AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

Soft tissue sarcomas, the fifth most common solid tumors in children, are relatively rare and accounting for about 6-7% of all childhood malignancies. About half of these tumors are rhabdomyosarcomas, and nonrhabdomyosarcoma soft tissue sarcomas (NRSTSs) account for the remainder (ie, about 3% of childhood malignancies).

NRSTSs are heterogeneous tumors that share some biologic characteristics but differ in histology. The most common types are synovial cell sarcomas, malignant fibrous histiocytomas, fibrosarcomas, and malignant peripheral nerve sheath tumors. Other histologic types are hemangiopericytomas, alveolar soft part sarcomas, leiomyosarcomas, liposarcomas, and desmoplastic small cell tumors.

Because soft tissue sarcomas are most common in adults, many treatment modalities are extrapolated from experiences in adult patients. Many pediatric tumors differ from their adult counterparts in terms of clinical behaviors and outcomes. The prognoses of infants and young children with NRSTSs tend to be better than those of adolescents and adults with similar diagnoses.

Pathophysiology

The soft tissues comprise various structural and supportive tissues in the body, including muscle, connective tissues, endothelium, synovium, fat, lymphatics, and fascias. Soft tissue sarcomas may arise in any part of the body. The most common sites are the trunk and the extremities.

Approximately 15-30% of patients have metastatic disease at presentation. The most common metastatic site is the lung. Other common sites for metastases are the skin, bone, liver, and lymph nodes. Spread to the brain and to the omentum and/or peritoneum is described as well. A brief discussion of the most common NRSTSs follows.

Fibrosarcoma

Fibrosarcoma is the most common NRSTS in children, in whom 2 peaks in incidence are observed. The first is in children younger than 5 years, and the second is in children and adolescents aged 10-15 years.

Congenital fibrosarcoma is usually observed in children younger than 2 years. This tumor occurs in the extremity in 70% of patients, it rarely is metastatic, and it is associated with the trisomy 11 chromosomal abnormality. The adult form of fibrosarcoma usually occurs in individuals aged 10-15 years, it most often affects the extremity, it has high metastatic potential (usually involving the lung), and it is genetically associated with clonal chromosomal translocations.

On histologic analysis, fibrosarcomas are spindle-shaped tumors with a characteristic herringbone pattern. Aggressive fibromatosis, nodular fasciitis, myositis ossificans, and inflammatory pseudotumor are among the most important differential diagnoses.

Congenital fibrosarcoma is usually treated with surgery alone, with survival rates of more than 90% in some series. The adult form of fibrosarcoma is treated with aggressive surgical resection; chemotherapy is considered in some patients. Overall, the survival rate is approximately 60%.

Malignant peripheral nerve sheath tumor

Malignant peripheral nerve sheath tumors account for approximately 5-10% of NRSTSs in children. These tumors are associated with neurofibromatosis type I, and they have a common chromosomal abnormality on band 17q11.

Malignant peripheral nerve sheath tumors most frequently occur on the extremity. Their pathologic appearance is similar to that of fibrosarcomas, but they are more aggressively malignant.

Surgery and radiation therapy are major modalities of treatment. Malignant peripheral nerve sheath tumors are considered chemoresponsive. However, the role of chemotherapy in the ultimate outcome of patients is still under study.

Malignant fibrous histiocytoma

Malignant fibrous histiocytomas are rarely observed in young children and usually affect individuals older than 10 years. These tumors primarily occur on an extremity.

Cytogenetic analysis demonstrates chromosome 19p⁺ and ringed chromosomes. Malignant fibrous histiocytomas has histologic features similar to those of fibrosarcomas except for the loss of the herringbone cellular pattern and except for a more malignant phenotype. Malignant fibrous histiocytomas are commonly observed in radiation-induced sarcomas. The most common metastatic site is the lung.

Surgical excision with irradiation to residual local disease is the therapy of choice. Chemotherapy may be useful in select cases. Chemotherapeutic regimens including vincristine, dactinomycin, and cyclophosphamide with and without irradiation have been somewhat successful in select pediatric and adult patients. Activity has also been observed with combinations of ifosfamide and etoposide. Optimal use of chemotherapy to treat this tumor is yet to be determined.

Synovial sarcoma

Synovial sarcoma is one of the most common NRSTSs, and it is rarely observed in children younger than 10 years. One third of these tumors occur in individuals younger than 20 years.

The most common chromosomal abnormality is t(x;18)(p11.2,q11.2), and the genes involved are SYT-SSX. Synovial sarcomas are usually on an extremity, with lower-extremity lesions more common than upper-extremity lesions. In terms of pathologic features, the 2 forms of tumor are a spindle-cell fibrous form and a glandular form with epithelial differentiation. The most common site for metastasis is the lung.

Surgical resection followed by radiation of residual disease is the best therapy. Chemotherapy may have a role in unresectable and metastatic disease. Series have demonstrated efficacy with the use of cisplatin, doxorubicin, and high-dose ifosfamide in combination with surgery and radiation therapy. Advanced-stage disease has been treated with regimens including cyclophosphamide and doxorubicin, as well as the combination of vincristine, dactinomycin, and cyclophosphamide. Low-stage disease is associated with a 70% survival rate. Patients with high-stage disease have a poor prognosis.

Alveolar soft part sarcoma

Alveolar soft part sarcomas are rare and usually arise in individuals aged 15-35 years. Among children, the primary site of occurrence is the head and neck; tumors of the orbit or tongue are most common.

Patients with alveolar soft part sarcomas usually present with an indolent, slow-growing mass. Alveolar soft part sarcoma often arises in skeletal muscle tissue. The most common site of metastasis is the lung, followed by the brain, bone, and lymph nodes.  

In several cases, a chromosomal abnormality on band 17q25 was demonstrated. Pathologic classification of this tumor is uncertain, but evidence suggests myogenic differentiation.

The primary treatment modality is surgery, with irradiation and chemotherapy reserved for recurrences. Surgical resection is also indicated for select metastatic sites.

The short-term prognosis is good, with 80% of patients surviving at 2 years after diagnosis. However, the long-term survival rate is poor regardless of the initial stage of disease.

Leiomyosarcoma

Leiomyosarcoma is a rare tumor in children and accounts for about 2% of NRSTSs. 

These tumors are pathologically derived from smooth muscle tissue. Leiomyosarcomas are associated with HIV disease, infection with the Epstein-Barr virus (EBV), and immunosuppressive states.

The most common site for these tumors is the GI tract, particularly the stomach. An important clinical presentation is the occurrence of leiomyosarcoma with extrarenal or adrenal paraganglioma and pulmonary chondroma; this Carney triad is most commonly observed in young women.

Surgical resection has been the most common treatment for this NRSTS. In general, patients with tumors in the GI tract have a poor prognosis. The prognosis is good with complete resection of tumors outside the GI tract. The role of radiation therapy and chemotherapy in the management of leiomyosarcoma is still unknown.

Liposarcoma

Although liposarcoma is primarily a disease of adults, it can occur in older children. This NRSTS rarely occurs in young children and infants; when it does, liposarcoma is usually benign if it is completely removed.

A consistent cytogenetic abnormality observed in myxoid liposarcoma tumors is the t(12;16)(q13;p11) translocation. The genes involved are FUS-CHOP.

The lower extremity and the trunk are the 2 most common sites of involvement. Liposarcoma rarely metastasizes. For this reason, the treatment of choice is wide local excision. The role of radiation therapy and chemotherapy in the setting of gross residual disease is being investigated.

Frequency

United States

NRSTSs account for approximately 3% of childhood malignancies. The most common NRSTS is fibrosarcoma, which accounts for 23.9%. Among individuals younger than 20 years, approximately 500-600 cases of NRSTS are diagnosed yearly.

Mortality/Morbidity

The 2 most important prognostic factors in children with NRSTS are the invasiveness of the tumor and its histologic grade. Except for malignant fibrous histiocytoma and fibrosarcoma, most NRSTSs in children are immature and poorly differentiated, with a highly malignant histologic grade. For patients with low-grade localized disease, the survival rate is 90%, compared with less than 15% for patients with high-grade, invasive, or metastatic disease.

See also the Prognosis section.

Race

The prevalence is slightly higher in African Americans than in whites (14 vs 10 cases per 1 million population).

Sex

The prevalence is slightly higher in male individuals and in female individuals (12 vs 10 cases per 1 million population).

Age

Among young children, rates for NRSTS are highest in infancy, when the disease affects approximately 15 per 1 million infants. Rates decrease in the second year of life to a fairly stable rate until about the age of 10 years, when approximately 8-10 per 1 million children are affected. For individuals older than 10 years, the incidence rate increases to about 15 cases per 1 million population per year.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

Patients with nonrhabdomyosarcoma soft tissue sarcomas (NRSTSs) usually present with painless, asymptomatic masses. The tumors may come to attention because of an episode of trauma in the affected area. Mass effect due to the tumor may cause specific signs or symptoms depending on the location of the mass. For instance, invasion of local neurovascular bundles in an involved extremity may lead to pain, swelling, numbness, or loss of function. Large masses in the chest wall may cause pulmonary dysfunction.

If advanced metastatic disease is present, systemic symptoms with fever, sweats, and weight loss may be observed.

Hemangiopericytomas have been associated with hypoglycemia and hypophosphatemic rickets. Hyperglycemia has been observed with fibrosarcoma of the lung.

Physical

Physical findings depend on the location of the mass. A mass is palpable in most patients.

Specific tumors may be associated with specific findings. Malignant peripheral nerve sheath tumors may be associated with neurofibromatosis type 1, which is characterized by café au lait spots, axillary freckling, neurofibromas, skeletal dysplasias, learning disabilities, and various neoplasms. CNS tumors may cause an abnormal neurologic findings depending on the location of the mass and the structures affected.

Causes

Genetic conditions such as Li-Fraumeni syndrome associated with P53 mutations and neurofibromatosis type 1 are the only known genetic risk factors for NRSTS. Neurofibromatosis type 1 is strongly associated with the development of malignant peripheral nerve sheath tumors.

Factors with an implied but unproven association with the development of sarcomas are low socioeconomic status, exposure to ionizing radiation, parental use of recreational drugs, and infection with retroviruses in immunocompromised children (eg, those with HIV or EBV infection).

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Other malignancies that cause masses in children must be considered during evaluation. Examples are lymphomas, osteosarcoma, Ewing sarcoma, rhabdomyosarcoma, and neuroblastoma. Benign lesions (eg, lipomas, rhabdomyomas) should be considered as well.

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• A baseline CBC count with differential provides parameters before therapy and is useful in evaluating for involvement of the bone marrow.
• Chemical tests to assess renal function and creatinine clearance provide baseline parameters before chemotherapy is given and further testing is performed.
• Liver function testing provides baseline parameters before chemotherapy and is helpful in evaluating for hepatic involvement.

Imaging Studies

• Chest radiography and chest CT are useful for evaluating for lung involvement. Perform these studies before the use of general anesthesia, which can cause pulmonary changes that might make the interpretation of images difficult.
• CT and MRI are used to determine the size of the mass and the extent of local involvement and impingement on adjacent structures.
  
  
  • CT and MRI also help in defining options for surgical resection. Contrast-enhanced studies are most helpful.
  • Abdominal CT scanning is important for assessing abdominal primary lesions and to determine hepatic involvement.

• Radionucleotide bone scanning is necessary to rule out bony involvement.
• Plain radiography of the involved areas may be useful in the initial evaluation of a mass, depending on its location and suspected involvement of bony structures.
• The roles of PET-CT and of ¹⁸F-fluorodeoxyglucose (FDG) positron emission tomography (PET) to image nonrhabdomyosarcoma soft tissue sarcoma (NRSTS) in children have not been well established. However, PET-CT may prove beneficial in distinguishing normal from pathologic processes, in the initial staging of a sarcoma, in monitoring responses to therapy, and in detecting recurrences.

Other Tests

• A cardiologist may need to be consulted to perform cardiac ECG and echocardiography in patients who will receive anthracycline-based chemotherapy or radiation therapy to the chest.
• Testing of renal glomerular filtration or creatinine clearance may be necessary before renal-toxic chemotherapy agents (eg, cisplatin, ifosfamide) are administered.

Procedures

• Carefully planned and executed biopsy of the mass lesion is required for diagnosis.
• • Whatever technique is used, adequate tissue must be obtained to yield a diagnosis. If possible, surgery should be accomplished in a manner that does not compromise the possibility for later local surgical control of the tumor.
  • A surgeon with expertise in oncologic surgery should perform this procedure. The surgeon's specific discipline depends on the location of the mass.
  • The best approach for small lesions in accessible areas may be excisional biopsy.
  • Large masses involving critical organs or structures may require incisional biopsy for diagnosis.
  • Delay the definitive surgical procedure until after adjuvant chemotherapy, radiation therapy, or both are given to shrink the tumor.
  • Fine-needle aspiration biopsy may be possible in certain cases. However, an open procedure is required if this technique yields nondiagnostic pathologic material.
  • Minimally invasive surgical techniques using fiberoptic surgical procedures may be appropriate in certain biopsy situations.
• Consider long-term venous access. In most cases, placement of an implanted or externalized central venous catheter is useful for monitoring laboratory results and for delivering chemotherapy and supportive care.
   
• Bilateral bone marrow aspirates and biopsy samples should be obtained in most cases to rule out tumoral involvement of the bone marrow. Strongly consider examining the bone marrow in all patients with NRSTS.
  
  
  • In children, these procedures are best performed in the posterior iliac crests.
  • These tests should be accomplished in conjunction with another procedure requiring sedation, if possible.
  • If patients have parameningeal tumors or tumors involving the CNS, lumbar puncture may be necessary to rule out contamination of the CSF with tumor cells.

Histologic Findings

Diagnosis of an NRSTS can be confirmed only with biopsy of the mass. Diagnosis of a specific tumor depends on the mesenchymal an/or support tissue it most closely represents. Immunostaining, electron microscopy, cytogenetic analysis, and tests for molecular markers of genetic rearrangements may all be used for final diagnosis, depending on the differentiation of the specific tumor. NRSTSs possess a wide range of histologic features.

A tumor is classified as low- or high-grade on the basis of its potential to metastasize. Low-grade lesions are unlikely to metastasize. Certain types of tumors are arbitrarily considered high grade; examples are synovial cell sarcomas and malignant peripheral nerve sheath tumors. Malignant and metastatic potential are based on the degree of anaplasia and mitotic activity the tumor specimen exhibits.

Staging

• Stages (Tumor, node, and metastases [TNM] system)
  
  
  • Involvement of an organ or tissue of origin (T1, N0, M0)
  • Invasion of contiguous organs or tissues or adjacent malignant effusion (T2, N0, M0)
  • Involvement of regional nodes  (T1 or T2, N1, M0)
  • Distant metastases (T1 or T2, N0 or N1, M1)
• Intergroup Rhabdomyosarcoma Study (IRS) groups
  
  
  • Group I - Complete resection
  • Group II - Microscopic residual disease after resection
  • Group III - Gross localized residual disease
  • Group IV - Metastatic disease

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

General treatment considerations for nonrhabdomyosarcoma soft tissue sarcoma (NRSTS) vary depending on the anatomic site of the tumor, its histologic features, and the extent of local and metastatic disease. Complete surgical resection is traditionally performed when possible, followed by radiation therapy to provide local control. Metastatic disease, disease of high metastatic potential, or large and unresectable primary tumors may require chemotherapy as part of the treatment plan. In general, multimodality therapy offers the greatest opportunity for survival.

• Chemotherapeutic agents that demonstrate the most activity against NRSTS are ifosfamide, cyclophosphamide, and doxorubicin. Other active agents are vincristine, etoposide, cisplatin, and actinomycin D. Ongoing clinical trials are under way to prospectively evaluate the exact role of chemotherapy in managing NRSTSs.
• Although NRSTSs are relatively radioresistant, radiation therapy is used for local control of incompletely excised tumors and microscopic disease.
  
  
  • Radiation therapy also has a role in the control and palliative treatment of certain metastatic diseases.
  • In children, radiation therapy raises concerns about the long-term development of irradiated tissues and about secondary malignancies.
  • In some centers, brachytherapy has been used with some success in managing pediatric cases of NRSTSs.

Surgical Care

• Wide local excision is the primary therapy for NRSTS. Every attempt is made to obtain negative tumor margins, which can be accomplished in 50-80% of patients.
   
  • The mainstay of local control for sarcomas of the head and neck is aggressive surgical resection. These tumors may be difficult to remove with wide surgical margins. However, modern reconstruction techniques with vascularized flaps, free composite grafts, and rotation flaps assist in complete resection.
  • Lesions in the extremities are usually totally resectable.
• Limb-salvage procedures or amputation are the surgical options in patients with limb tumors. Limb or ray amputation may be needed to manage tumors of the hands or feet.
   
  
  • In rapidly growing, young children, limb-salvage is not always the best option in terms of function because frequent limb-lengthening procedures may be needed.
  • New orthopedic limb-lengthening procedures and prostheses may make limb salvage more feasible than it once was in select patients.
• Dissection of the lymph nodes is not always warranted because of the infrequency of lymph node involvement in association with NRSTSs.
  
  
  • The rate of involvement is 6-9% in pediatric cases, usually high-grade NRSTSs.
  • Lymph node resection is warranted if the lymph nodes are enlarged on examination or scanning or if the tumor arises in an area near lymph nodes.
• Surgical staging is important in making treatment decisions. Appropriate staging also allows for prognostication.
  
  
  • The TNM staging system is useful and takes into account the size of the tumor (>5 or <5 cm), the involvement of lymph nodes, and the presence or absence of metastatic disease.
  • Another staging system, one used by the IRS researchers, is based on the extent of disease after initial surgical resection.
  • See Staging above for definitions of the TNM stages and IRS groups.

Consultations

For limb salvage procedures or amputation, consultation with a physical therapist and occupational therapist is essential to maximize functional outcome and recovery. Use of these services in select other patients may be necessary depending on the site and surgical procedure.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

The chemotherapeutic agents described below are used in select cases of nonrhabdomyosarcoma soft tissue sarcoma (NRSTS). Dosages and schedules of treatment for individual agents vary with the clinical environment with the particular patient. For each agent, general facts, representative pediatric dosages, and toxicities are noted.

Drug Category: Chemotherapeutic agents

Cancer chemotherapy is based on an understanding of tumor cell growth and how drugs affect this growth. After cells divide, they enter a period of growth (ie, phase G1), followed by DNA synthesis (ie, phase S). The next phase is a premitotic phase (ie, G2), then finally a mitotic cell division (ie, phase M).

The cell division rate varies for different tumors. Most common cancers increase very slowly in size compared to normal tissues, and the rate may decrease further in large tumors. This difference allows normal cells to recover more quickly than malignant ones from chemotherapy, and it is the rationale behind current cyclic dosage schedules.

Antineoplastic agents interfere with cell reproduction. Some agents are cell cycle specific, while others (eg, alkylating agents, anthracyclines, cisplatin) are not phase specific. Cellular apoptosis (ie, programmed cell death) also is a potential mechanism of many antineoplastic agents. Refer to specific protocol for duration of therapy with each drug and timing of administration within each treatment cycle.

Drug Name	Cyclophosphamide (Cytoxan, Neosar)
Description	Alkylating agent; mechanism of action of active metabolites may involve cross-linking of DNA, which may interfere with growth of normal and neoplastic cells. Usually administered IV. Available PO. Use with high doses in combination with aggressive fluid hydration and monitoring of renal output. Chemically related to nitrogen mustards.
Adult Dose	2.2 g/m2/dose IV
Pediatric Dose	Administer as in adults
Contraindications	Documented hypersensitivity; severely depressed bone-marrow function
Interactions	Allopurinol may increase risk of bleeding or infection and enhance myelosuppressive effects; may potentiate doxorubicin-induced cardiotoxicity; may reduce digoxin serum levels and antimicrobial effects of quinolones; chloramphenicol may increase half-life while decreasing metabolite concentrations; may increase effect of anticoagulants; coadministration with high doses of phenobarbital may increase rate of metabolism and leukopenic activity; thiazide diuretics may prolong cyclophosphamide-induced leukopenia and neuromuscular blockade by inhibiting cholinesterase activity
Pregnancy	D - Unsafe in pregnancy
Precautions	Hemorrhagic cystitis can occur at high doses if adequate hydration and urine output not maintained; mesna used for bladder protection with cyclophosphamide and ifosfamide; fluid retention resolves with low doses of furosemide; fluid retention secondary to syndrome of inappropriate antidiuretic hormone secretion (SIADH)–type effect may compromise renal output; myelosuppression, nausea, vomiting, alopecia, cystitis, water retention, decreased fertility, and cardiac necrosis (at high doses)

Drug Name	Ifosfamide (Ifex)
Description	Alkylating agent. Inhibits DNA and protein synthesis and, thus, cell-proliferation by causing DNA cross-linking and denaturation of double helix.
Adult Dose	1.8 g/m2/d IV for 5 d
Pediatric Dose	Administer as in adults
Contraindications	Documented hypersensitivity; depressed bone marrow function
Interactions	Phenobarbital, phenytoin, chloral hydrate, and other drugs that interfere with cytochrome P450 (CYP) activity may alter effects
Pregnancy	D - Unsafe in pregnancy
Precautions	Fluid hydration and vigorous renal output minimize renal tubular damage; mesna and vigorous fluid hydration minimize cystitis; high doses cause renal Fanconi syndrome; myelosuppression, nausea, vomiting, alopecia, cystitis, neurotoxicity, and renal tubular damage

Drug Name	Cisplatin (Platinol)
Description	Alkylating agent. Forced diuresis with IV fluids, mannitol, and furosemide necessary to minimize renal effects. Inhibits DNA synthesis and, thus, cell proliferation by causing DNA cross-linking and denaturation of double helix.
Adult Dose	60-120 mg/m2 IV
Pediatric Dose	Administer as in adults
Contraindications	Documented hypersensitivity; preexisting renal insufficiency; myelosuppression; hearing impairment
Interactions	Increases toxicity of bleomycin and ethacrynic acid
Pregnancy	D - Unsafe in pregnancy
Precautions	During administration, consider forced diuresis with mannitol; severe nausea and vomiting; renal toxicity manifests as renal Fanconi syndrome; ototoxicity, particularly high-frequency hearing loss; audiologic testing required during therapy; myelosuppression, nausea, vomiting, alopecia, renal, neurotoxicity, ototoxicity, and allergic reactions

Drug Name	Etoposide (Toposar, VePesid)
Description	VP-16 is plant alkaloid. Usually administered IV as slow or continuous infusion. Use PO in certain diagnoses. Rapid infusion causes hypotension and allergic reactions. Inhibits topoisomerase II and causes breakage of DNA strands, arresting cellular proliferation in late S or early G2 portion of cell cycle.
Adult Dose	100 mg/m2 IV on days 1-5
Pediatric Dose	Administer as in adults
Contraindications	Documented hypersensitivity
Interactions	May prolong effects of warfarin and increase clearance of methotrexate; has additive effects with cyclosporine in cytotoxicity of tumor cells
Pregnancy	D - Unsafe in pregnancy
Precautions	Infuse over 1 h to avoid hypotension; long-term concern with high cumulative doses is secondary malignancy, particularly acute myelogenous leukemia; myelosuppression, alopecia, nausea, vomiting, mucositis, mild neurotoxicity, hepatic, hypotension, and allergic reactions

Drug Name	Vincristine (Oncovin, Vincasar PFS)
Description	Plant alkaloid. Inhibits cellular mitosis by inhibiting function of intracellular tubulin, binding to microtubule and spindle proteins in S phase. Administer IV only in free-flowing vein or central venous catheter. Pain due to peripheral neuropathy usually treated with acetaminophen or codeine.
Adult Dose	2 mg IV bolus
Pediatric Dose	1.5 mg/m2 IV bolus; not to exceed 2 mg/dose
Contraindications	Documented hypersensitivity; IT administration (may cause death)
Interactions	Acute pulmonary reaction may occur if taken concurrently with mitomycin-C; asparaginase, CYP3A4 inhibitors (eg, itraconazole, quinupristin-dalfopristin, sertraline, ritonavir), granulocyte-macrophage colony-stimulating factors (GM-CSF, eg, sargramostim, filgrastim), or nifedipine increase toxicity; CYP3A4 inducers (eg, carbamazepine, phenytoin, phenobarbital, rifampin) may decrease effects
Pregnancy	D - Unsafe in pregnancy
Precautions	Vesicant and causes severe chemical burns if administered SC; accidental delivery to CNS causes death; neurotoxicity usually manifests as pain (particularly of jaw, back, leg), constipation to the point of ileus, foot drop, loss of reflexes, ptosis, and vocal cord paralysis; neurotoxicity, alopecia, SIADH, hepatic, and hypotension

Drug Name	Dactinomycin (Actinomycin D)
Description	Antibiotic derived from Streptomyces bacterium. Apparently inhibits DNA synthesis. Vesicant administered in free-flowing vein or central catheter.
Adult Dose	0.5 mg IV bolus qd for 5 d
Pediatric Dose	0.045 mg/kg/dose IV for 1 d; alternative is 0.015 mg/kg/dose IV for 5 d
Contraindications	Documented hypersensitivity; chicken pox; herpes zoster; concomitant radiation
Interactions	Increases risk of hepatotoxicity with enflurane or halothane
Pregnancy	D - Unsafe in pregnancy
Precautions	Myelosuppression, nausea, vomiting, alopecia, mucositis and hepatitis; extremely corrosive, use precautions against extravasation and dilute appropriately before administration

Drug Category: Colony-stimulating factors

Colony-stimulating factors are used for supportive care. They act as hematopoietic growth factors that stimulate the development of granulocytes. They are used to treat or prevent neutropenia when patients are receiving myelosuppressive chemotherapy for cancer and to reduce the period of neutropenia associated with bone marrow transplantation. Colony-stimulating factors are also used to mobilize autologous progenitor cells in peripheral blood in bone marrow transplantation and in the management of chronic neutropenia.

Drug Category: Antiemetic agents

Antineoplastic-induced vomiting is stimulated through the chemoreceptor trigger zone (CTZ), which then stimulates the vomiting center (VC) in the brain. Increased activity of central neurotransmitters (dopamine in the CTZ or acetylcholine in the VC) appears to be a major mediator for inducing vomiting. After antineoplastic agents are administered, serotonin (5-HT) is released from enterochromaffin cells in the GI tract. With this release of serotonin and with its subsequent binding to 5-HT3 receptors, vagal neurons are stimulated and transmit signals to the VC, resulting in nausea and vomiting.

Antineoplastic agents may cause nausea and vomiting so intolerable that patients may refuse further treatment. Some antineoplastic agents are more emetogenic than others. Prophylaxis with antiemetic agents before and after cancer treatment is often essential to ensure administration of the entire chemotherapy regimen.

Effective antiemetics include ondansetron, granisetron, metoclopramide, diphenhydramine, lorazepam, perphenazine, prochlorperazine, and trimethobenzamide.

Drug Name	Granisetron (Kytril)
Description	Potent serotonin 5-HT3 receptor antagonist to prevent and treat chemotherapy- and irradiation-induced nausea and vomiting.
Adult Dose	1 mg PO/IV q24h; may increase to bid if needed
Pediatric Dose	20 mcg/kg/dose PO/IV q24h; may increase to bid if needed
Contraindications	Documented hypersensitivity to granisetron or other 5-HT3 antagonists (eg, dolasetron [Anzemet], ondansetron [Zofran])
Interactions	CYP3A substrate; CYP3A inducers (eg, phenobarbital) may decrease effects, whereas inhibitors (eg, erythromycin, clarithromycin) may increase toxicity
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Commonly causes abdominal pain, constipation, diarrhea, headache, lack or loss of strength, unusual tiredness, weakness, or vomiting; caution in liver disease

Drug Category: Uroprotective antidotes

Mesna is a prophylactic detoxifying agent used to inhibit hemorrhagic cystitis caused by ifosfamide or cyclophosphamide.

In the kidney, mesna disulfide is reduced to free mesna. Free mesna has thiol groups that react with acrolein, the ifosfamide and cyclophosphamide metabolite considered responsible for urotoxicity.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Inpatient Care

• Inpatient care involves admissions for chemotherapy and for supportive care related to therapy.
• Patients must be hospitalized to manage episodes of fever and neutropenia and to start broad-spectrum antibiotic coverage while culture results or recovery from illness are awaited.

Further Outpatient Care

• Frequent outpatient visits are required to monitor the effects and adverse effects of therapy.
  
  
  • CBCs should be assessed once or twice a week while patients are receiving G-CSF therapy.
  • Periodically monitoring the toxic effects of chemotherapy on liver and renal function is required with serum chemistry levels.
  • Supportive treatment with blood products, including packed RBCs and platelets, may be necessary if patients are given chemotherapy
• Long-term follow-up is required after therapy is completed to monitor the following:
  
  
  • Disease recurrence
  • Development of a secondary malignancy, particularly if the patient received radiation therapy and/or chemotherapy with etoposide
  • Growth and development
  • Cardiac function in children who received anthracycline chemotherapy (Periodically perform ECG and echocardiography.)

Prognosis

• According to IRS groups, survival rates are as follows:
  
  
  • Group I - 82%
  • Group II - 67%
  • Group III - 12%
  • Group IV - 5
• The IRS survival data emphasize the need for further research and study to improve the prognosis of high-risk patients.
• Many factors contribute to survival, but the degree of resectability at the time of diagnosis is the most important factor identified to date.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Failure to consider that patients should be treated at institutions participating in cooperative group trials in pediatric oncology

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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Article Last Updated: Jun 7, 2006