Localized Osteosarcoma

Overview

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.

References

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