AUTHOR INFORMATION

Section 1 of 12

Authored by Timothy P Cripe, MD, PhD, Associate Professor of Pediatric Hematology/Oncology, University of Cincinnati; Director, Translational Research Trials Office, Department of Pediatrics, Cincinnati Children's Hospital Medical Center

Timothy P Cripe, MD, PhD, is a member of the following medical societies: American Association for the Advancement of Science, American Society of Hematology, and American Society of Pediatric Hematology/Oncology

Edited by Samuel Gross, MD, Professor Emeritus, Department of Pediatrics, University of Florida, Clinical Professor, Department of Pediatrics, UNC, Adjunct Professor, Department of Pediatrics, Duke University; Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine.com, Inc; Steven K Bergstrom, MD, Assistant to the Chairman, Department of Pediatrics, Division of Hematology-Oncology, Kaiser Permanente Medical Center of Oakland, CA; Helen SL Chan, MBBS, FRCP(C), FAAP, Senior Scientist, Research Institute; Professor, Division of Hematology/Oncology, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Canada; and Max J Coppes, MD, PhD, MBA, Executive Director, Center for Cancer and Blood Disorders, Children's National Medical Center

Author's Email:	Timothy P Cripe, MD, PhD
Editor's Email:	Samuel Gross, MD

eMedicine Journal, July 25 2006, VOLUME 7, Number 7

INTRODUCTION

Section 2 of 12

Background: Osteosarcoma is the third most common cancer in adolescence, occurring less frequently than only lymphomas and brain tumors. It is thought to arise from a primitive mesenchymal bone-forming cell and is characterized by production of osteoid. The mainstay of therapy is removal of the lesion. Limb-sparing procedures can often be used to preserve function. Chemotherapy is also required to treat micrometastatic disease, which is present but not detectable in most patients at diagnosis.

Pathophysiology: Osteosarcoma is a bone tumor that can occur in any bone. It most commonly occurs in the long bones of the extremities near metaphyseal growth plates. The most common sites are femur (42%, with 75% of tumors in the distal femur), tibia (19%, with 80% of tumors in the proximal tibia), and humerus (10%, with 90% of tumors in the proximal humerus). Other locations of note are the skull or jaw (8%) and pelvis (8%).

Any sarcoma that arises from bone is technically called an osteogenic sarcoma. Therefore, this term includes fibrosarcoma, chondrosarcoma, and osteosarcoma, all named for their morphologic characteristics. The focus of this article is osteosarcoma. A number of variants of osteosarcoma exist and include conventional types (ie, osteoblastic, chondroblastic, fibroblastic types) and telangiectatic, multifocal, parosteal, and periosteal types.

Frequency:

• In the US: The incidence is 400 cases per year (4.8 cases per million persons <20 y).

Mortality/Morbidity: The overall 5-year survival rate for patients whose condition was diagnosed between 1974 and 1994 was 63% (59% for male patients, 70% for female patients).

Race: The incidence is slightly higher in African Americans than in Caucasians (data from the National Cancer Institute [NCI] Surveillance, Epidemiology, and End Results [SEER] Study Pediatric Monograph, 1975-1995).

• In African Americans, the annual incidence is 5.2 cases per million population younger than 20 years.

• In Caucasians, the annual incidence is 4.6 cases per million population younger than 20 years.

Sex: The incidence is slightly higher in male individuals than in female individuals.

• In male individuals, the incidence is 5.2 cases per million population per year.

• In female individuals, the incidence is 4.5 cases per million population per year.

Age: Osteosarcoma is rare in children younger than 5 years, in whom the annual incidence is approximately 0.5 case per million population. The incidence increases steadily with age; a relatively dramatic increase in adolescence corresponds with the growth spurt.

• In children aged 5-9 years, the annual incidence is 2.6 cases for African Americans and 2.1 cases for Caucasians per million population.

• In children aged 10-14 years, the annual incidence is 8.3 cases for African Americans and 7 cases for Caucasians per million population.

• In adolescents aged 15-19 years, the annual incidence is 8.9 cases for African Americans and 8.2 cases for Caucasians per million population.
  
  
• Patients whose disease is diagnose during their growth spurt are taller than average, though patients identified in adulthood have average height.

CLINICAL

Section 3 of 12

History: Symptoms may be present for weeks, months, or occasionally longer before osteosarcoma is diagnosed. The most common presenting symptom of osteosarcoma is pain, particularly with activity. Patients may complain of a sprain, arthritis, or so-called growing pains. The patient often has a history of trauma, though pathologic fractures are not particularly common. The exception is the telangiectatic type of osteosarcoma, which is commonly associated with pathologic fractures. If pain affects a lower extremity, it may result in a limp.

The patient may have a history of swelling, depending on the size of the lesion and its location. Systemic symptoms, such as fever and night sweats, are rare. Tumoral spread to the lungs only rarely results in respiratory symptoms, and such symptoms usually indicate extensive lung involvement. Metastases to other sites are extremely rare; therefore, other symptoms are unusual. Only 15-20% of patients present with metastases, which primarily affect the lungs, but they can also affect other bones. Manifestations at several bone sites at diagnosis may indicate multifocal sclerosing osteosarcoma.

Osteosarcoma most commonly involves the distal femur and proximal tibia, followed by the proximal humerus and mid and proximal femur. As many as 20% of patients present with tumors of the flat bones of the body including the skull and pelvis. Tumors of the jaw are relatively uncommon.

Physical: Physical findings are usually limited to those of the primary tumor site.

• Mass: A palpable mass may be present. The mass may be tender and warm, though these signs are indistinguishable from those of osteomyelitis. Increased skin vascularity over the mass may be discernible. Pulsations or a bruit may be detectable.



• Decreased range of motion: Joint involvement should be obvious on physical examination.



• Lymphadenopathy: Involvement of local or regional lymph nodes is unusual.



• Respiratory findings: Auscultation is usually uninformative unless extensive pulmonary disease is present.

Causes: The exact cause of osteosarcoma is unknown. However, a number of risk factors are known.

• Rapid bone growth appears to predispose patients to osteosarcoma, as suggested by the increased incidence during the adolescent growth spurt, the high incidence among large dogs (eg, Great Danes, St Bernards, German shepherds), and the typical location of osteosarcomas near the metaphyseal growth plate of long bones.



• Exposure to radiation is the only known environmental risk factor.



• A genetic predisposition may exist.


• • Retinoblastoma, especially the combination of a constitutional mutation of the RB gene (germline retinoblastoma) with radiation therapy, is associated with a particularly high risk of osteosarcoma development. Of note, the genetic locus retinoblastoma at band 13q14 has also been implicated in the pathogenesis of sporadic osteosarcoma.
  
  
  
  • Bone dysplasias, including Paget disease, fibrous dysplasia, enchondromatosis, and hereditary multiple exostoses, increase the risk for osteosarcoma.
  
  
  
  • Li-Fraumeni syndrome (germline TP53 mutation) is a predisposing factor for osteosarcoma.
  
  
  
  • Rothmund-Thomson syndrome (ie, autosomal recessive association of congenital bone defects, hair and skin dysplasias, hypogonadism, cataracts) is associated with an increased risk of osteosarcoma.
  
  
  

DIFFERENTIALS

Section 4 of 12

Ewing Sarcoma and Primitive Neuroectodermal Tumors
Histiocytosis
Nonrhabdomyosarcoma Soft Tissue Sarcomas
Osteomyelitis
Rhabdomyosarcoma

Other Problems to be Considered:

Stress fracture
Hematoma
Chondroblastoma
Chondromyxoid fibroma
Osteochondroma
Osteoblastoma
Bone cysts
Giant cell tumor
Fibrosarcoma
Chondrosarcoma

WORKUP

Section 5 of 12

Lab Studies:

• Most recommended laboratory studies are related to the use of chemotherapy. Therefore, assessing organ function before, during, and after chemotherapy is important.



• The only blood tests with prognostic significance are measurements of lactate dehydrogenase (LDH) and alkaline phosphatase levels. Patients with elevated alkaline phosphatase values at diagnosis are more likely than others to have pulmonary metastases. Patients without metastases with an elevated LDH level are less likely to do well than those with an LDH level in the reference range.



• Important laboratory studies include tests of the following:


• • LDH, alkaline phosphatase (prognostic significance)
  
  
  
  • CBC, including differential and platelet count
  
  
  
  • Aspartate aminotransferase (AST), alanine aminotransferase (ALT), bilirubin, and albumin levels to assess liver function
  
  
  
  • Electrolyte concentrations, including sodium, potassium, chloride, bicarbonate, calcium, magnesium, and phosphorus levels
  
  
  
  • BUN and creatinine values to assess renal function
  
  
  
  • Urine (urinalysis)
  
  
  

Imaging Studies:

• Plain radiography


• • Plain radiograph of the suspected lesions should be obtained in 2 views.
  
  
  
  • No single feature on radiographs is diagnostic. Osteosarcomatous lesions can be purely osteolytic (about 30% of patients), purely osteoblastic (about 45% of patients), or a mixture of both.
  
  
  
  • Elevation of the periosteum may appear as the characteristic Codman triangle. Extension of tumor through the periosteum may result in a so-called sunburst appearance (about 60% of patients).
  
  
  
  • The entire bone and adjacent joint should be imaged to assess for skip lesions and joint involvement.
  
  
  
  • Telangiectatic osteosarcomas are often cystic and can be mistaken for an aneurysmal bone cyst.
  
  
  
• Chest radiography: Chest radiographs (posteroanterior and lateral views) should be obtained to evaluate for pulmonary metastases. If metastases are present and visible on chest images, this modality then can be used for follow-up of specific lesions.



• CT scanning


• • Both a CT scan of the primary lesion and a high-resolution CT scan of the chest (at 3.75- to 7.5-mm intervals) should be obtained.
  
  
  
  • CT scanning of the primary lesion helps in delineating the location and extent of the tumor and is critical for surgical planning.
  
  
  
  • CT of the chest is more sensitive than plain radiography for assessing pulmonary metastases. In the ideal situation, the chest CT should be obtained before biopsy to avoid ambiguity that can arise from postanesthesia atelectasis.
  
  
  
• Magnetic resonance imaging


• • MRI of the primary lesion is the best method for assessing the extent of intramedullary disease.
  
  
  
  • MRI findings are best correlated with the extent of disease assessed at the time of definitive surgery.
  
  
  
  • MRI should include joint-to-joint imaging to rule out skip lesions.
  
  
  
• Radionuclide bone scanning with technetium-99m diphosphonate


• • An evaluation for the presence of metastatic or multifocal disease with bone scanning is imperative.
  
  
  
  • Abnormal areas should subsequently be imaged by using CT or MRI.
  
  
  
• 18F-Fluoro-deoxy-glucose positron emission tomography or thallium-201 scintigraphy


• • The use of these radionuclide studies for diagnostic and prognostic purposes in osteosarcoma is still under investigation.

  • Initial published data suggest the results of these can be more predictive of the response to chemotherapy then MRI or CT findings.
  
  
  

Other Tests:

• Audiography: Hearing loss is an adverse effect of cisplatin.



• Echocardiography or multiple-gated acquisition (MUGA) scanning: Cardiac function should be assessed before and at various intervals after treatment with doxorubicin (Adriamycin).

Procedures:

• An orthopedic surgeon should perform biopsy (see Surgical Care).



• Resections of the primary lesion and of any pulmonary metastases are essential for cure. These should be performed by orthopedic and thoracic surgeons, respectively (see Surgical Care).



• Presurgical (neoadjuvant) chemotherapy often aids resection by shrinking tumors and enables the assessment of histopathologic responsiveness of the tumor, a major predictor of the outcome.

In general, the characteristic feature of osteosarcoma is the presence of osteoid in the lesion, even at sites distant from bone (eg, the lung). Although osteoid is usually obvious, electron microscopy is occasionally required to visualize its formation. Stromal cells may be spindle shaped and atypical with irregularly shaped nuclei.

A number of distinct histologic types of osteosarcoma are described. The conventional type is the most common in childhood and adolescence. This type has been subdivided on the basis of the predominant features of the cells (ie, osteoblastic, chondroblastic, fibroblastic types), though the subtypes are clinically indistinguishable. The telangiectatic type contains large, blood-filled spaces and is common in adolescence and early adulthood. The parosteal type is usually located in the bony cortex, it is easier to cure than the conventional type, and it can be seen in childhood or adulthood. The low-grade periosteal type, which also arises from the cortex but which usually encircles the bone, most often occurs in older patients who have a long history of symptoms, which reflects its indolent nature.

Staging: The purpose of staging tumors is to stratify risk groups. The conventional staging system used for other solid tumors is not appropriate for skeletal tumors because these tumors rarely involve lymph nodes or spread regionally. Rather, the staging system Enneking devised is based on grade, extramedullary spread, and metastases. These features are most important for nonmalignant skeletal tumors; most osteosarcomas are highly malignant. For osteosarcoma, the foremost initial question regarding staging is whether the tumor has metastasized.

Other features of the tumor, though technically not used in staging, may affect the prognosis. These include the LDH and alkaline phosphatase levels, the site of primary tumor (mostly related to ease of complete resection), the histologic response to chemotherapy, and the cause of disease. Patients with a good histologic response before surgery, the definition of which is still debated, appear to have an improved prognosis. Those with lesions arising from Paget disease have a particularly poor prognosis. Patients with isolated lesions of the jaw tend to do better and have a relatively low incidence of metastases.

Other features are being investigated for their prognostic significance. Examples include cellular expression of membrane-type matrix metalloproteinase type 1, Fas, CXCR4, Twist, microvessel density, and microarray signatures. Each of these features was prognostic in small series, but none have been tested prospectively, and testing for them has not yet become standard of care. The presence of metastases and a histologic response remain the most important predictors of outcome. Serum markers lose their significance when they are considered in multivariate analysis.

The osteosarcoma staging system can be summarized as follows:

• Stages


• • Stage I - Low-grade lesions
  
  
  
  • Stage II - High-grade lesions
  
  
  
  • Stage III - Metastatic disease
  
  
  
• Substages


• • A - Intramedullary lesion
  
  
  
  • B - Local extramedullary spread
  
  
  
• Site of primary


• • Distal extremity - Best prognosis
  
  
  
  • Distal femur - Intermediate prognosis

  • Axial skeleton - Worst prognosis
  
  
  

TREATMENT

Section 6 of 12

Medical Care: Before the use of chemotherapy which began in the 1970s, osteosarcoma was treated primarily with surgical resection, usually amputation. Despite such good local control of their disease, more than 80% of patients subsequently developed recurrent disease that typically manifests as pulmonary metastases. The high recurrence rate indicates that most patients have micrometastatic disease at diagnosis. Therefore, the use of adjuvant (postoperative) systemic chemotherapy is critical for the treatment of patients with osteosarcoma.

Neoadjuvant (preoperative) chemotherapy not only facilitates subsequent surgical removal by shrinking the tumor but also provides oncologists with an important risk parameter. Patients who have a good histopathologic response to neoadjuvant chemotherapy (>95% tumor cell kill or necrosis) have a prognosis better than those whose tumors do not respond favorably. Therefore, an assessment of neoadjuvant tumor cell kill has been incorporated into current chemotherapy trials to provide risk-adapted treatment regimens to determine if dose-intensification can improve the survival of patients with a poor initial histologic response.

Surgical Care: The orthopedic surgeon is of paramount importance in the care of patients with osteosarcoma. However, surgery should be conducted only in collaboration with a pediatric oncologist familiar with and knowledgeable about ongoing clinical trials to facilitate optimal care. Patients with suspected osteosarcoma are often referred to the orthopedic surgeon first for diagnosis.

In addition, because osteosarcomas are not particularly responsive to radiotherapy, surgery is the only option for definitive tumor removal (ie, local control). In addition, prosthesis or bone stabilization may be required after surgical resection. Therefore, close involvement of the orthopedic surgeon at diagnosis and during and after therapy is critical.

• Biopsy


• • Open biopsy is preferred because it avoids sampling error and provides adequate tissue for biologic studies. Other options include trephine biopsy, which is preferred for vertebral bodies and iliac crests. Fine-needle aspiration is not recommended.

  • Incision for an open biopsy should be planned carefully to avoid tumoral contamination of neurovascular structures and to allow for en bloc removal during eventual definitive surgery.

  • Regardless of the technique chosen, a frozen section should be examined to be certain that the tumor was sampled accurately. If possible, extraosseous components should be sampled rather than bone to decrease the risk of fracture.

  • Bone holes should be sealed with polymethacrylate, and extraosseous holes should sealed with absorbable gelatin sponge (Gelfoam) to decrease the risk of hematoma and tumoral spread.

  • Drains should be closed suction (to prevent infection) in line with the skin incision (to prevent tumor contamination in adjacent tissue).
  
  
  
• Definitive resection


• • The primary aim of definitive resection is the patient’s survival. As such, margins on all sides of the tumor must contain normal tissue (ie, wide margin).

  • The width of the margin is important only for the marrow, where an adequate margin is thought to be 5-7 cm from the edge of the abnormality, as shown on MRIs or bone scans.

  • Radical margins, defined as removal of the entire compartment involved (joint to joint for bone and origin to insertion for muscle), are usually not required to achieve a cure.

  • A marginal or intralesional margin may be functionally helpful as debulking therapy, but it is not locally curative.
  
  
  
  • Amputation may be the treatment of choice.
  
  
  
  • Patients usually prefer limb-salvage reconstruction (if possible) over amputation, but recent studies of late effects show that patients with amputations may long-term quality of life equivalent to that of patients undergoing limb salvage. These data are largely based on patients who underwent limb-salvage at least decades ago; therefore, the effect of modern limb-salvage techniques on this assessment is not clear.

  • The reconstruction technique must be chosen on the basis of individual considerations, as described below.
    • Autologous bone grafting: Advantages include no rejection and a low rate of infection. This technique should be used only in skeletally mature patients because periosteal infusion inhibits epiphyseal growth.

    • Allografting: Graft healing and infection can be problematic with this technique, particularly during chemotherapy. Rejection can also occur.

    • Prosthetic: Prosthetic joints can be solitary or expandable. They are usually expensive, and their longevity is unknown.

    • Rotationplasty: This technique is suitable for tumors of the distal femur or proximal tibial when the knee cannot be spared and particularly for large tumors for which high amputation is the only alternative. Young or athletic patients may functionally benefit from this procedure. After tumoral resection, vessels are repaired or looped and kept in continuity. The distal portion of the leg is rotated 180° and reattached to the thigh at the proximal resected edge. The rotation allows the ankle to become a functional knee joint, so the length of the leg should be adjusted to match the contralateral knee. The foot acts as the anchor for the prosthesis. Patients can learn to use the leg effectively.
  
  
  
• Resection of pulmonary nodules


• • Metastatic lung nodules can be cured by means of complete surgical resection, most often wedge resection. Lobar resection or pneumonectomy is occasionally required to achieve clear margins. This procedure should be done at the time of primary tumor resection.
  
  
  
  • Although bilateral nodules can be resected by using a median sternotomy, surgical exposure is superior with a lateral thoracotomy. Therefore, staged bilateral thoracotomy procedures are recommended for bilateral disease (ie, 2 lateral thoracotomy procedures separated by a few weeks).
  
  
  
  • For osteosarcoma that recurs as only lung lesions more than 1 year after the patient completion therapy, surgical resection alone can be curative because the likelihood of metastases to other sites is low. If disease recurs sooner than 1 year after therapy, chemotherapy is warranted because the risk of other micrometastatic disease is high.
  
  
  

Consultations: As is usual for any child with cancer, consultations with an oncologist and with any subspecialist related to the specific clinical circumstances are strongly recommended. Social service professions, psychologist, dentists, dietitians, and child-life specialists are usually involved with patients and their families throughout the course of their treatment.

Diet: Patients receiving methotrexate should not be given folate supplementation or prophylaxis with trimethoprim-sulfamethoxazole (Bactrim). Diet is not otherwise restricted.

Activity: Restrictions on activity vary with the location of the tumor and on the type of surgical procedure required for treatment.

MEDICATION

Section 7 of 12

The chemotherapeutic drugs most active in osteosarcoma are doxorubicin, cisplatin, and high-dose methotrexate (for which a low dose is ineffective). A number of pilot studies are currently being conducted to test the efficacy and safety of alkylator dose escalation, In addition, other therapies are being tested, such as the following:

• Anthracycline escalation by using a cardioprotectant

• Topoisomerase I inhibitors

• Cyclosporin A to block the P-glycoprotein pump, which causes multidrug resistance

• Muramyl tripeptide phosphatidyl ethanolamine (MTP-PE) and other immune enhancers

• Monoclonal antibody against the Her2/neu antigen, which is overexpressed in some osteosarcomas

• Inhibitors of epidermal growth factor receptor, as based on its high rate of expression in osteosarcomas

As usual, physicians caring for patients with osteosarcoma should consult a pediatric oncologist affiliated with a center that participates in national or international trials to determine both the current standard treatment protocol and whether an appropriate investigational study is open for patient accrual.

Drug Category: Antineoplastic agents -- These agents disrupt DNA replication or cell division, thereby inhibiting tumor growth and promoting the death of tumor cells.

Drug Name	Doxorubicin (Adriamycin, Rubex) -- Mechanisms of action include DNA intercalation, topoisomerase-mediated DNA strand breaks, and oxidative damage by means of free-radical production.
Adult Dose	Varies by protocol
Pediatric Dose	Varies by protocol; protocol CCG-7921 used 25 mg/m2/d continuous IV infusion over 72 h, not to exceed 450 mg/m2
Contraindications	Documented hypersensitivity; severe heart failure, cardiomyopathy, impaired cardiac function; preexisting myelosuppression
Interactions	May decrease phenytoin and digoxin plasma levels; phenobarbital may decrease plasma levels; cyclosporine may induce coma or seizures; mercaptopurine increases toxicity; cyclophosphamide increases cardiac toxicity
Pregnancy	D - Unsafe in pregnancy
Precautions	Cardiotoxicity (may cause congestive heart failure when cumulative dose >450 mg/m2); other adverse effects include myelosuppression, nausea, diarrhea, alopecia, transient liver function abnormalities, hyperpigmentation of nail beds and dermal creases; tissue damage with extravasation

Drug Name	Cisplatin (Platinol, CDDP) -- Mechanism of action is platination of DNA, mechanism analogous to alkylation leading to interstrand and intrastrand DNA crosslinks and inhibition of DNA replication.
Adult Dose	Varies by protocol
Pediatric Dose	Varies by protocol; protocol CCG-7921 used 120 mg/m2 IV infused over 4 h on day 1 of each chemotherapy cycle
Contraindications	Documented hypersensitivity; renal impairment; hearing impairment; myelosuppression
Interactions	May potentiate ototoxicity of aminoglycosides; may increase nephrotoxicity of other drugs (eg, amphotericin B); loop diuretics increase risk of nephrotoxicity; increases toxicity of bleomycin
Pregnancy	D - Unsafe in pregnancy
Precautions	Administer adequate hydration before and 24 h after cisplatin dosing to reduce risk of nephrotoxicity; myelosuppression, ototoxicity, and nausea and vomiting may occur

Drug Name	Methotrexate (Folex PFS, high dose) -- Folate analog. Competitively inhibits dihydrofolate reductase, inhibiting DNA replication and RNA transcription; patients should receive adequate hydration and alkalinization to ensure effective drug clearance.
Adult Dose	Varies by protocol
Pediatric Dose	12 g/m2 IV infused over 4 h; not to exceed 20 g/dose Protocol CCG-7921 administered high-dose methotrexate on days 21 and 28 of each chemotherapy cycle
Contraindications	Documented hypersensitivity; alcoholism; hepatic insufficiency; documented immunodeficiency syndromes; preexisting blood dyscrasias (eg, bone marrow hypoplasia, leukopenia, thrombocytopenia, significant anemia)
Interactions	Charcoal lowers levels; coadministration with etretinate may increase hepatotoxicity; folic acid or its derivatives contained in some vitamins may decrease response; coadministration with NSAIDs may be fatal; indomethacin and phenylbutazone can increase plasma levels; may decrease phenytoin serum levels; probenecid, salicylates, procarbazine, and sulfonamides may increase effects and toxicity; may increase plasma levels of thiopurines
Pregnancy	X - Contraindicated in pregnancy
Precautions	Caution in ascites or pleural effusions, which can result in third spacing and delay clearance; caution in renal dysfunction (creatinine clearance [CrCl] should be >60 mL/min/1.73 m2); caution in liver dysfunction; adverse effects include myelosuppression, mucositis, nausea, vomiting, diarrhea, drowsiness, blurred vision, encephalopathy, paresis, seizures, transient liver function abnormalities, alopecia, rashes, photosensitivity, depigmentation or hyperpigmentation of skin, interstitial pneumonitis, osteoporosis, fever, infertility, menstrual dysfunction

Drug Name	Ifosfamide (Ifex) -- DNA alkylator, leading to interstrand and intrastrand DNA crosslinks, DNA-protein crosslinks, and inhibition of DNA synthesis.
Adult Dose	Varies by protocol
Pediatric Dose	Varies by protocol; 1.8 - 3.6 mg/m2/d IV for 5 d each cycle (ie, total cumulative dose of 9-18 mg/m2 per cycle)
Contraindications	Documented hypersensitivity, severely depressed bone marrow function
Interactions	Substrate of cytochrome P450 (CYP) 3A4; phenobarbital, phenytoin, chloral hydrate, and other drugs that induce with CYP activity, may increase ifosfamide clearance; coadministration with warfarin increases international normalized ratio (INR)
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Administer with mesna and extensive hydration to prevent hemorrhagic cystitis; causes myelosuppression, nausea, alopecia, and infertility

Drug Category: Antiemetic agents -- Emesis is a clinically significant adverse effect of chemotherapeutic drugs, particularly the drugs used to treat osteosarcoma. Patients often require several antiemetics, and antiemetic regimens should be tailored for each patient. Commonly used antiemetics include serotonin receptor antagonists (eg, dolasetron, granisetron, ondansetron, tropisetron), corticosteroids (eg, dexamethasone), and dopamine receptor antagonists (eg, metoclopramide, prochlorperazine). The American Society of Clinical Oncology published evidence-based clinical practice guidelines for the use of antiemetics used for chemotherapy-induced nausea and vomiting.

Drug Name	Ondansetron (Zofran) -- Selectively antagonizes serotonin 5-HT3 receptors.
Adult Dose	0.15 mg/kg PO/IV q8h started 30 min before chemotherapy
Pediatric Dose	Administer as in adults
Contraindications	Documented hypersensitivity
Interactions	Although CYP inducers (barbiturates, rifampin, carbamazepine, and phenytoin) may change half-life and clearance, dosage adjustment not usually required
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Caution in liver toxicity and history of anaphylaxis (use premedication)

Drug Name	Dexamethasone (Decadron) -- Several glucocorticoid and mineralocorticoid effects, including relief of emesis.
Adult Dose	10 mg/m2 PO/IV/IM for 1 dose; followed by 5-10 mg/m2 PO/IV/IM q6h; not to exceed 20 mg/dose
Pediatric Dose	Administer as in adults
Contraindications	Documented hypersensitivity; active bacterial or fungal infection
Interactions	Effects decrease with coadministration of barbiturates, phenytoin and rifampin; dexamethasone decreases effect of salicylates and vaccines used for immunization
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Increases risk of several complications, including severe infections; monitor adrenal insufficiency when tapering; abrupt discontinuation of glucocorticoids may cause adrenal crisis; hyperglycemia, edema, osteonecrosis, myopathy, peptic ulcer disease, hypokalemia, osteoporosis, euphoria, psychosis, myasthenia gravis, growth suppression, and infections are possible complications of glucocorticoid use

Drug Name	Prochlorperazine (Compazine) -- Selectively antagonizes dopamine D2 receptors.
Adult Dose	5-10 mg PO/IM tid/qid; not to exceed 40 mg/d 5-10 mg IV over 2 min; 25 mg PR bid
Pediatric Dose	0.4 mg/kg/d PO/PR divided tid/qid; 0.1-0.15 mg/kg/dose IV/IM tid/qid
Contraindications	Documented hypersensitivity; bone marrow suppression; narrow-angle glaucoma; severe liver or cardiac disease
Interactions	Coadministration with other CNS depressants or anticonvulsants may cause additive effects; may cause hypotension with epinephrine
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Drug-induced Parkinson syndrome or pseudoparkinsonism frequent, particularly in pediatric patients; akathisia most common extrapyramidal reaction in elderly; lowers seizure threshold; caution with history of seizures

Drug Category: Colony-stimulating factors -- These agents act as hematopoietic growth factors that stimulate development of granulocytes. They are used to treat or prevent neutropenia when a patient is receiving myelosuppressive cancer chemotherapy and to reduce the period of neutropenia associated with bone marrow transplantation.

Drug Name	Filgrastim (Neupogen) -- Granulocyte colony-stimulating factor (G-CSF) that activates and stimulates production, maturation, migration, and cytotoxicity of neutrophils. Shortens time to recovery of neutrophils after chemotherapy by stimulating bone marrow production of neutrophil precursors. Also stimulates granulocytic antibacterial functions.
Adult Dose	5 mcg/kg/d SC beginning >24 h after last dose of chemotherapy
Pediatric Dose	Administer as in adults; discontinue when absolute neutrophil count (ANC) rises above a predetermined level, usually 1000-10,000/mL; must be discontinued at least 24 h before start of further chemotherapy
Contraindications	Documented hypersensitivity, hypersensitivity to Escherichia coli–derived proteins
Interactions	Do not use 12-24 h before or 24 h after administering cytotoxic chemotherapy because increases sensitivity of rapidly dividing myeloid cells to cytotoxic chemotherapy
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Adverse effects include bone pain; osteoporosis; splenomegaly; exacerbation of preexisting skin disorders; hematuria or proteinuria; thrombocytopenia; elevated levels of uric acid, LDH, and alkaline phosphatase; fever; transient hypotension

Drug Category: Antidotes -- These agents are used to manage poisoning and overdose, prevent toxic effects, or treat metabolic disorders in which toxic substances accrue. Mechanisms of action are variable and include antagonism, toxin transformation, altered metabolism, chelation, and directed antibody responses.

Drug Name	Leucovorin (Wellcovorin) -- Also called citrovorum factor or folinic acid. Overrides folate antagonist (methotrexate) and protects against severe methotrexate-induced toxic effects. Discontinue when serum methotrexate level <10-7 mol/L.
Adult Dose	10 mg/m2 PO/IV q6h; may increase dose to 100 mg/m2 and give up to q3h Alternative: 1 g/d continuous IV infusion depending on serum methotrexate level
Pediatric Dose	Administer as in adults
Contraindications	Documented hypersensitivity; pernicious anemia
Interactions	Decreases effect of methotrexate, phenytoin, phenobarbital, and sulfamethoxazole and trimethoprim combinations; increases toxicity of fluorouracil
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	May cause rash, pruritus, erythema

Drug Name	Dexrazoxane (Zinecard) -- Used preventatively as cardioprotectant to reduce incidence and severity of anthracycline cardiotoxicity; therefore, raises maximum tolerated dose. Exact mechanism unknown. Derivative of ethylenediaminetetraacetic acid (EDTA) and potent intracellular chelating agent. May interfere with iron-mediated free-radical generation that may be partly responsible for anthracycline-induced cardiomyopathy. Dose determined by the doxorubicin dose (ie, 10X doxorubicin dose).
Adult Dose	Administer ratio of 10:1 (dexrazoxane to doxorubicin) IV within 30 min before doxorubicin; not to exceed 1250 mg/m2
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; nonanthracycline chemotherapy regimens
Interactions	None reported
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Myelosuppression, alopecia, nausea, vomiting, diarrhea

Drug Name	Mesna (Mesnex) -- Inactivates acrolein and prevents urothelial toxicity without affecting cytostatic activity. Used as prophylactic detoxifying agent to inhibit hemorrhagic cystitis caused by ifosfamide and cyclophosphamide. In kidney, mesna disulfide reduced to free mesna, which has thiol groups that react with acrolein, the ifosfamide or cyclophosphamide metabolite considered responsible for urotoxicity.
Adult Dose	Dose depends on dose of ifosfamide or cyclophosphamide, typically 60-100% of antineoplastic agent used; may be administered as initial bolus then continuous IV infusion, or as intermittent IV infusions before and after chemotherapy regimen
Pediatric Dose	Administer as in adults
Contraindications	Documented hypersensitivity
Interactions	May increase warfarin effect, adjust dose according to target INR
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Monitor morning urine samples for hematuria before ifosfamide or cyclophosphamide dose; common adverse effects include hypotension, headache, GI toxicity, and limb pain

FOLLOW-UP

Section 8 of 12

Further Inpatient Care:

• Patients receiving chemotherapy generally require inpatient admission for drug administration and monitoring. In protocol CCG-7921, definitive surgery was performed after 2 cycles of induction chemotherapy. Four maintenance cycles were given beginning 2-3 weeks after surgery. Given the assumption of no therapeutic delays, the entire course of treatment lasted approximately 46 weeks.



• If patients have fever and neutropenia, admission is required for intravenous antibiotics and monitoring.



• Admission is required perioperatively for local-control procedures (eg, surgical resection, amputation), usually around week 10 of therapy. Resection of metastatic disease (eg, lung nodules) is usually performed at the same time.



• Patients may require admission for a multitude of other medical problems during chemotherapy. Examples include varicella infection (for intravenous acyclovir and monitoring), mucositis (for pain control, usually with narcotics), dehydration, meningitis, constipation, fungal pneumonia, and cystitis, among others.

Further Outpatient Care:

• CBC: Perform a CBC twice each week for patients receiving G-CSF. Discontinue G-CSF when the ANC has reached a predetermined level (usually 1.0 or 5.0 X 10⁹ [1000 or 5000/mL]).



• Blood chemistries: Monitoring blood chemistries, including monitoring with renal and liver function tests, is important for patients receiving parenteral nutrition or for those who have a history of organ toxicity (especially if nephrotoxic or hepatotoxic antibiotics or other drugs are continued).



• Monitoring for recurrence: After completing chemotherapy, patients should continue to undergo regular blood workup and radiographic scanning on an outpatient basis, with the frequency decreasing over time. In general, these visits occur every 3 months for the first year, every 6 months for the second year and perhaps a third year, and yearly thereafter.



• Long-term follow-up: Five years of longer after patients finish therapy, they are considered long-term survivors. They should be seen annually in a late-effects clinic and monitored with appropriate studies depending on their therapy and toxic effects. Visits may include hormonal, psychosocial, cardiologic, and neurologic evaluations.

In/Out Patient Meds:

• Trimethoprim-sulfamethoxazole: At some treatment centers, clinicians routinely prescribe prophylaxis against pneumocystic pneumonia; others do not.



• Fluconazole: Systemic fungal prophylaxis is not necessary.



• Clotrimazole: Prophylactic therapy for thrush may be discontinued when chemotherapy has been completed.



• Chlorhexidine mouth rinse: Prophylaxis against gingivitis and other mouth infections may be discontinued when chemotherapy is completed.

Transfer:

• Pediatrician or general practitioner: Although the major therapy for cancer should take place at a center staffed by pediatric oncologists, the referring physicians should continue to play an important role in children's care throughout treatment. The referring physician can be critical in performing the first evaluation of an illness, particularly if the child lives far from the oncology center.



• Orthopedic surgeon: The orthopedic surgeon is often the first subspecialist to evaluate the patient with a suspected bone tumor. The surgeon's involvement is not only critical to establishing the diagnosis with biopsy but also paramount for local control (amputation vs limb-salvage resection). In addition, the orthopedic surgeon should continue to follow up with patient to assess function of the limb and prosthesis.

Deterrence/Prevention:

• No preventive measures for childhood cancers are known.

Complications:

• Cardiomyopathy is primarily a result of anthracycline (doxorubicin) use. Patients should receive routine follow-up echocardiography after they complete therapy.



• Secondary malignant neoplasms may arise as a result of chemotherapy, particularly with alkylating agents.



• Infertility is a nearly universal effect of the high-dose alkylating agents used to treat osteosarcoma.

Prognosis:

• The prognosis for patients with osteosarcoma primarily depends on whether metastases are detectable at diagnosis. Patients who present with metastases or with multifocal disease have a poor prognosis, with long-term survival rates of less than 25%.



• For patients with initially localized disease, the prognosis depends mainly on 2 variables: resectability and the response to chemotherapy. Those who have completely resectable disease and those whose tumors have an excellent histologic response to neoadjuvant chemotherapy have the best likelihood for a cure.



• Before the 1970s, the 5-year survival rate of patients with nonmetastatic osteosarcoma was <20%, even with aggressive surgery (mostly amputations).


• • The fact that most relapses occurred at metastatic sites (primarily the lung) attests to the fact that most patients have undetectable metastatic disease at diagnosis (ie, micrometastatic disease).

  • With the introduction of postoperative (adjuvant) chemotherapy, survival rates began to improve.

  • According to data from the NCI SEER program, the 5-year survival rate from 1975-1984 was 49% and from 1985-1994 was 63%. For the latter period, female patients fared slightly better than male patients (5-year survival rates of 70% vs 59%).
  
  
  
• Results of the most recent cooperative group trial conducted by the Children's Cancer Group and the Pediatric Oncology Group are not yet known.


• • A recent group from Italy monitored patients after therapy for a median of 11.5 years and demonstrated a 61% disease-free survival rate.

  • Patients with an unfavorable histologic response to neoadjuvant chemotherapy historically fared worse than those with a favorable response (>90% necrosis).

  • In the Italian study, patients with <90% necrosis were treated with relatively intensive longer-term therapy and had outcomes similar to those of patients with a favorable histologic response. This result suggested that risk-adapted dose-intensified therapy may be beneficial.
  
  
  
• Improving the survival rate and functional outcome and minimizing the short- and long-term adverse effects will continue to be goals of clinical trials for osteosarcoma.


• • The major challenge is curing patients with unresectable metastatic disease.

  • Strategies currently under consideration include dose intensification (eg, anthracycline dose-escalation facilitated by dexrazoxane cardioprotection), immune modulators, monoclonal antibodies targeting tumor-cell antigens (eg, Her2/neu), and antiangiogenic agents that target components of the tumor vascular supply.

  • High-dose administration of the bone-seeking radioisotope samarium is also being tested (with autologous stem-cell support) for safety and efficacy in metastatic or nonresectable osteosarcoma limited to bone.

  • Finally, the role of the emerging field of oncolytic viruses for the treatment of osteosarcoma has yet to be explored.
  
  
  

Patient Education:

• Chemotherapy: Parents and patients (if appropriate) must undergo formal education about chemotherapy to learn about the adverse effects of their medications. They must know what is expected to happen as a result of the therapy, and they should encouraged to call with any questions.



• Central venous catheters: When patients have central venous catheters that exit the skin (eg, Hickman or Broviac catheters), the patient or the parents must learn to care for the line properly.


• • This care usually involves daily heparin flushes.
  
  
  
  • They must also know their limitations (eg, restriction from swimming).
  
  
  
  • Patients with subcutaneous catheters (eg, Mediport catheters) do not need to perform daily-care routines, but they should learn to apply a topical anesthetic (eg, lidocaine-prilocaine [EMLA] cream) at least 1 hour before an anticipated needle stick.
  
  
  

MISCELLANEOUS

Section 9 of 12

Medical/Legal Pitfalls:

• Mild symptoms from osteosarcoma are commonly ascribed to other causes, such as growing pains, arthritis, or antecedent trauma. Because the ability to remove the lesion and the functional result partly depend on the local extent of the disease, making the diagnosis as early as possible is imperative.



• Whether metastatic disease represents a distinct tumor subtype is unclear; therefore, whether metastases in most cases can be prevented with early detection is also unclear.



• Early detection and, most importantly, appropriate referral to an orthopedic surgeon and an oncologist should minimize medicolegal issues.

TEST QUESTIONS

Section 10 of 12

CME Question 1: A 13-year-old male adolescent is injured while playing basketball and complains of thigh pain. Which finding on plain radiographs could represent an osteosarcoma?

A: Osteoblastic lesion in the diaphysis
B: Osteolytic lesion near the metaphysis with periosteal elevation
C: Mixed osteolytic-osteoblastic lesion in the diaphysis with a surrounding onion-skin pattern of new bone formation
D: A and B
E: A, B, and C

The correct answer is E: Osteosarcoma can have virtually any appearance on plain radiographs. The location and onion-skin pattern described in C is more suggestive of Ewing sarcoma than osteosarcoma, but biopsy is needed to prove the diagnosis.

CME Question 2: A 24-year-old woman was treated for a distal femoral osteosarcoma at the age 15 years with a limb-sparing procedure. Which tests is important to periodically perform as part of her follow-up care?

A: Hearing screen
B: Renal function tests
C: Thyroid function tests
D: Complete blood count
E: Pulmonary function tests

The correct answer is D: Patients treated with high-dose alkylating agents are at higher-than-usual risk of myelodysplasia and leukemia; therefore, their CBC should be monitored periodically. Although patients undergoing chemotherapy for osteosarcoma may have damage to their hearing and kidneys, this complication usually occurs during therapy and does not require routine follow-up after treatment. None of the chemotherapeutic drugs used for osteosarcoma is expected to affect lung or thyroid function. An echocardiogram is usually obtained because of the history of anthracycline (doxorubicin) exposure.

Pearl Question 1 (T/F): Osteosarcoma that manifests with a pathologic fracture is most likely a parosteal type.

The correct answer is False: Patients with telangiectatic osteosarcomas most commonly present with fractures.

Pearl Question 2 (T/F): Isolated osteosarcoma of the foot is best treated with amputation alone.

The correct answer is False: Chemotherapy must also be given to prevent the growth of micrometastases.

Pearl Question 3 (T/F): The most common site of osteosarcoma is the distal femur.

The correct answer is True: Almost 42% of osteosarcomas occur in the femur.

Pearl Question 4 (T/F): Multiple pulmonary metastases are treated best with chemotherapy and radiation therapy.

The correct answer is False: Surgical resection of pulmonary nodules is the only known way to cure such lesions.

PICTURES

Section 11 of 12

Caption: Picture 1. Lateral plain radiograph of the knee shows an osteosarcoma of the distal femur. The lesion is mainly posterior, with disruption and elevation of the periosteum (Codman triangle), and extends beyond the bone into the soft tissue.
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Caption: Picture 2. Anteroposterior plain radiograph of the same with distal femoral osteosarcoma as in Image 1. The osteolytic lesion is apparent on the right side of the image.
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Caption: Picture 3. MRI of the same distal femoral osteosarcoma as in Images 1-2; the uninvolved side is shown for comparison.
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Caption: Picture 4. Close-up MRI of the same distal femoral osteosarcoma as in Images 1-3.
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Picture Type: MRI

BIBLIOGRAPHY

Section 12 of 12

• Antunes M, Bernardo J, Salete M, et al: Excision of pulmonary metastases of osteogenic sarcoma of the limbs. Eur J Cardiothorac Surg 1999 May; 15(5): 592-6[Medline].
• Bacci G, Briccoli A, Mercuri M, et al: Osteosarcoma of the extremities with synchronous lung metastases: long- term results in 44 patients treated with neoadjuvant chemotherapy. J Chemother 1998 Feb; 10(1): 69-76[Medline].
• Bacci G, Ferrari S, Bertoni F, et al: Long-term outcome for patients with nonmetastatic osteosarcoma of the extremity treated at the istituto ortopedico rizzoli according to the istituto ortopedico rizzoli/osteosarcoma-2 protocol: an updated report. J Clin Oncol 2000 Dec 15; 18(24): 4016-27[Medline].
• Bacci G, Longhi A, Ferrari S, et al: Prognostic significance of serum lactate dehydrogenase in osteosarcoma of the extremity: experience at Rizzoli on 1421 patients treated over the last 30 years. Tumori 2004 Sep-Oct; 90(5): 478-84[Medline].
• Bacci G, Briccoli A, Longhi A, et al: Treatment and outcome of recurrent osteosarcoma: experience at Rizzoli in 235 patients initially treated with neoadjuvant chemotherapy. Acta Oncol 2005; 44(7): 748-55[Medline].
• Bacci G, Mercuri M, Longhi A, et al: Grade of chemotherapy-induced necrosis as a predictor of local and systemic control in 881 patients with non-metastatic osteosarcoma of the extremities treated with neoadjuvant chemotherapy in a single institution. Eur J Cancer 2005 Sep; 41(14): 2079-85[Medline].
• Briccoli A, Rocca M, Salone M, et al: Resection of recurrent pulmonary metastases in patients with osteosarcoma. Cancer 2005 Oct 15; 104(8): 1721-5[Medline].
• Chan HS, Grogan TM, Haddad G, et al: P-glycoprotein expression: critical determinant in the response to osteosarcoma chemotherapy. J Natl Cancer Inst 1997 Nov 19; 89(22): 1706-15[Medline].
• Davis AM, Devlin M, Griffin AM, et al: Functional outcome in amputation versus limb sparing of patients with lower extremity sarcoma: a matched case-control study. Arch Phys Med Rehabil 1999 Jun; 80(6): 615-8[Medline].
• DeLaney TF, Park L, Goldberg SI, et al: Radiotherapy for local control of osteosarcoma. Int J Radiat Oncol Biol Phys 2005 Feb 1; 61(2): 492-8[Medline].
• Eikenes L, Tari M, Tufto I, et al: Hyaluronidase induces a transcapillary pressure gradient and improves the distribution and uptake of liposomal doxorubicin (Caelyx) in human osteosarcoma xenografts. Br J Cancer 2005 Jul 11; 93(1): 81-8[Medline].
• Eilber F, Giuliano A, Eckardt J, et al: Adjuvant chemotherapy for osteosarcoma: a randomized prospective trial. J Clin Oncol 1987 Jan; 5(1): 21-6[Medline].
• Entz-Werle N, Stoetzel C, Berard-Marec P, et al: Frequent genomic abnormalities at TWIST in human pediatric osteosarcomas. Int J Cancer 2005 Nov 10; 117(3): 349-55[Medline].
• Ferrari S, Smeland S, Mercuri M, et al: Neoadjuvant chemotherapy with high-dose Ifosfamide, high-dose methotrexate, cisplatin, and doxorubicin for patients with localized osteosarcoma of the extremity: a joint study by the Italian and Scandinavian Sarcoma Groups. J Clin Oncol 2005 Dec 1; 23(34): 8845-52[Medline].
• Gherlinzoni F, Picci P, Bacci G, Campanacci D: Limb sparing versus amputation in osteosarcoma. Correlation between local control, surgical margins and tumor necrosis: Istituto Rizzoli experience. Ann Oncol 1992 Apr; 3 Suppl 2: S23-7[Medline].
• Goorin AM, Shuster JJ, Baker A, et al: Changing pattern of pulmonary metastases with adjuvant chemotherapy in patients with osteosarcoma: results from the multiinstitutional osteosarcoma study. J Clin Oncol 1991 Apr; 9(4): 600-5[Medline].
• Gralla RJ, Osoba D, Kris MG, et al: Recommendations for the use of antiemetics: evidence-based, clinical practice guidelines. American Society of Clinical Oncology [published erratum appears in J Clin Oncol 1999 Dec;17(12):3860]. J Clin Oncol 1999 Sep; 17(9): 2971-94[Medline].
• Grimer RJ, Bielack S, Flege S, et al: Periosteal osteosarcoma--a European review of outcome. Eur J Cancer 2005 Dec; 41(18): 2806-11[Medline].
• Hudson M, Jaffe MR, Jaffe N, et al: Pediatric osteosarcoma: therapeutic strategies, results, and prognostic factors derived from a 10-year experience. J Clin Oncol 1990 Dec; 8(12): 1988-97[Medline].
• Ilhan IE, Vural G, Berberoglu S, et al: Quantitative thallium-201 scintigraphy in childhood osteosarcoma: Comparison with technetuim-99m MDP and magnetic resonance imaging in the evaluation of chemotherapeutic response. Pediatr Hematol Oncol 2005 Mar; 22(2): 153-62[Medline].
• Knight KR, Kraemer DF, Neuwelt EA: Ototoxicity in children receiving platinum chemotherapy: underestimating a commonly occurring toxicity that may influence academic and social development. J Clin Oncol 2005 Dec 1; 23(34): 8588-96[Medline].
• Krailo M, Ertel I, Makley J, et al: A randomized study comparing high-dose methotrexate with moderate-dose methotrexate as components of adjuvant chemotherapy in childhood nonmetastatic osteosarcoma: a report from the Childrens Cancer Study Group. Med Pediatr Oncol 1987; 15(2): 69-77[Medline].
• Kreuter M, Bieker R, Bielack SS, et al: Prognostic relevance of increased angiogenesis in osteosarcoma. Clin Cancer Res 2004 Dec 15; 10(24): 8531-7[Medline].
• Laverdiere C, Hoang BH, Yang R, et al: Messenger RNA expression levels of CXCR4 correlate with metastatic behavior and outcome in patients with osteosarcoma. Clin Cancer Res 2005 Apr 1; 11(7): 2561-7[Medline].
• Link MP, Goorin AM, Miser AW, et al: The effect of adjuvant chemotherapy on relapse-free survival in patients with osteosarcoma of the extremity. N Engl J Med 1986 Jun 19; 314(25): 1600-6[Medline].
• Link MP, Goorin AM, Horowitz M, et al: Adjuvant chemotherapy of high-grade osteosarcoma of the extremity. Updated results of the Multi-Institutional Osteosarcoma Study. Clin Orthop 1991 Sep; (270): 8-14[Medline].
• Longhi A, Pasini A, Cicognani A, et al: Height as a risk factor for osteosarcoma. J Pediatr Hematol Oncol 2005 Jun; 27(6): 314-8[Medline].
• Man TK, Chintagumpala M, Visvanathan J, et al: Expression profiles of osteosarcoma that can predict response to chemotherapy. Cancer Res 2005 Sep 15; 65(18): 8142-50[Medline].
• Marchese VG, Ogle S, Womer RB, et al: An examination of outcome measures to assess functional mobility in childhood survivors of osteosarcoma. Pediatr Blood Cancer 2004 Jan; 42(1): 41-5[Medline].
• McCarville MB, Christie R, Daw NC, et al: PET/CT in the evaluation of childhood sarcomas. AJR Am J Roentgenol 2005 Apr; 184(4): 1293-304[Medline].
• Meyers PA, Schwartz CL, Krailo M, et al: Osteosarcoma: a randomized, prospective trial of the addition of ifosfamide and/or muramyl tripeptide to cisplatin, doxorubicin, and high-dose methotrexate. J Clin Oncol 2005 Mar 20; 23(9): 2004-11[Medline].
• Mialou V, Philip T, Kalifa C, et al: Metastatic osteosarcoma at diagnosis: prognostic factors and long-term outcome--the French pediatric experience. Cancer 2005 Sep 1; 104(5): 1100-9[Medline].
• Mikulic D, Ilic I, Cepulic M, et al: Tumor angiogenesis and outcome in osteosarcoma. Pediatr Hematol Oncol 2004 Oct-Nov; 21(7): 611-9[Medline].
• Morgan E, Baum E, Bleyer WA, et al: Treatment of patients with metastatic osteogenic sarcoma: a report from the Children's Cancer Study Group. Cancer Treat Rep 1984 Apr; 68(4): 661-4[Medline].
• Nagarajan R, Clohisy D, Weigel B: New paradigms for therapy for osteosarcoma. Curr Oncol Rep 2005 Nov; 7(6): 410-4[Medline].
• Olson DM, Lye SJ, Skinner K, Challis JR: Early changes in prostaglandin concentrations in ovine maternal and fetal plasma, amniotic fluid and from dispersed cells of intrauterine tissues before the onset of ACTH-induced pre-term labour. J Reprod Fertil 1984 May; 71(1): 45-55[Medline].
• Paiva MG, Petrilli AS, Moises VA, et al: Cardioprotective effect of dexrazoxane during treatment with doxorubicin: a study using low-dose dobutamine stress echocardiography. Pediatr Blood Cancer 2005 Dec; 45(7): 902-8[Medline].
• Pignatti G, Bacci G, Picci P, et al: Telangiectatic osteogenic sarcoma of the extremities. Results in 17 patients treated with neoadjuvant chemotherapy. Clin Orthop 1991 Sep; (270): 99-106[Medline].
• Ries LAG, Smith MA, Gurney JG, et al: Cancer incidence and survival among children and adolescents: United States SEER Program 1975-1995. NIH publication No. 99-4649 Bethesda, Md: National Institutes of Health; 1999:[Full Text].
• Saab R, Rao BN, Rodriguez-Galindo C, et al: Osteosarcoma of the pelvis in children and young adults: the St. Jude Children's Research Hospital experience. Cancer 2005 Apr 1; 103(7): 1468-74[Medline].
• Stohr W, Langer T, Kremers A, et al: Cisplatin-induced ototoxicity in osteosarcoma patients: a report from the late effects surveillance system. Cancer Invest 2005; 23(3): 201-7[Medline].

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