Pediatric Osteosarcoma

Osteosarcoma can occur in any bone. It most commonly occurs in the long bones of the extremities near metaphyseal growth plates. The most common sites include the femur (42%), with 75% of those tumor arising 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.[1] Other locations of note include 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. Numerous variants of osteosarcoma are known and include conventional types (ie, osteoblastic, chondroblastic, fibroblastic types) and telangiectatic, multifocal, parosteal, and periosteal types.

The exact cause of osteosarcoma is unknown. However, numerous risk factors are known.

• Rapid bone growth appears to predispose patients to osteosarcoma, as suggested by the increased incidence during the adolescent growth spurt,[2]  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.

• There appears to be a cluster of tumor suppressor genes on chromosome 3.[3]

• A genetic predisposition may be present.[4, 5]

  • 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.

United States data

The incidence is 400 cases per year (4.8 cases per million persons < 20 y).[6]

Race-, sex-, and age-related demographics

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).[1]  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.

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. The male to female ratio is 1.4:1.[7]

The incidence of osteosarcoma increases steadily with age; a relatively dramatic increase in adolescence corresponds with the growth spurt. Osteosarcoma is rarely diagnosed in patients younger than 5 years (about 1% of cases).[8]

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 diagnosed during their growth spurt are taller than average, although patients identified in adulthood have average height.

Patients with the periosteal type of osteosarcoma have a more favorable outcome. In an analysis of 119 patients, the overall survival was 83% at 10 years.[9]

The prognosis for patients with conventional high-grade 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 less than 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%.[1]  For the latter period, female patients fared slightly better than male patients (5-year survival rates of 70% vs 59%). In a small dataset of patients younger than 5 years, outcome appeared to be similar to that of older patients.[8]

Results of the most recent cooperative group trial conducted by the Children's Oncology Group suggest that the addition of ifosfamide to standard 3 drug regimen was not helpful, but that the addition of the immune-enhancing drug muramyl tripeptide increased 6-year overall survival from 70% to 78% for localized disease.[10, 11]  The use of MTP-PE requires further investigation before becoming standard therapy.

Surgical resection of recurrent disease can achieve cure in about 25% of patients.[12]

In a cohort study of 733 long-term (>5 y) survivors of osteosarcoma, Nagarajan et al reported overall survival of 88.6% at 20 years. Of interest in this group was the incidence of second malignancy (5.4%), those who reported at least 1 chronic medical condition (86.9%), and those who reported activity limitations (29.1%). The cohort includes a larger number of patients with amputations than would be seen in recently treated patients.[13]

Improving the survival rate and functional outcome and minimizing the short-term and long-term adverse effects remain 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 under investigation (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 is currently being explored (ClinicalTrials.gov, NCT00503295 and NCT00931931).

Morbidity/mortality

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).

Complications

The following complications have been reported:

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

• Reports have included vascular inflammation, dyslipidemia, and early atherogenesis.[14]

• 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.

• Hearing loss is common due to cisplatin and should be monitored carefully during treatment.[15]

• Long-term quality-of-life measurements suggests patients with amputations do as well as those with limb-salvage.[16, 17]

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 properly care for the line. This care usually involves daily heparin flushes.

Patients 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.

Those affected by osteosarcoma often describe symptoms that begin weeks, months, or occasionally longer before being diagnosed. The most common presenting symptom is pain, particularly with activity. Patients often describe symptoms that suggest a sprain, arthritis, or "growing pains." They often identify a history of trauma as a trigger when the pains begin, although pathologic fractures are not particularly common (the exception being the telangiectatic subtype of osteosarcoma, which is commonly associated with pathologic fractures). If pain affects a lower extremity, patients often walk with a limp.

The lesion may cause swelling, depending on the size and location. Systemic symptoms, such as fever and night sweats, are rare. While 15-20% of patients initially present with lung metastasis, these rarely cause respiratory symptoms.  Breathing symptoms usually indicate extensive lung involvement. Metastases to other sites are extremely rare, making other symptoms uncommon. 

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 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, although 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.

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)[18, 19]

• CBC count, 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 are listed below:

• Plain radiography

  • Plain radiography of the suspected lesions should be performed using 2 views (see images shown below).

    Lateral plain radiograph of the knee reveals 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.
    Anteroposterior plain radiograph of the same with distal femoral osteosarcoma as shown in image above. The osteolytic lesion is apparent on the right side of the image.

  • 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-mm 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 scanning of the chest is more sensitive than plain radiography for assessing pulmonary metastases. In the ideal situation, the chest CT scan 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. See the following images.

    MRI of the same distal femoral osteosarcoma as in images shown under the plain radiography section above; the uninvolved side is shown for comparison.
    Close-up MRI of the same distal femoral osteosarcoma as shown in image above, and in images shown under the plain radiography section above.

  • 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 using CT scanning or MRI.

• 18F-Fluoro-deoxy-glucose positron emission tomography (PET) or thallium-201 scintigraphy

  • The use of these radionuclide studies for diagnostic and prognostic purposes in osteosarcoma is still under investigation.[20]

  • Initial published data suggest the results of these can be more predictive of the response to chemotherapy than MRI or CT findings[21] and can detect disease missed by conventional imaging.[22]

  • Changes in PET scan findings with neoadjuvant chemotherapy appear to be predictive of histologic response.[23]

Other tests include the following:

• 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).

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.

Upon histologic examination of the tumor, two elements are important. The first important element, the type of the tumor, can be assessed by examining the biopsy specimen. The second important element, the response to treatment, can be assessed only by evaluating the tissue resected after chemotherapy.

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.

Numerous 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), although the subtypes are clinically indistinguishable. The telangiectatic type contains large blood-filled spaces and is common in adolescence and early adulthood.[24] The parosteal type is usually located in the bony cortex, is easier to cure than the conventional type, and can be seen in childhood or adulthood. The low-grade periosteal type, which also arises from the cortex but usually encircles the bone, most often occurs in older patients who have a long history of symptoms, which reflects its indolent nature.

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, although technically not used in staging, may affect the prognosis. These include the site of primary tumor (mostly related to difficulty of obtaining a complete resection, such as with pelvic tumors),[25] 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 (generally >90% or >95% necrosis), appear to have an improved prognosis.[26] Those with only one metastasis appear to do better than those with multiple metastases.[19] Those with lesions that arise 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,[27] Twist, microvessel density,[28, 29] P-glycoprotein expression,[30] and microarray signatures. Each of these features was prognostic in small series; however, 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

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 manifested 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.[31, 32]

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 margins[33] or in the palliative setting. High doses, including those up to 80 Gy, are thought to be required to achieve some tumor kill. Localized proton beam therapy may be useful to achieve high tumor doses and spare normal surrounding tissue for unresectable lesions.[34] 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.[35]

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.[36] The National Comprehensive Cancer Network recommends that enrollment in a clinical trial should be considered for all patients with osteosarcoma.[37]

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). Moreover, 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 be 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.[26] If disease recurs sooner than 1 year after therapy, chemotherapy is warranted because the risk of other micrometastatic disease is high.

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.

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.[38]

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.

Class Summary

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.

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.

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.

Ifosfamide (Ifex)

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

Class Summary

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.[39]

Ondansetron (Zofran)

Selectively antagonizes serotonin 5-HT3 receptors.

Dexamethasone (Decadron)

Dexamethasone elicits glucocorticoid effects and has minimal-to-no mineralocorticoid effects. The antiemetic mechanism for corticosteroids is unknown, but inhibition of prostaglandin synthesis and cell membrane permeability are thought to be involved. Dexamethasone is used in combination with other antiemetic agents.

Prochlorperazine (Compazine)

Selectively antagonizes dopamine D2 receptors.

Class Summary

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.

Class Summary

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.

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).

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.

The following are included in further outpatient care:

• CBC count: Perform a CBC count twice each week for patients receiving G-CSF. Discontinue G-CSF when the ANC has reached a predetermined level (usually 1 or 5 X 109 [1000 or 5000/µL]).

• 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.

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.

Inpatient and outpatient medications include the following:

• 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.

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.

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.