Osteosarcoma

WHAT IS OSTEOSARCOMA?

Osteosarcoma is the most common type of bone cancer and is a disease in which cancer (malignant) cells are found in the bone. It is a bone tumor that occurs predominantly in adolescents and young adults. It accounts for approximately 5% of the tumors in childhood. In children and adolescents, 50% of these tumors arise from the bones around the knee.

Malignant fibrous histiocytoma of bone (MFH) is a rare tumor of the bone. It may occur following radiation treatments. MFH is generally treated the same as osteosarcoma and appears to have a similar response to treatment.

Ewing’s sarcoma is another kind of bone cancer, but the cancer cells look different under a microscope than osteosarcoma cancer cells.



HOW TO DETECT OSTEOSARCOMA?

A patient has symptoms ,such as pain and swelling of a bone or a bone region, is suspected that the problem is osteosarcoma, and should receive X-ray, CT or MRI examination. A biopsy of tissue from the affected area will be performed. The tissue will be looked at under a microscope to see if there are any cancer cells.

Stage of osteosarcoma

Localized osteosarcoma

Localized tumors are limited to the bone of origin. Approximately one half of the tumors arise in the femur, with 80% of these arising adjacent to the knee joint in young patients. Other primary sites in descending order of frequency are tibia, humerus, pelvis, jaw, fibula, and ribs. Osteosarcoma of the head and neck is more likely to be low-grade than osteosarcoma of the appendicular skeleton and is more likely to arise in older patients. The prognosis for osteosarcoma of the head and neck with surgery alone is better than surgery alone for appendicular lesions.

Metastatic Osteosarcoma

Radiologic evidence of metastatic tumor deposits in lung, other bones, or other distant sites is found in 10% to 20% of patients at diagnosis; 85% to 90% of metastatic disease is in the lungs. The second most common site of metastasis is another bone. Presentations with multiple bone metastases carry an extremely grave prognosis.



HOW TO TREAT OSTEOSARCOMA?

Randomized clinical trials have established that both neoadjuvant and adjuvant chemotherapy are effective in preventing relapse in patients with nonmetastatic occult tumors.

Localized Osteosarcoma/Malignant Fibrous Histiocytoma of Bone

Complete surgical resection is crucial for patients with localized osteosarcoma; however, at least 80% of patients treated with surgery alone will develop metastatic disease.

A number of single-arm trials evaluated the role of chemotherapy administered both preoperatively and postoperatively. Some of these trials evaluated the necrosis of the primary tumor following chemotherapy and used this information to determine subsequent therapy. Current chemotherapy protocols include combinations of the following agents: high-dose methotrexate, doxorubicin, cyclophosphamide, cisplatin, ifosfamide, etoposide, and carboplatin. Overall, relapse-free survival ranges between 50% to 75% in these trials.

Almost all patients with osteosarcoma should undergo surgical resection of the primary tumor. The type of surgery required for complete ablation of the primary tumor depends on a number of factors that must be evaluated on an individual basis. If limb-sparing is contemplated, the biopsy should be performed by the surgeon who will do the definitive operation, since incision placement is crucial. Rotationplasty and limb-sparing procedures have been evaluated for both functional result and effect on survival. There is no difference in overall survival between patients treated by amputation and those treated with a limb-sparing procedure. If the pathologic examination of the surgical specimen shows inadequate margins, an immediate amputation should be considered, especially if the histologic response to preoperative chemotherapy was poor. Patients with primary tumors of the femur have the highest local recurrence rate as compared to patients with primary tumors of the tibia/fibula. In general, more than 80% of patients with extremity osteosarcomas can be treated by a limb-sparing operation and do not require amputation. While limb-sparing tumor resection is the current practice for local control at most pediatric institutions, there are few data to indicate that limb-salvage of the lower limb is substantially superior to amputation in regard to patient quality of life. Patients with pelvic osteosarcoma may benefit from radiotherapy if surgical margins are inadequate.

Localized, completely resectable high-grade osteosarcoma

Most patients receive preoperative (neoadjuvant) chemotherapy followed by extirpative surgery (amputation, limb salvage, or rotationplasty) and postoperative adjuvant chemotherapy. In some trials, the type of postoperative adjuvant chemotherapy is determined by the degree of necrosis observed in the primary tumor.

Preoperative chemotherapy (either systemically or intra-arterially) followed by extirpative surgery (amputation, limb salvage, or rotationplasty). After surgery, tumor necrosis is used to determine degree of response to the initial chemotherapy. If tumor necrosis exceeds a preset level (90%-95%), the preoperative chemotherapy regimen is continued; if necrosis is inferior, an alternative regimen is used. This approach has not been examined in a randomized study.

For lesions that cannot be removed, intensive combination of chemotherapy and high-dose, very well-collimated and localized radiation will be performed.

For patients with malignant fibrous histiocytoma of bone (MFH), wide local excision is recommended regardless of tumor grade. Most patients with MFH will need preoperative chemotherapy to achieve a wide local excision.

Metastatic Disease

Osteosarcoma

The progression-free survival rate for patients with metastatic osteosarcoma is approximately 20%. Patients with pulmonary metastatic disease only may have a better survival rate (approximately 40%).

The most frequently used approach is to initiate preoperative chemotherapy followed by surgical ablation of the primary tumor and resection of metastatic disease. This is followed by postoperative combination chemotherapy. The chemotherapeutic agents used include high-dose methotrexate, doxorubicin, cisplatin, high-dose ifosfamide, etoposide, and in some reports, carboplatin or cyclophosphamide.

An alternative approach is surgical ablation of the primary tumor and metastases, where possible, followed by combination chemotherapy. The chemotherapeutic regimens utilized in the treatment of metastatic osteosarcoma include high-dose methotrexate, doxorubicin, cyclophosphamide, cisplatin, ifosfamide, etoposide, and carboplatin.

Malignant Fibrous Histiocytoma of Bone

Patients with unresectable or metastatic malignant fibrous histiocytoma of bone have a very poor outcome.

Recurrent Osteosarcoma

Recurrence of osteosarcoma is most common in the lung. Patients with recurrent osteosarcoma should be assessed for surgical resectability, as they may sometimes be cured with aggressive surgical resection with or without chemotherapy. The ability to achieve a complete resection of recurrent disease is the most important prognostic factor at first relapse, with a 5-year survival rate of 20% to 45% following complete resection of metastatic pulmonary tumors and 20% following complete resection of metastases at other sites. Survival for patients with unresectable metastatic disease is less than 5%. Factors that suggest a better outcome include fewer pulmonary nodules, unilateral pulmonary metastases, or longer intervals between primary tumor resection and metastases. The lung is the most common site of recurrence for osteosarcoma. Resection of metastatic disease followed by observation alone results in low overall and disease-free survival. Factors associated with better outcome include unilateral lung involvement, solitary pulmonary nodule, longer interval from initial diagnosis, and achieving a second complete remission. A high percentage of patients with pulmonary nodules identified in only one lung who underwent staged bilateral thoracotomy were found to have palpable nodules that were not visualized on CT scan. The incidence of local relapse was higher in those patients who had a poor pathologic response of the primary to chemotherapy in the primary tumor.

The selection of further treatment depends on many factors, including the site of recurrence, the patient’s previous primary treatment, and individual patient considerations. Ifosfamide with mesna uroprotection, alone or in combination with etoposide, has shown activity in up to one third of patients with recurrent osteosarcoma who have not previously received this drug. Cyclophosphamide and etoposide have activity in recurrent osteosarcoma. Peripheral blood stem cell transplant utilizing high-dose chemotherapy does not appear to improve outcome. High-dose samarium-153-EDTMP coupled with peripheral blood stem cell support may provide significant pain palliation in patients with bone metastases.



WHAT IS THE EWING’S FAMILY OF TUMORS?

The Ewing’s family of tumors (EFTs) include: Ewing’s tumor of bone (ETB); extraosseous Ewing’s (tumor growing outside of the bone, EOE); primitive neuroectodermal tumor (PNET), also known as peripheral neuroepithelioma; and Askin’s tumor (PNET of the chest wall). These tumors are rare diseases in which cancer (malignant) cells are found in the bone and soft tissues.

EFTs occur most frequently in the second decade of life and account for 4% of childhood and adolescent malignancies. The incidence in boys is slightly higher than in girls (ratio of 1.1:1).

ETB is estimated to be 60% of the EFTs. The sites of origin for ETB are: distal (27%) and proximal extremities (25%), pelvis (20%), chest (20%), and spine and skull (9%).

For the EOE, the most common sites are: trunk (32%), extremity (26%), head and neck (18%), retroperitoneum (16%), and all other sites (8%).

Common sites for PNET are the chest (44%), abdomen/pelvis (26%), extremities (20%), head and neck (6%), and all other sites (4%). Except for the head and neck, the sites of origin of EOE and PNET are similar.



Localized: For Ewing’s tumor of bone, the tumor is defined as localized when, by clinical and imaging techniques, it has not spread beyond the primary site or regional lymph nodes. There may be contiguous extension into adjacent soft tissue.
Metastatic: These tumors have spread to distant sites, most commonly lung, bone, and/or bone marrow. Lymph node and, in particular, central nervous system metastases are less common.
Treatment

The successful treatment of patients with tumors of the Ewing’s family (EFTs) requires the use of multidrug chemotherapy, in addition to radiation therapy and/or surgical therapy to the primary tumor. Many patients with metastatic disease at diagnosis respond well to the therapy given to patients with localized disease; however, in most cases the disease is only partially controlled or recurs. Patients with only lung metastases have a better event-free survival than those with metastases to bone and/or bone marrow.

Localized Tumors of the Ewing’s Family

Standard treatment

Because almost all patients with apparently localized disease at diagnosis have occult metastatic disease, multidrug chemotherapy as well as local disease control with surgery and/or radiation is indicated in the treatment of all patients.

Current standard chemotherapy includes vincristine, doxorubicin, and cyclophosphamide (VAdriaC) alternating with ifosfamide and etoposide. The combination of ifosfamide and etoposide has shown activity in Ewing’s tumor of bone (ETB).

Local control can be achieved by surgery and/or radiation. Surgery is generally the preferred approach if the lesion is resectable. If a very young child has an ETB, surgery may be a less morbid therapy than radiation therapy because of the retardation of bone growth caused by radiation. Another potential benefit for surgical resection of the primary tumor is information concerning the amount of necrosis in the resected tumor. Patients with residual viable tumor in the resected specimen have a worse outcome compared to those with complete necrosis. Radiation therapy should be employed for patients who do not have a surgical option that preserves function and should be used for patients whose tumors have been excised but with inadequate margins.

Radiation therapy is generally administered in fractionated doses totaling approximately 5,580 cGy to the prechemotherapy tumor volume. Hyperfractionated radiation therapy has not been associated with improved local control or decreased morbidity. In addition, some patients may require surgical resection following radiation therapy.

Metastatic Tumors of the Ewing’s Family

Prognosis of patients with metastatic disease is poor.

Standard treatment

Standard treatment with alternating vincristine, doxorubicin, cyclophosphamide, and ifosfamide/etoposide combined with radiation therapy to all sites of gross disease and possibly selected surgical excision for patients with metastatic Ewing’s tumor of bone/Ewing’s tumor of soft tissue often results in complete or partial responses; however, the overall cure rate is 20%. Patients with metastatic disease showed no benefit from the addition of ifosfamide and etoposide to a standard regimen of vincristine, doxorubicin, cyclophosphamide and actinomycin D. For patients with lung/pleural metastases only, cure rates are approximately 30%. Patients who did not receive lung irradiation had a worse outcome than those receiving lung radiation. Patients with only bone/bone marrow metastases have an approximate 20% to 25% cure rate. Patients with combined lung and bone/bone marrow metastases have a <15% cure rate.

Radiation therapy should be delivered in a setting in which stringent planning techniques are applied by those experienced in the treatment of the Ewing’s family of tumors. Such an approach will result in local control of tumor with acceptable morbidity in most patients. Radiation therapy to the primary tumor as well as to the sites of metastatic disease should be considered but may interfere with delivery of chemotherapy if too much bone marrow is included in the field. Metastatic sites of disease in bone and soft tissues should receive fractionated-radiation therapy doses totaling between 4,500 cGy to 5,600 cGy. All patients with pulmonary metastases should undergo whole-lung radiation, even if complete resolution of pulmonary metastatic disease has been achieved with chemotherapy. Radiation doses are modulated based on the amount of lung to be irradiated, and pulmonary function. Doses between 1,200 cGy and 1,500 cGy are generally used if whole lungs are treated.

More intensive therapies, many of which incorporates high-dose chemotherapy with or without total-body irradiation in conjunction with stem cell support have not shown improvement in event-free survival rates for patients with bone and/or bone marrow metastases. The impact of high-dose chemotherapy with peripheral blood stem cell support for patients with lung metastases is currently unknown.

Recurrent Tumors of the Ewing’s Family

Patients with both local and distant recurrence have a worse outcome than those with either local or distant recurrence. Patients who relapse ≥2 years after diagnosis and patients who have local recurrences that can be treated with radical surgery and intensive chemotherapy have the most favorable outcomes. The selection of further treatment depends on many factors, including the site of recurrence and prior treatment, as well as individual patient considerations. Ifosfamide and etoposide are active in EFTs and should be considered for patients who have not previously received these agents. The combination of cyclophosphamide plus topotecan has been shown to be active in patients with recurrent or refractory disease. Aggressive attempts to control the disease, including myeloablative regimens, may be warranted. Allogeneic stem cell transplantation does not improve event-free survival when compared with autologous stem cell transplantation, and is associated with a higher complication rate. Radiation therapy to bone lesions may provide palliation although radical resection may improve outcome. Patients with pulmonary metastases should receive whole-lung irradiation. Residual disease in the lung may be surgically removed.



HOW TO ESTIMATE THE PROGNOSIS OF OSTEOSARCOMA?

Major prognostic factors include site, tumor volume, and the presence of metastases. Clinical and biological factors for ETB and, to some extent EOE, are discussed below.

Site, size, age, and sex: In ETB the most favorable sites are distal extremities. Central location (e.g., skull, clavicle, vertebrae, and ribs), proximal extremities and the pelvis are associated with a much less favorable prognosis. Size is also significant, but larger lesions tend to occur in the more unfavorable sites. Younger children have better event-free survival than older adolescents and young adults. Girls with ETB have a better prognosis than boys.
Clinical findings: The presence of fever, anemia, or an elevated lactic dehydrogenase (LDH) is poor prognostic signs for patients with ETB. Increased serum LDH levels prior to treatment correlate with metastatic disease and shorter disease-free survival.
Surgical resectability: Surgical resection for ETB, EOE, and for PNET is an important variable. This applies to both complete resection and incomplete resection with only microscopic residual disease.
Chemotherapy: Approximately 20% to 30% of the patients with ETB have overt metastases at the time of diagnosis. For EOE, 13% have overt metastases at diagnosis. Less than 20% of children with localized ETB survive their disease with only local therapy, i.e., a complete surgical excision and/or intensive radiation therapy. The overall survival markedly improved when multiagent intensive chemotherapy was added to radiation therapy, and the 5-year survival is up to 70% in many large studies, and 10-year event-free survival is approximately 50%.
Metastases: Although the prognosis is thought to be poor, it has been observed that with intensive therapy, survival in patients with ETB who have only pulmonary metastases is slightly higher than for patients with bone or bone marrow metastases.
Routine histopathology: Traditionally, a major distinction has been made between classical Ewing’s sarcoma (which shows minimal evidence of differentiation) and PNET (which shows evidence of neural differentiation), however, the degree of neural differentiation does not influence outcome.
Biological features: Reverse transcription polymerase chain reaction (RT-PCR) of the fusion transcripts from 112 patients with ETB and EOE revealed that the type I EWS-FL1 transcript was an important favorable prognostic feature in patients with localized primary tumors. In a study of a relatively small number of patients, overexpression of the p53 protein was a highly unfavorable prognostic feature. The presence of additional cytogenetic abnormalities, in particular loss of 16q, may be unfavorable. RT-PCR can be used to examine bone marrow for the presence of detectable translocation transcripts. In a single retrospective study among patients who did not have clinically detectable metastatic disease, positive RT-PCR for fusion transcripts was associated with a greater risk of recurrence after treatment. Telomerase activity (TA) as determined by RT-PCR in peripheral blood during therapy and follow-up was found to correlate significantly with prognosis; high TA with poor prognosis, low TA with good prognosis.
Response to preoperative therapy: Multiple studies have shown that patients with minimal or no residual tumor after presurgical chemotherapy have a significantly better event-free survival compared to patients with larger amounts of viable tumor. Massive tumor necrosis after induction chemotherapy is a very favorable sign.