Epidemiology

            Osteosarcoma is 20% of all bone tumors. The annual incidence of osteosarcoma is 3-1 million.

            Risk Factors

1. Subclinical trauma

2. Radiation

3. Chemotherapy: alkylating agents and anthracyclines

4. Children with retinoblastoma deletions of chromosome 13q with family

5. Pre-existing bone disorders: Paget’s disease

see table no. 47 Classification of malignant tumors of bone

Type histologic tumor type

A) .Osteogenic 1. Osteosarcoma

                                                2. osteogenic paraostial sarcoma

B) Chondrogenic 1. primary chondrosarcoma

                                                2. Secondary chondrosarcoma

3. Dedifferentiated chondrosarcoma (grade histological simultaneously contains 2)

                                                4. mesenchymal chondrosarcoma

C) Of unknown origin 1. Ewing tumor

                                                2. Malignant adamantinoma

                                                3. histiocytomas (fibrous) malignant

D) Fibrinogenic 1. Fibrosarcoma

E) Notocordal 1. chordoma

F) Vascular 1. Malignant hemangioendothelioma

                                                2. Malignant hemangiopericytomas

G) Hematopoietic 1. Myeloma

            Based on their natural biology and evolution of bone tumors were classified into 5 categories:

            1. Benign / dormant: natural development trend slow to heal spontaneously. Treated by curettage bone heals and do not require surgical treatment unless they are symptomatic.

            2. Benign / active: slowly progressive; curettage bone heals no damage, local recurrence rate is high. Wide local excision achieves local control in most cases.

            3. Benign / aggressive: aggressive local development without causing metastasis. Tumor extends through the capsule reactive zone. Excision of the tumor with normal bone area gets local control.

            4. Malignancies / low degrees: tumors have low potential to metastasize. Local control is obtained by excision of the tumor with normal bone area. It does not require chemotherapy treatment.

            5. Malignancies / high degrees: tumors grow rapidly and metastasize early and often. There are tumor nodules outside the tumor reactive and away from the same segment of bone. It is recommended surgical treatment for local control and cytostatic therapy to prevent lung metastases.

Histological Types of osteosarcoma

            Osteogenic sarcoma is a malignant sarcoma fusiform cells that produce bone or osteoid.

            1. Osteogenic classic sarcoma (high grade)

                        a) central osteogenic sarcoma (low grade)

b) sclerosing multifocal osteogenic sarcoma (high grade)

                        c) fibrosarcomatos osteogenic sarcoma (high grade)

                        d) teleangiectatic osteogenic sarcoma (high grade)

            2. ostegenic periosteal sarcoma (high grade)

            3. osteogenic paraostial sarcoma (low grade)

            Tumor markers

            Alkaline phosphatase is increased in 60% of patients with osteogenic sarcomas. A return to normal of the alkaline phosphatase indicates the effectiveness cancer therapy or surgery. When alkaline phosphatase is increased it reflects the size of the tumor mass. The persistence of elevated values after treatment shows its inefficiency.

            Signs and symptoms: bone pain, swelling of the affected area, functional impotence.

Most tumors arise around the knee joint, the femur or tibia metaphysics (60%). Miscellaneous locations are: 10% humerus, pelvis 9%, 9% lower jaw. High grade sarcoma bone metastasis mainly in lung and rarely in other bones.

            Definitive diagnosis is determined by tumor biopsy.

            Biopsy Tumor biopsy is recommended to be performed by the doctor who performs surgery.

            Headquarters biopsy must be removed “en bloc” with the tumor when it is resected to prevent local recurrence.

            The incision should be as short and parallel to the long axis of the affected bone. The material must contain component extra-osseous biopsy, and bone cortex.

            Incisional biopsy is preferred because get more material for histology and cytogenetics.

            Needle biopsy is indicated for vertebrae, pelvis, hip joint.

            For diagnosis and staging is recommended: history, clinical examination, anteroposterior radiography and lateral bone segment containing the tumor, blood count, urea, creatinine, liver function tests, alkaline phosphatase, calcium, magnesium, creatinine clearance, EKG, CT the affected bone, MRI of the affected bone, chest x-ray, CT lung, bone scan, angiography, bone scintigraphy with Thallium 201.

see table no. 48 bone sarcoma staging system (AJCC)

            The histology of the tumor (G)

                        G1 – low grade (includes Broders histological grade G1 and G2)

G2 – high degrees (include Broders histological grade G3 and G4)

                                    G1 – well differentiated

                                    G2 moderately differentiated

                                    G3- poorly differentiated

                                    G4- not undifferentiated

            Primary Tumor (T)

                        T1 tumor intra-compartment (intra-osseous)

                        T2 tumor extra-compartment (extended soft tissues)

The compartment is defined as an anatomical structure or space surrounded by natural barriers.

            Regional lymph nodes (N)

            N0- without lymph invasion

            N1- metastases in the lymph nodes

Metastasis (M)

            M0- without distant metastases

            Remote metastases M1

            Stages (AJCC)                   G                                     T           N                 M

            Stg.IA                           G1-2 (low)                           T1         N0             M0

            Stg.IB                           G1-2 (low)                           T2         N0             M0

            Stg.II A                         G3-4 (high)                         T1          N0             M0

            Stg.II B                         G3-4 (high)                         T2          N0             M0

Stg.III                         undefined

            Stg.IV A                      Any G                                  Any T      N1             M0

            Stg.IV B                       Any G                               Any T        Any N        M1

Table no. GTM 49 surgical staging proposed by Enneking (1980)

            Histological grading (G)

            G1- low grade tumors

            G2 – high grade tumors

            Primary Tumor (T)

            T1 tumor intra- compartment

            T2 tumor extra-compartment

Matastaze (M)

            M0- distant metastases

            M1 distant metastasis including lymph node

           Stages                  G                               T                                          M

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            Stg.IA                   G1                          T1                                         M0

            Stg.IB                   G1                          T2                                          M0

            Stg.II A                 G2                          T1                                          M0

Stg.II B                 G2                          T2                                          M0

            Stg.III A                any G                     T1                                         M1

            Stg.III B               any G                     T2                                           M1

            Stg.IV (none)

           TREATMENT

            Treatment depends on the patient’s age, tumor headquarters and the presence or absence of metastases.

I. For patients with low grade osteosarcoma (G1), stg.I and II (localized) recommended treatment is surgical resection

II. For patients with high grade osteosarcoma (G2) stg.I and II multimodality therapy is recommended consisting of preoperative chemotherapy cycles 3-4, restaging after preoperative chemotherapy and surgical resection of primary tumor.

Postoperative 3 weeks after surgery, chemotherapy is continued on the histological examination results resected piece.

a) localized disease (stg.I and II) in States

Indicate intensive multi-agent chemotherapy followed by limb salvage surgery. Postoperative multi-agent chemotherapy treatment is continued.

b) localized disease (stg.I and II) in the pelvis and vertebrae

These tumors cannot be resected with negative margins. It is recommended radiotherapy associated with chemotherapy.

III. Stg.IV bone sarcomas (lung metastases)

a) In patients with resectable lung metastases (<15 pulmonary nodules) and primary limb tumor.

It recommends alternating chemotherapy and surgery.

It is given a course of chemotherapy followed by resection of the primary tumor. It continues with a second course of chemotherapy followed by resection of pulmonary metastases. Postoperative multi-agent chemotherapy is administered.

b) In patients with inoperable metastases indicate chemotherapy. Sometimes it diminishes lung metastases than making possible surgery.

IV. Relapsing disease after initial treatment of bone sarcoma

Most relapses occur in the lung.

In patients with resectable lung metastases surgical resection is recommended.

Adjuvant Chemotherapy (the patient has already been treated intensively) is indicated if:

v injury occurred 6 months – 1 year initially following treatment

v more than 3 lung injuries

v pulmonary metastasis invading the pleura

Therapeutic Modalities

Surgery

Enneking and al surgical procedures classified under the plan with respect to surgical tumor dissection and removal method to obtain tumor:

1. Intralesional method: go through pseudocapsule direct tumor lesion. It remains macroscopic tumor and entire surgical field is potentially contaminated. Curettage is a intralesional process.

2. The process margin is one in which the entire lesion is removed in one piece. Plan dissection passes through pseudocapsule or reactive zone surrounding the lesion. When performed for a sarcoma remains macroscopic disease.

3. Excision range (intra-compartment). A wide excision resection joint called “en bloc” includes the entire tumor reactive zone and an area of ​​normal tissue. In patients with sarcoma can leave high grade tumor nodules away from home in the same bone structure (skip metastases)

4. Radical Excision (extra-compartment). A radical procedure involves removing the entire tumor origin and structure of the lesion. Plan fascia dissection is outside the limits or edges of bone.

Limb salvage surgery

 In most cases it is recommended limb salvage surgery. The surgical procedure consists of limb salvage resection, reconstruction of the defect and transferring muscle and soft tissue resection to cover premises and to ensure mobility.

            The following guidelines must be observed:

1.       Let there be no major neuromuscular invasion

 2. Wide resection of the affected bone

3. Resection “en bloc” headquarters previous biopsy and tissue potentially contaminated

4. Resection of 3-4 cm beyond abnormal detected by CT, MRI or bone scan

 5. Resection of adjacent joint capsule

6. Proper motor muscle reconstruction by regional transfer

7. Adequate coverage with soft tissue

Amputation is recommended in large lesions of the proximal femur and pelvis.

            In the 1105 International statistics were performed non metastatic osteosarcoma 649 and 351 amputations resection with 5-year survival from 41% to 87%.

Radiotherapy

            It is not recommended in the treatment of primary osteosarcoma.

It is used:

a) Patients who refused surgical treatment, requiring palliative or axial lesions.

b) Sarcomas axial skeletal and facial bone sarcomas are treated by surgical treatment limited Assign associated with radiotherapy.

c) Advanced inoperable pelvic injuries.

d) Palliative metastatic lesions.

7000-8000 cGy dose used is administered in weeks 7-9.

Chemotherapy

The drugs most used in monochemotherapy are (see table no. 50):

see table no. 50 cytostatic agents used in the treatment of bone sarcoma

Monochemotherapy

1. doxorubicin 90 mg / m2 i.v. Day 1 (or 30 mg / m2 1-3 days)

Repeat every 3 weeks.

30% response rate.

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2. high-dose methotrexate 8-12 g / m2

Is repeated weekly or every 2 weeks.

50% response rate.

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3. high dose cisplatin 120 mg / m2 / day i.v.

Repeat every 3 weeks.

20% response rate

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4. Ifosfamide 6-14g / m2 i.v. (Associated with mesna).

Repeat every 3 weeks.

The response rate of 20-67%

Polichemotherapy

            1. BCD

    Bleomycin 30-40 u.i / m2 i.v. Day 1

    Cyclophosphamide 1200 mg / m2 (associated with mesna) day 1

    Dactinomycin 1.2mg / m2 / day IV. Day 1

    Repeat 3 saptamni response rate 55%

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2. doxorubicin 60 mg / m2 day 1 i.v.

   Cisplatin 120 mg / m2 i.v.

   Repeat every 3 weeks with a 40-60% response rate

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3. Ifosfamide 18g / m2 total dose. It is given 2g / m2 over 4 hours and then 2 g / m2 / day for 8 days as a continuous infusion.

Bleomycin 20 IU / m2 / day 8-9 days (last day of ifosfamide administration)

                 G-CSF 480 mg / kg s.c. (1½ vials) from the 9th day.

    Response rate 75%

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4. T20 protocol using high doses of MTX 12g / m2 and lasts 17 weeks. In the 19th week intervene surgically.

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