PEDS: Osteosarcoma
Background Epidemiology
Osteosarcoma is the most common primary malignant bone tumor in children. It arises from the mesenchymal cells and has a male predominance in the teen years. There are 1 - 3 cases /million-year. It is associated with Rb gene inactivation (tumor suppressor gene) with a short arm deletion of Ch 17. p53 is localized here. cKit and TP53 mutations are found in osteosarcomas. Osteosarcomas may develop in long term survivors of retinoblastoma. Hereditary osteosarcomas may arise in and out of previously irradiated areas and in children treated without radiation for retinoblastomas.
There is a bimodal age distribution with a peak at around 17 years and a second smaller peak around the late 70s.
Presentation and Workup and Staging
Presentation
Osteosarcoma occurs in the metaphysis of the long bones especially around the knee. The distal femur accounts for about 50% of the cases with the tibia accounting for an additional 26%, the humerus 10% and the pelvis 5%. The usual clinical presentation is swelling and pain. Occasionally patients present with a pathologic fracture.
On plain films, the tumor has a characteristic "sunburst pattern" and a Codman's Triangle. It has poorly defined margins, interrupted periosteal new bone formation and soft tissue invasion. CT and MRI help determine the extent of intramedulary invasion and extent of soft tissue extension. Bone scans have nearly 100% sensitivity. The most common site of distant metastases is the lung and bones.
Clinical Prognostic Factors
Clinical prognostic factors include:
- Duration of presenting symptoms (shorter is worse)
- Tumor size (larger is worse)
- location of primary (head, spine, rib, pelvic sites are worse)
- weight loss > 10 pounds
Tumor size seems strongly predictive of outcome and has been described as an absolute tumor dimension (> 10 cm), a relative tumor length as a fraction of involved long bone (> 1/3 of involved bone) or absolute tumor volume (> 70 or 150 cm3),
Staging
Halperin (Ped. Rad. Onc., 5th Ed., Ch 10) reports no commonly used staging system, but describes several. The AJCC uses a TNMG staging system for adult osteosarcomas with T staging determined by tumor size (T1 < 8 cm; T2 > 8 cm; and T3 discontinuous tumors), Node status, and mets to lungs (M1a) or other places M1b. The Stage grouping is based on tumor grade and size with Stage I low grade and A/B on T size. Stage II is high grade and Stage III is discontinuous high grade, Stage IVA/B depending on where mets are found. .
Another staging system is the German-Austrian-Swiss Osteosarcoma Study Group (COSS) for high grade extremity or trunk osteosarcomas identifying superior survival with limb disease over axial disease. They also note that tumors involving less than 1/3 of the bone had better prognosis.
The Musculo-Skeletal Tumor Society (Enneking) uses grade and extent of disease, but most tumors are stage II/III (high grade).
Treatment
The major modalities of treatment are surgery, radiation therapy and chemotherapy. Osteosarcoma has a reputation of being radioresistant, which is unjustified. The Cade Technique used radiotherapy to delay surgery as a means of identifying patients who would benefit from amputation as opposed to those who would develop interval lung metastases. Radiation therapy was formerly used to treat highly bulky tumors resulting in a high rate of reported local failures. The D0 (dose to reduce survival by 37% (1/e) based on the linear/quadratic dose response hypothesis) and a broad shoulder of the survival curve ( higher Dq) are reported to be similar to most other mammalian tumors. Dose response studies have been performed. From these studies persistent tumor was always found with doses ≤ 50 Gy. Viable tumor in dose escalation studies was still identified in 1 of 10 in those receiving < 100 Gy. Chemotherapy with 60 Gy has demonstrated in post-amputation specimens no evidence of viable tumor (Caceres/Peru), although complications were common: pathologic fracture, soft tissue fibrosis/necrosis, local infection and moist desquamation. This result is inconsistent with Caceres' previously reported results which were much poorer.
Surgery
Surgery remains the mainstay for osteosarcomas.
Local Disease
As in adult osteosarcomas, the biopsy site is critical. It should be selected to allow further revision and to allow access to the infiltrating edge of the tumor. Minimal to no cortical bone should be removed to reduce the risk of pathologic fracture.
Amputation to clear margins is definitive. In amputation above the most proximal extent of disease,with negative margins, the chance of stump recurrence is negligible.
Limb sparing/salvage procedures may be selected if there is no evidence of neurologic or vascular compromise by the local tumor, adequate margins can be obtained and good functional outcome (± reconstruction) can be achieved.
Contraindications to limb sparing procedures include the presences of a pathologic fracture, poor response to neoadjuvant chemotherapy, skeletal imaturity leading to significant growth discrepancies.
Surgical margins considered adquate are defined. A radical margin is amputation of the affected limb such as hip disarticulation for a distal femur lesion. A wide margin is defined as excision of the tumor with a cuff of surrounding normal tissue. A marginal margin is excision of the tumor and its active pseudocapsule.
Local control is improved with adequate surgical margin and response to neoadjuvant chemotherapy. Limb sparing surgery has a slightly greater risk of local tumor recurrence than does amputation. Amputation has a slightly greater risk of recurrence than disarticulation. Excellent response to neoadjuvant chemotherapy will allow the surgeon to have a tighter margin and exclude more normal tissue with reduced morbidity. Unfortunately, there is no clear mechanism to a priori identify whether a marginal excision is reasonable. Imaging cannot provide this data.
Metastatic Disease
Surgery is useful in treating osteosarcoma with limited pulmonary metastases. Aggressive multi-agent chemotherapy surgical managment of the primary tumor and resection of pulmonary metastases have significantly increased survival. The most common sites of relapse are lung and bone. Earlier diagnosis of pulmonary metastases and surgical excision, including repeated thoracotomies appear to have prolong survival in the face of multiple pulmonary recurrences. There is some question whether CT imaging is helpful or creates a lead time bias in determining survival benefit.
Surgical considerations for metastatectomy:
- Interval between recurrences and primary treatment
- Aggressiveness of the proposed intervention
- Unilateral or bilateral disease
- Primary treatment
- Hilar/nodal involvement
- Available salvage chemotherapies after surgery
- The role of salvage surgery for bone metastases is unknown
Recurrence | EFS at 5 years | OS at 5 years |
---|---|---|
Second | 18% | 32% |
Third | 0% | 26% |
Fourth | 13% | 28% |
Radiation Therapy
The survival rate for surgery alone is around 20%. Adjuvant therapy is required. Initially the Cade Technique was used as a means to delay surgery to spare amputation where lung mets would claim the patient in six months or less. With the advent of chemotherapy, radiation therapy is rarely used for primary treatment except in surgically inaccessible sites. Data from the Cade Technique treatments make it reasonable to consider radiation in certain situations.
- Most common bone tumor in children
- Peaks at 10-19 years
- 75% in long bones
- Indications for Radiation
- Inoperable site
- Pre-op radiation for marginally resectable tumor
- Dose: EBRT ≥ 60 Gy in 6 weeks minimum
- Sm-153 on protocol but severe pancytopenias are seen.
AOST 331 Radiation Guidelines
- Surgery is the preferred primary modality. Radiation is indicated when complete resection cannot be achieved
- Radiation Doses:
- Post-Op microscopically positive: 60 Gy
- Post-OP macroscopic residual: 66 Gy
- Definitive: 70 Gy (c/w normal tissue complications)
Concurrent chemotherapy- radiation concerns and considerations:
- Avoid high dose methotrexate when CSN/spinal cord radiation is given
- Avoid ifosfamide when bladder radiation is given
- Avoid doxorubicin when axial radiation is given due to intestinal toxicity