eMedicine Specialties > Pediatrics: General Medicine > Oncology

Osteosarcoma: Treatment & Medication

Author: 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
Contributor Information and Disclosures

Updated: Aug 7, 2008

Treatment

Medical Care

Before the use of chemotherapy, which began in the 1970s, osteosarcoma was primarily treated with surgical resection, usually amputation. Despite good local control of the 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 the time of diagnosis. Therefore, the use of adjuvant (postoperative) systemic chemotherapy is critical for the treatment of patients with osteosarcoma.15,16

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.

Osteosarcoma cells have a high level of resistance to radiotherapy; thus, this treatment modality is not incorporated into standard treatment regimens. Retrospective studies suggest it may be helpful in some cases, including in those with close or positive surgical margins17 or in the palliative setting. High doses, including those up to 80 Gy, are thought to be required to achieve some tumor kill. The bone seeking isotope, Samarium-153-EDTMP, may be helpful for palliation of metastases positive on bone scan findings, but this treatment requires hematopoietic stem cell rescue due to its hematologic toxicity.18

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 carefully planned 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; an adequate margin is thought to be 5-7 cm from the edge of the abnormality, as shown on MRI 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 not usually 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 studies of late effects reveal that patients with amputations may have long-term quality of life equivalent to that of patients undergoing limb salvage. These data are largely based on patients who underwent limb-salvage 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; 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.10 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

The chemotherapeutic drugs most active in osteosarcoma are doxorubicin, cisplatin, and high-dose methotrexate (for which a low dose is ineffective). Whether chemotherapy dose escalation can improve outcome in patients with a poor histologic response is the subject of an ongoing study in the United States and Europe. One report suggests that, although dose intensification increases the number of patients with a good histologic response, it does not change overall survival.19

In addition, other therapies are being tested, such as the following:20

  • Anthracycline escalation using a cardioprotectant21
  • Muramyl tripeptide phosphatidyl ethanolamine (MTP-PE)22 and other immune enhancers (eg interferon)
  • Monoclonal antibody against the Her2/neu antigen, which is overexpressed in some 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.

Antineoplastic agents

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


Doxorubicin (Adriamycin, Rubex)

Mechanisms of action include DNA intercalation, topoisomerase-mediated DNA strand breaks, and oxidative damage by means of free-radical production.

Adult

Varies by protocol

Pediatric

Varies by protocol; protocol CCG-7921 used 25 mg/m2/d continuous IV infusion over 72 h, not to exceed 450 mg/m2

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

Documented hypersensitivity; severe heart failure, cardiomyopathy, impaired cardiac function; preexisting myelosuppression

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

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


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

Varies by protocol

Pediatric

Varies by protocol; protocol CCG-7921 used 120 mg/m2 IV infused over 4 h on day 1 of each chemotherapy cycle

May potentiate ototoxicity of aminoglycosides; may increase nephrotoxicity of other drugs (eg, amphotericin B); loop diuretics increase risk of nephrotoxicity; increases toxicity of bleomycin

Documented hypersensitivity; renal impairment; hearing impairment; myelosuppression

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Administer adequate hydration before and 24 h after cisplatin dosing to reduce risk of nephrotoxicity; myelosuppression, ototoxicity, and nausea and vomiting may occur


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

Varies by protocol

Pediatric

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

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

Documented hypersensitivity; alcoholism; hepatic insufficiency; documented immunodeficiency syndromes; preexisting blood dyscrasias (eg, bone marrow hypoplasia, leukopenia, thrombocytopenia, significant anemia)

Pregnancy

X - Contraindicated; benefit does not outweigh risk

Precautions

Caution in ascites or pleural effusions, which can result in third spacing and delay clearance; caution in renal dysfunction (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


Ifosfamide (Ifex)

DNA alkylator, leading to interstrand and intrastrand DNA crosslinks, DNA-protein crosslinks, and inhibition of DNA synthesis.

Adult

Varies by protocol

Pediatric

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)

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)

Documented hypersensitivity, severely depressed bone marrow function

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Administer with mesna and extensive hydration to prevent hemorrhagic cystitis; causes myelosuppression, nausea, alopecia, and infertility

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.23


Ondansetron (Zofran)

Selectively antagonizes serotonin 5-HT3 receptors.

Adult

0.15 mg/kg PO/IV q8h started 30 min before chemotherapy

Pediatric

Administer as in adults

Although CYP inducers (barbiturates, rifampin, carbamazepine, and phenytoin) may change half-life and clearance, dosage adjustment not usually required

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Caution in liver toxicity and history of anaphylaxis (use premedication)


Dexamethasone (Decadron)

Several glucocorticoid and mineralocorticoid effects, including relief of emesis.

Adult

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

Administer as in adults

Effects decrease with coadministration of barbiturates, phenytoin and rifampin; dexamethasone decreases effect of salicylates and vaccines used for immunization

Documented hypersensitivity; active bacterial or fungal infection

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

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


Prochlorperazine (Compazine)

Selectively antagonizes dopamine D2 receptors.

Adult

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

0.4 mg/kg/d PO/PR divided tid/qid; 0.1-0.15 mg/kg/dose IV/IM tid/qid

Coadministration with other CNS depressants or anticonvulsants may cause additive effects; may cause hypotension with epinephrine

Documented hypersensitivity; bone marrow suppression; narrow-angle glaucoma; severe liver or cardiac disease

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

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

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.


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

5 mcg/kg/d SC beginning >24 h after last dose of chemotherapy

Pediatric

Administer as in adults; discontinue when absolute neutrophil count (ANC) rises above a predetermined level, usually 1000-10,000/µL; must be discontinued at least 24 h before start of further chemotherapy

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

Documented hypersensitivity, hypersensitivity to Escherichia coli –derived proteins

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

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

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 vary and include antagonism, toxin transformation, altered metabolism, chelation, and directed antibody responses.


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

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

Administer as in adults

Decreases effect of methotrexate, phenytoin, phenobarbital, and sulfamethoxazole and trimethoprim combinations; increases toxicity of fluorouracil

Documented hypersensitivity; pernicious anemia

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

May cause rash, pruritus, erythema


Dexrazoxane (Zinecard)

Preventatively used 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

Administer ratio of 10:1 (dexrazoxane to doxorubicin) IV within 30 min before doxorubicin; not to exceed 1250 mg/m2

Pediatric

Not established

Documented hypersensitivity; nonanthracycline chemotherapy regimens

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Myelosuppression, alopecia, nausea, vomiting, diarrhea


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 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

Administer as in adults

May increase warfarin effect, adjust dose according to target INR

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Monitor morning urine samples for hematuria before ifosfamide or cyclophosphamide dose; common adverse effects include hypotension, headache, GI toxicity, and limb pain

More on Osteosarcoma

Overview: Osteosarcoma
Differential Diagnoses & Workup: Osteosarcoma
Treatment & Medication: Osteosarcoma
Follow-up: Osteosarcoma
Multimedia: Osteosarcoma
References
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Further Reading

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Keywords

osteosarcoma, osteogenic sarcoma, osteoblastic osteosarcoma, chondroblastic osteosarcoma, fibroblastic osteosarcoma, telangiectatic osteosarcoma, multifocal osteosarcoma, parosteal osteosarcoma, periosteal osteosarcoma, bone cancer, bone tumor, fibrosarcoma, chondrosarcoma, limp, arthritis, lymphadenopathy, retinoblastoma, Paget disease, fibrous dysplasia, enchondromatosis, hereditary multiple exostoses, Li-Fraumeni syndrome, Rothmund-Thomson syndrome, hearing loss

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Contributor Information and Disclosures

Author

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
Disclosure: Nothing to disclose.

Medical Editor

Samuel Gross, MD, Professor Emeritus, Department of Pediatrics, University of Florida, Clinical Professor, Department of Pediatrics, UNC, Adjunct Professor, Department of Pediatrics, Duke University
Samuel Gross, MD is a member of the following medical societies: American Association for Cancer Research, American Society for Blood and Marrow Transplantation, American Society of Clinical Oncology, American Society of Hematology, and Society for Pediatric Research
Disclosure: Nothing to disclose.

Pharmacy Editor

Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine.com, Inc
Disclosure: Pfizer Inc Stock Investment from broker recommendation; Avanir Pharma Stock Investment from broker recommendation

Managing Editor

Steven K Bergstrom, MD, Assistant to the Chairman, Department of Pediatrics, Division of Hematology-Oncology, Kaiser Permanente Medical Center of Oakland
Steven K Bergstrom, MD is a member of the following medical societies: Alpha Omega Alpha, American Society of Clinical Oncology, American Society of Hematology, American Society of Pediatric Hematology/Oncology, Children's Oncology Group, and International Society for Experimental Hematology
Disclosure: Nothing to disclose.

CME Editor

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
Helen SL Chan, MBBS, FRCP(C), FAAP is a member of the following medical societies: American Academy of Pediatrics, American Association for Cancer Research, American Society of Hematology, and Royal College of Physicians and Surgeons of Canada
Disclosure: Nothing to disclose.

Chief Editor

Max J Coppes, MD, PhD, MBA, Executive Director, Center for Cancer and Blood Disorders, Children's National Medical Center, Washington, DC; Professor of Medicine, Oncology, and Pediatrics, Georgetown University
Max J Coppes, MD, PhD, MBA is a member of the following medical societies: American Association for Cancer Research, American Society of Pediatric Hematology/Oncology, and Society for Pediatric Research
Disclosure: Nothing to disclose.

 
 
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