tomography (CT) scans and bone scans using isotopes are recommended as part of the staging process to detect lung and bone metastases, respectively.

Staging

The process of identifying the extent of the cancer is called staging. Accurately identifying the stage of a cancer helps determine what treatment will be most effective. Staging is particularly important for determining whether a cancer has spread from its original site to other parts of the body. Although there are more sophisticated staging systems for patients with osteosarcoma, it is most convenient to categorize the cancer as localized, metastatic, and recurrent.

Localized Osteosarcoma Localized cancers are limited to the bone of origin. In these cases, smaller tumors that are separate from the primary cancer, called “local skip metastases”, may be apparent within the bone, indicating a worse prognosis. Approximately 50% of primary osteosarcomas occur in the upper leg. Of these, 80% arise adjacent to the knee joint in young patients. Other primary sites are the lower leg, upper arm, pelvis, jaw, and ribs.

Metastatic Osteosarcoma Metastatic osteosarcoma has spread beyond the primary site of origin. Metastatic disease is diagnosed when staging tests reveal evidence of disease in the lung, other bones, or other distant sites. More than 80% of patients with metastatic osteosarcoma have cancer that has spread to the lung. The second most common site of spread is another bone.

Recurrent Osteosarcoma Patients with recurrent osteosarcoma have disease that has recurred after a complete response or have disease that was not eradicated with initial treatment. The most common sites for recurrent osteosarcoma are the lungs and bone.

Localized Osteosarcoma

Localized osteosarcoma affects only the bone in which it developed and the tissues next to the bone, such as muscle and tendon. There is no detectable spread of the cancer to other areas of the body. In young adults, most localized osteosarcomas occur around the knee.

The following is a general overview of treatment for localized osteosarcoma. Treatment may consist of surgery, chemotherapy, or both. 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 Localized Osteosarcoma

Effective treatment of localized 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 diagnosed with localized osteosarcoma actually have micrometastases that are undetectable by 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 consisting of the 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 specialty cancer centers that treat 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 US is the Children’s Cancer Study Group.

Surgery

The ultimate goal of surgery for localized osteosarcoma is to remove the cancer without amputation. The specific type of surgery a patient undergoes depends on the location and extent of the cancer. For surgery to be successful, the cancer and a large margin of healthy tissue surrounding the cancer must be removed. Patients undergo a preoperative examination to determine whether it is possible to achieve wide surgical margins of healthy tissue, thereby avoiding amputation. If the preoperative examination determines that it is not possible to remove an adequate margin of normal tissue, an amputation should be considered. This is particularly true when there is a poor response to systemic treatment, such as chemotherapy, before surgery.

Even with the advent of chemotherapy as systemic treatment, surgery is still an important component of treatment for osteosarcoma. Research shows that chemotherapy without surgery results in worse outcomes. Researchers at MD Anderson Cancer Center evaluated 31 pediatric patients who initially underwent treatment with intent-to-cure utilizing chemotherapy alone.[1] After 3 months of treatment, the second phase of the study began in which patients received more chemotherapy instead of surgery. The researchers reported that only 3 of 31 patients were cured with the administration of chemotherapy alone. Overall, 48% of patients survived, 23% were cancer free. These rates are not comparable to the typical cure rates of treatment with chemotherapy and surgery together, indicating that treatment of osteosarcoma with chemotherapy alone is insufficient.

Chemotherapy

The main improvement in the treatment of localized osteosarcoma over the past 30 years has been the advent of chemotherapy. Historically, systemic therapy was administered as an adjuvant, or after surgery. Clinical trials performed during the 1980’s have shown that treatment of localized osteosarcoma with adjuvant chemotherapy improves a patient’s chance of survival and decreases the risk of cancer recurrence compared to surgery alone.[2],[3] More recently, chemotherapy has been administered before surgery in order to shrink the cancer prior to surgical removal.

Neoadjuvant Chemotherapy: The administration of chemotherapy before surgery is referred to as neoadjuvant therapy. This approach has the potential advantage of delivering widespread systemic treatment quickly and reducing the size of the primary cancer in order to increase the number of patients eligible for limb-sparing surgical treatment. The more a cancer is reduced by neoadjuvant chemotherapy, the more likely a patient will live longer and be disease free.

Neoadjuvant Chemotherapy, Surgery, and Adjuvant Chemotherapy: Since the 1980’s, the treatment of osteosarcoma has been further improved with the addition of neoadjuvant chemotherapy to conventional surgery and adjuvant chemotherapy. This strategy has resulted in curing 50-65% of patients compared to approximately 20% when surgery is used alone. If treatment includes chemotherapy before surgery, more than 80% of extremity osteosarcomas can be treated by a limb-sparing operation and do not require amputation.

Certain chemotherapy agents are more effective in treating osteosarcoma than others. The results of most clinical trials evaluating chemotherapy suggest that combinations of chemotherapy agents are more effective than single agents. The most commonly used chemotherapy agents include Platinol®, doxorubicin, and methotrexate. Other agents that may be used include cyclophosphamide, Ifex®, etoposide, and Paraplatin®.

For example, two studies have shown good survival with the neoadjuvant/adjuvant regimen including doxorubicin, Platinol®, methotrexate, and Ifex®. Italian and Scandinavian researchers reported that, after an average of five years, 73% of patients remained disease free.[4] Six patients who experienced a recurrence underwent further treatment. Overall survival was 87%. In a second Italian study that evaluated 300 patients with localized osteosarcoma of the extremity, 59% of patients were disease free at eight years.[5]

A more recent study from Italy and Scandinavia reported good results for a high-dose ifosfamide, high-dose methotrexate, cisplatin, and doxorubicin regimen supported by G-CSF (a drug to boost white blood cell levels).[6] One hundred and eighty-two patients with localized osteosarcoma of the extremity were treated with two cycles of therapy before surgery and three cycles after surgery. Treatment-related mortality was 1.6%. The five-year survival without relapse was 64% and the overall survival was 77%.

Italian researchers have reported the outcomes of 1126 patients with non-metastatic osteosarcoma of the lower extremities.[7] They reported a five-year event-free survival (survival without cancer recurrence) of 55% and five-year overall survival of 66%. Positive surgical margins (evidence of cancer at the edge of the tissue that was surgically removed) and poor response to chemotherapy were associated with an increased risk of local recurrence (recurrence near the site of the original cancer). These results suggest that patients with positive surgical margins may benefit from an amputation or other aggressive therapy.

Dose-Intensity: The total amount of drug delivered over a specific period of time is referred to as the dose-intensity of a particular treatment regimen. Chemotherapy can be given all at once or over an extended period of time. However, the effect of the treatment is reduced if the optimal dose intensity is decreased by delays or interruptions in treatment.

One study conducted by Italian researchers demonstrated that delays or reduction of doses negatively impact the therapeutic effect of neoadjuvant or adjuvant chemotherapy. In this study, 144 patients with osteosarcoma of the extremity were treated with neoadjuvant chemotherapy between 1986 and 1989.[8] Patients who received 90% or more of the scheduled dose-intensity had a survival of 76.5%. Survival dropped to 57.3% for patients who received less than 90% of the scheduled dose-intensity.

Radiation Therapy

Radiation therapy has a limited role in the treatment of localized osteosarcoma. The standards and options for use of radiation therapy in the management of patients with osteosarcoma have been reviewed.[9] Studies have suggested that radiation therapy may provide a benefit when adequate surgery cannot be achieved.[10],[11] However, routine use of preventive radiation therapy after chemotherapy is not endorsed.

Effect of Age

Most osteosarcomas occur in teenagers or young adults. However, the disease does occur in older individuals and their outcomes could be different than younger patients. However, a recent study from Italy looked at the outcomes of 34 patients with osteosarcoma of the extremities who were between the ages of 41 and 60 years.[12] In this group of patients 30 had limb salvage, three underwent amputation and one patient died from preoperative treatment. The five-year event-free survival was 56% and the overall survival was 70%. These authors concluded that neoadjuvant chemotherapy improves prognosis and reduces amputations at rates similar to that observed in younger individuals with osteosarcoma.

A larger European study involving 238 patients with high-grade localized osteosarcoma reported a 46% survival at five years.[13]

Treatment of Secondary Osteosarcoma

Osteosarcoma occurs as a secondary cancer in some patients who have been treated for other cancers. Secondary osteosarcoma occurs most frequently following radiation therapy. Patients with secondary osteosarcoma have the same prognosis as patients with primary osteosarcoma if they are treated aggressively with surgery and multiple chemotherapy drugs. Two studies have demonstrated that approximately 50% of patients with secondary osteosarcoma will live 7-8 years or more.

In the first study, the Cooperative German-Austrian-Swiss Osteosarcoma Study Group evaluated outcomes of 30 patients with secondary. All but six patients had received prior radiation therapy and 14 patients had received prior chemotherapy. Seventeen of the secondary osteosarcomas occurred in a previously irradiated area. All but three patients had localized osteosarcoma at diagnosis. Results showed that 50% of the patients lived seven years or more and 30% were free of cancer progression.[14]

A more recent study from Canada found that radiation-induced bone sarcoma had similar outcomes to primary osteosarcoma if treated aggressively.[15]

The second study included 23 patients with secondary osteosarcomas related to prior radiation treatment for childhood or adolescent cancers. Following treatment with surgery and intensive preoperative and postoperative chemotherapy, 50% of patients survived eight years or more and 41% were free of cancer progression. The average time between radiotherapy for the initial cancer and the diagnosis of secondary osteosarcoma was eight years.[16]

Factors that Impact Prognosis

The most important factors in long-term outcomes of patients with localized osteosarcoma are the degree of anti-cancer response to neoadjuvant chemotherapy and whether or not the cancer could be completely removed with surgery. Patients whose primary cancer is reduced by more than 95% following initial chemotherapy have a better prognosis than those with less cancer reduction.

Outcomes vary for osteosarcoma depending on where it originates in the body. Patients with osteosarcoma of the head and face and other flat bones experience good survival with complete removal of the involved bone plus chemotherapy.[17] In general, patients with osteosarcoma in their extremities, arms or legs, have a better outcome than patients with osteosarcoma of the central part of the skeleton, such as the pelvis. This is probably due to a later diagnosis for cancers in the pelvic region. However, researchers at the Johns Hopkins University found that neoadjuvant and adjuvant treatment of patients with osteosarcoma of the head and neck resulted in survival comparable to those reported with osteosarcoma of the extremity. Of the 27 patients involved in this study, 66% survived two years or more and 55% survived five years or more.[18]

Researchers from St. Jude Children’s Research Hospital have reported that the absolute tumor size at diagnosis was significantly predictive of overall and event-free survival following treatment.[19]

Researchers from Italy have also found that an elevated level of serum lactate dehydrogenase (LDH) is an independent risk factor for patients at high risk of relapse.[20] The importance of this observation is that patients with a high LDH may need more aggressive treatment than patients without an elevated LDH.

Researchers have also determined that the specific cell type of the osteosarcoma affects outcome after treatment.[21] In a study of over 1000 patients with osteosarcoma of the extremity, the frequency of specific cell types was as follows:

  • Osteoblastic=70%
  • Chrondroblastic=13%
  • Fibroblastic=9%
  • Telangiectatic=6%

Responses to neoadjuvant therapy were significantly better for fibroblastic, telangiectatic and worse for chrondroblastic tumors. Five-year survival, by cell type, was as follows:

  • Fibroblastic=83%
  • Telangiectatic=75%
  • Osteoblastic=62%
  • Chrondroblastic=60%

The importance of these observations is to plan therapy that is more aggressive or different for those with a predicted poor outcome with standard therapy.

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 localized 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 localized osteosarcoma include the following:

Neoadjuvant Chemotherapy without Adjuvant Chemotherapy: Neoadjuvant therapy has become more important because it reduces the size of the cancer and makes surgery more effective. Due to these positive results with neoadjuvant therapy, researchers have recently questioned the need for adjuvant therapy.

The addition of adjuvant chemotherapy for patients who have received neoadjuvant therapy and definitive surgery does not appear to increase survival and may contribute to the development of secondary cancers. This conclusion is based on the results of a small study that compared the outcomes of 19 patients with localized osteosarcoma treated with neoadjuvant chemotherapy and surgery with 35 patients who received both adjuvant and neoadjuvant chemotherapy. There was no difference in survival between the groups. In addition, 4 patients in the adjuvant therapy group died of secondary cancers, compared to none in the no-adjuvant therapy group. This is a small study and needs to be duplicated in larger clinical trials.[22]

Radiation Protectors: Radiation protectors are drugs that selectively protect normal tissues from radiation treatment, while exposing cancer cells. Over the past 50 years, many radiation protectors have been tested in the laboratory for prevention of radiation damage to normal cells and tissues. Radiation protectors are considered supportive care. Supportive care refers to treatments designed to prevent and control the side effects of cancer and its treatment. Side effects not only cause patients discomfort, but may also prevent the delivery of therapy at its planned dose and schedule, resulting in sub-optimal effects. In order to achieve optimal outcomes from treatment and improve quality of life, it is imperative that side effects are appropriately managed.

Ethyol® is the only radiation protector that has been approved for use by the US Food and Drug Administration. Clinical trials have demonstrated that Ethyol® can reduce both acute and late radiation-induced side effects. The development of Ethyol® has resulted in the successful administration of enough radiation therapy to eliminate cancers, while maintaining patient quality of life.

Italian researchers have reported that Ethyol® is protective for children with osteosarcoma. In this study, 29 children with osteosarcoma were treated with platinum-based adjuvant and neoadjuvant combination chemotherapy with Ethyol® or chemotherapy alone. Low blood counts were less frequent in patients receiving Ethyol®. Though no difference in survival was reported, researchers suggested that a larger trial may provide this evidence. Ethyol® has also been shown to protect women with ovarian cancer from the side effects of Platinol®-based chemotherapy.[23]

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 to make the cell 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 suggest that gene therapies will be tested in patients with osteosarcoma in the near future.[24],[25],[26],[27]

Hyperthermia: Applying heat to the blood supply of an extremity affected by osteosarcoma has been evaluated 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 clinical trials directly 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.[28]

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.[29] More than half of the patients experienced a significant reduction in their cancer following the preoperative treatment with hyperthermia.

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.[30] Both a 3-drug and a 4-drug regimen were evaluated. In the 3-drug regimen, there was a better response rate to intra-arterial chemotherapy compared to standard intravenous infusion, but no difference was noted in the 4-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®.[31]

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.[32] Following treatment, local recurrences occurred in 19 of these patients and 23 had distant metastasis.

Vaccines: Vaccines are a potentially non-toxic way to eliminate small remaining areas of cancer, but at the present time there are no vaccines approved for treating any cancer. However, the UK Children’s Cancer Study Group has evaluated a vaccine, known as Onyvax-105 (105AD7), and has found that the vaccine elicits an immune response in patients with osteosarcoma.[33] This vaccine will need to be tested in randomized trials to determine if it is effective or not.

High-Dose Chemotherapy with Autologous Stem Cell Support: High-dose chemotherapy with autologous stem cell support, also referred to as autologous stem cell transplantation, is used to treat a variety of cancers and has also been explored as a method of increasing dose-intensity in patients with osteosarcoma.

High-dose chemotherapy therapy generally kills more cancer cells than standard-dose therapy, but also kills more healthy cells, including hematopoietic stem cells (immature blood cells). A hematopoietic stem cell transplant replaces the stem cells that are destroyed during high-dose chemotherapy. An autologous hematopoietic stem cell transplant makes use of a patient’s own stem cells. The stem cells are collected prior to therapy and stored, then administered to the patient after high-dose therapy.

A recent study from Turkey demonstrated the feasibility of using this approach prior to surgery in 22 patients with localized osteosarcoma.[34] They administered two cycles of therapy consisting of ifosfamide, cisplatin and doxorubicin each supported by autologous stem cells. The three-year disease-free survival was 70% and the overall survival was 83%. One advantage to this approach is that the treatment period is shorter.

Metastatic Osteosarcoma

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.[16]

Recurrent Osteosarcoma

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]

References

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[15] Shaheen M, Deheshi BM, Riad S, et al. Prognosis of radiation-induced bone sarcoma is similar to primary osteosarcoma. Clinical Orthopedic Related Research. 2006;450:76-81.

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[23] Petrilli AS, Oliveira DT, Ginani VC. Use of amifostine in the therapy of osteosarcoma in children and adolescents. J Pediatr Hematol Oncol. 2002;24:188-91.

[24] 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.

[25] 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.

[26] 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.

[27] 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.

[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.

[29] 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.

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[31] 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.

[32] 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.

[33] Pritchard-Jones K, Spendlove K, Wilton C, et al. Immune responses to the 105AD7 human anti-idiotypic vaccine after intensive therapy for osteosarcoma. British Medical Journal. 2005;92:1358-1365.

[34] Arpaci F, Ataergin S, Ozet A, et al. The feasibility of neoadjuvant high-dose chemotherapy and autologous peripheral blood stem cell transplantation in patients with nonmetastatic high grade localized osteosarcoma: results of a phase II study. Cancer. 2005;104:1058-1065.

[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 Oncology2002;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.

[6] Claude L, Rousmano S, Carrie C. Standards and options for use of radiation therapy in the management of patients with osteosarcoma. Update 2004. Bulletin of Cancer 2005;92:891-906.

[7] 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.

[8] 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.

[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 Ther2001;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.

[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 Oncol1987;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 Oncology2002;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 of Clinical 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 Oncol2001;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. Tumori1999;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.

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