eMedicine Specialties > Pediatrics: General Medicine > Oncology
Nonrhabdomyosarcoma Soft Tissue Sarcomas
Updated: Dec 3, 2008
Introduction
Background
Soft tissue sarcomas, the fifth most common solid tumors in children, are relatively rare and account 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 4% of childhood malignancies).
NRSTSs are heterogeneous tumors that share some biologic characteristics but differ in histology. The most common types include dermatofibrosarcoma protuberans, synovial cell sarcoma, malignant fibrous histiocytoma, fibrosarcoma, and malignant peripheral nerve sheath tumor. Other histologic types include hemangiopericytoma, alveolar soft part sarcoma, leiomyosarcoma, liposarcoma, epithelioid sarcoma, and desmoplastic small round cell tumor.
Childhood NRSTs are not well studied. 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 include 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.
Infantile fibrosarcoma (IFS) is almost exclusively observed in children younger than 2 years. Many of these sarcomas are congenital. This tumor occurs in the extremity in 70% of patients and is rarely metastatic. IFSs are characterized by the unique cytogenetic translocation t(12;15)(p13;q25) that results in the fusion of the gene TEL/ETV6 to TRKC/NTRK3.
The adult form of fibrosarcoma is rare in children and usually occurs in individuals aged 10-15 years, most often affects the extremity, and has greater metastatic potential than its infantile counterpart (usually involving the lung). In contrast to IFS, the adult form of fibrosarcoma is not associated with a characteristic cytogenetic translocation.
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.
IFS 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 with or without radiation therapy; chemotherapy is considered in some patients that are considered unresectable at diagnosis. Overall, the survival rate is approximately 60% in the adult type.
Dermatofibrosarcoma protuberans
Dermatofibrosarcoma protuberans is also a common NRSTS in children. Dermatofibrosarcoma protuberans are cutaneous soft tissue sarcomas that clinically present as plaquelike areas of cutaneous thickening that are usually fixed to the dermis but are freely mobile over deeper soft tissues. The most common sites of presentation are the trunk and extremities.
Histologically, dermatofibrosarcoma protuberans is composed of benign spindle cells arranged in a storiform pattern. Most dermatofibrosarcoma protuberans stain positive for CD34; this is useful in differentiating this tumor from normal fibroblasts and dermatofibromas. Cytogenetic analysis reveals the presence of chromosomal abnormalities, either supernumerary ring chromosomes or t(17,22) that causes a fusion of the genes for collagen 1A1 (COL1A1) and platelet-derived growth factor B (PDGF-B). This results in constitutive expression of PDGF-B, and stimulation of the PDGF receptor in tumor cells.
Most dermatofibrosarcoma protuberans are classified as low-grade sarcomas; however, 10-15% are intermediate-grade to high-grade sarcomas. They rarely metastasize, although they can locally recur. The treatment of dermatofibrosarcoma protuberans is comparable to the treatment of most NRSTSs and involves wide resection with negative margins. Mohs micrographic surgery is increasing in popularity as a method of resection for these tumors. Adjuvant radiation therapy is used postoperatively for tumors that have close or microscopically positive margins if further surgery cannot be performed.
The role of adjuvant chemotherapy in the treatment of dermatofibrosarcoma protuberans is currently under investigation. Imatinib targets the PDGF receptor, which is activated in dermatofibrosarcoma protuberans. Several series have shown a benefit of imatinib in patients with advanced or metastatic dermatofibrosarcoma protuberans;1 it is now approved for the treatment of adults with dermatofibrosarcoma protuberans.
Malignant peripheral nerve sheath tumors
Malignant peripheral nerve sheath tumors (MPNSTs) account for approximately 5-10% of NRSTSs in children. These tumors are associated with neurofibromatosis type I (NF1), and they have a common chromosomal deletion on chromosome 17q.
Malignant peripheral nerve sheath tumors most frequently arise from a large peripheral nerve or a neurofibroma in patients with NF1. Their pathologic appearance is similar to that of fibrosarcomas, with dense cellular proliferations of spindle shaped cells with irregular wavy nuclei.
Surgery and radiation therapy are the major modalities of treatment. Malignant peripheral nerve sheath tumors are considered chemoresponsive. However, the role of adjuvant chemotherapy in the overall outcome of patients is still under investigation. Factors associated with a poor outcome include large tumor size, age greater than 7 years, presence of NF1, and tumor necrosis greater than 25%.
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 have 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 has yet to be determined.
Synovial sarcoma
Synovial sarcoma is one of the most common NRSTSs, comprising approximately 40% of these malignancies, although it is rarely observed in children younger than 10 years. One third of these tumors occur in individuals younger than 20 years.
Over 90% of synovial sarcomas have the presence of a fusion of the SYT/SSX genes t(x;18)(p11,q11). This gene fusion results in aberrant transcription. The detection of the SYT/SSX fusion using real-time polymerase chain reaction (RT-PCR) or fluorescence in-situ hybridization (FISH) techniques is very useful in the pathologic diagnosis of this malignancy. Synovial sarcomas are usually found 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. Metastasis develop in about 40% of patients. The most common site for metastasis is the lung (90%), followed by the lymph nodes (5-15%) and bone (5-10%).
Surgical resection followed by radiation of residual disease is the best therapy.2 Chemotherapy may have a role in unresectable and metastatic disease. Several series have demonstrated efficacy with the use of doxorubicin and high-dose ifosfamide in combination with surgery and radiation therapy. Low-stage disease is associated with a 70% survival rate. Patients with advanced 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.
Cytogenetics reveal der(17) t(X;17)(p11;q25) causing the fusion protein ASPL-TFE3. Pathologic classification of this tumor is uncertain, but evidence suggests myogenic or epithelioid 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 2 years after diagnosis. However, the long-term survival rate is poor regardless of the initial stage of disease.
Leiomyosarcoma
Leiomyosarcoma accounts for about 2% of NRSTSs.
These tumors are pathologically derived from smooth muscle tissue. Leiomyosarcomas are associated with human immunodeficiency virus (HIV) disease, infection with the Epstein-Barr virus (EBV), and immunosuppressive states.
The most common site for these tumors is the GI tract (20-30%), 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 under investigation.
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, it usually carries an excellent prognosis if completely resected. 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 under investigation.
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 most important prognostic factors associated with a poor outcome in children with NRSTS are the histologic grade, tumors larger than 5 cm, presence of metastases, and extent of resection. 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 Prognosis.
Race
The prevalence is slightly higher in blacks 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
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 many, if not most, patients.
Specific tumors may be associated with specific findings. Malignant peripheral nerve sheath tumors may be associated with neurofibromatosis type 1 (NF1), 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, NF1, and germline mutation of the retinoblastoma susceptibility gene, RB, are known genetic risk factors for NRSTS. Gorlin syndrome has been associated with an increased risk of development of fibrosarcoma and leiomyosarcoma. NF1 is strongly associated with the development of malignant peripheral nerve sheath tumors.
Other factors with an association with the development of NRSTs include exposure to ionizing radiation, childhood cancer survival, and infection with retroviruses in immunocompromised children (eg, those with HIV or Epstein-Barr virus [EBV] infection). Individuals with HIV have an increased risk of developing leiomyosarcoma related to EBV infection.
Differential Diagnoses
| Aggressive fibromatosis (Desmoid tumor) | Langerhans cell histiocytosis |
| Cysts | Lipoma |
| Dermatofibroma | Neuroblastoma |
| Ewing Sarcoma and Primitive Neuroectodermal
Tumors | Neurofibroma |
Other Problems to Be Considered
Other malignancies that cause masses in children must be considered during evaluation. Examples include lymphomas, osteosarcoma, Ewing sarcoma, rhabdomyosarcoma, and neuroblastoma. Benign lesions (eg, lipomas, rhabdomyomas) should be considered as well.
Workup
Laboratory Studies
- In patients with nonrhabdomyosarcoma soft tissue sarcoma (NRSTS), 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 positive emission tomography (PET)-CT and of18 F-fluorodeoxyglucose (FDG) PET to image 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.3,4
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 cerebrospinal fluid (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-grade 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
There is no validated staging system for NRSTSs in children. The Intergroup Rhabdomyosarcoma Study (IRS) group staging system is most commonly used, as follows:
- 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
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. The standard of care for high-grade NRSTs is to achieve local control by complete surgical resection, preferably limb-preserving, with radiation therapy. However, most of the data have been extrapolated from trials involving adults.
The role of radiation therapy in children with NRSTSs has yet to be defined and is the future of current Children's Oncology Group (COG) studies. For low-grade NRSTSs the use of radiation therapy after complete surgical excision is controversial. Thus, for low-grade NRSTSs, radiation therapy is generally used adjuvantly when surgical margins are involved. 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 include ifosfamide, cyclophosphamide and doxorubicin. Other chemotherapeutic agents that have shown activity either alone or in combination are vincristine, etoposide, cisplatin, and dactinomycin. 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.
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 tumor, node, and metastases (TNM) staging system is useful and takes into account the size of the tumor (>5 cm 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
Patients with sarcomas, particularly children, should be treated at comprehensive cancer centers with devoted multidisciplinary sarcoma programs that involve a pediatric sarcoma oncologist, oncologic surgeons, radiation oncologists, radiologists, and soft tissue pathologists.
For limb salvage procedures or amputation, consultation with a physical therapist and occupational therapist is essential to maximize functional outcome and recovery. The use of these services in certain other patients may be necessary, depending on the site and surgical procedure.
Medication
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.
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.
Doxorubicin (Adriamycin)
Anthracycline antibiotic. Vesicant administered in free-flowing peripheral vein or central venous catheter. Several mechanisms of action: DNA intercalation, topoisomerase-mediated breaks in DNA strands, and oxidative damage due to production of free radicals.
Dosing
Adult
45-75 mg/m2/dose IV given over 48 h
Pediatric
Administer as in adults
Interactions
May decrease plasma levels of phenytoin and digoxin; phenobarbital may decrease plasma levels; cyclosporine may induce coma or seizures; mercaptopurine increases toxicity; cyclophosphamide increases cardiac toxicity
Contraindications
Documented hypersensitivity; myocardial damage; cumulative dose >450 mg/m2 (relative contraindication)
Precautions
Pregnancy
D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions
Extravasation leads to severe chemical burn; cardiac toxicity (to the point of cardiac failure) is dose limiting in cumulative fashion; monitoring cardiac function with ECG or multiple-gated acquisition (MUGA) scanning required during therapy; cardiotoxicity, myelosuppression, nausea, vomiting, alopecia, and hepatic mucositis
Cyclophosphamide (Cytoxan, Neosar)
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.
Dosing
Adult
2.2 g/m2/dose IV
Pediatric
Administer as in adults
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
Contraindications
Documented hypersensitivity; severely depressed bone-marrow function
Precautions
Pregnancy
D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
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)
Ifosfamide (Ifex)
Alkylating agent. Inhibits DNA and protein synthesis and, thus, cell-proliferation by causing DNA cross-linking and denaturation of double helix.
Dosing
Adult
1.8 g/m2/d IV for 5 d or 3 g/m2/d IV for 3 d
Pediatric
Administer as in adults
Interactions
Phenobarbital, phenytoin, chloral hydrate, and other drugs that interfere with cytochrome P450 (CYP) activity may alter effects
Contraindications
Documented hypersensitivity; depressed bone marrow function
Precautions
Pregnancy
D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
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
Cisplatin (Platinol)
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.
Dosing
Adult
60-120 mg/m2 IV
Pediatric
Administer as in adults
Interactions
Increases toxicity of bleomycin and ethacrynic acid
Contraindications
Documented hypersensitivity; preexisting renal insufficiency; myelosuppression; hearing impairment
Precautions
Pregnancy
D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
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
Etoposide (Toposar, VePesid)
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.
Dosing
Adult
100 mg/m2 IV on days 1-5
Pediatric
Administer as in adults
Interactions
May prolong effects of warfarin and increase clearance of methotrexate; has additive effects with cyclosporine in cytotoxicity of tumor cells
Contraindications
Documented hypersensitivity
Precautions
Pregnancy
D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
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
Vincristine (Oncovin, Vincasar PFS)
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.
Dosing
Adult
2 mg IV bolus
Pediatric
1.5 mg/m2 IV bolus; not to exceed 2 mg/dose
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
Contraindications
Documented hypersensitivity; IT administration (may cause death)
Precautions
Pregnancy
D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
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
Dactinomycin (Actinomycin D)
Antibiotic derived from Streptomyces bacterium. Apparently inhibits DNA synthesis.
Vesicant administered in free-flowing vein or central catheter.
Dosing
Adult
0.5 mg IV bolus qd for 5 d
Pediatric
0.045 mg/kg/dose IV for 1 d; alternative is 0.015 mg/kg/dose IV for 5 d
Interactions
Increases risk of hepatotoxicity with enflurane or halothane
Contraindications
Documented hypersensitivity; chicken pox; herpes zoster; concomitant radiation
Precautions
Pregnancy
D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions
Myelosuppression, nausea, vomiting, alopecia, mucositis and hepatitis; extremely corrosive, use precautions against extravasation and dilute appropriately before administration
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.
Filgrastim (Neupogen)
G-CSF that activates and stimulates production, maturation, migration, and cytotoxicity of neutrophils. Enhances dosage intensification with chemotherapy and speeds recovery from neutropenia.
Dosing
Adult
5 mcg/kg/d SC until absolute neutrophil count (ANC) is 10,000/mcL
Pediatric
5-10 mcg/kg/d IV/SC; doses begin 24-48 h after course of myelosuppressive chemotherapy and continued until recovery (past nadir)
Interactions
None reported
Contraindications
Documented hypersensitivity
Precautions
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
Do not use 12-24 h before or 24 h after cytotoxic chemotherapy because it increases sensitivity of rapidly dividing myeloid cells to cytotoxic chemotherapy; may cause bone pain or headache
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.
Ondansetron (Zofran)
Selective 5-HT3 receptor antagonist that peripherally and centrally blocks 5-HT. Prevents nausea and vomiting associated with emetogenic chemotherapy for cancer. Sometimes combined with dexamethasone to potentiate antiemetic effect.
Dosing
Adult
8 mg PO bid for chemotherapy prophylaxis; alternative is 0.15 mg/kg IV q8h for 3 doses or 32 mg IV once as single dose
Pediatric
0.15 mg/kg/dose IV 30 min before chemotherapy for prophylaxis and after chemotherapy q4h for 2 doses; alternative is 0.15 mg/kg/dose PO/IV q4-6h
Interactions
Although CYP inducers (eg, barbiturates, rifampin, carbamazepine, phenytoin) may change half-life and clearance, dosage adjustment not usually required
Contraindications
Documented hypersensitivity
Precautions
Pregnancy
B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions
Commonly causes headache; may cause dizziness
Granisetron (Kytril)
Potent serotonin 5-HT3 receptor antagonist to prevent and treat chemotherapy- and irradiation-induced nausea and vomiting.
Dosing
Adult
1 mg PO/IV q24h; may increase to bid if needed
Pediatric
20 mcg/kg/dose PO/IV q24h; may increase to bid if needed
Interactions
CYP3A substrate; CYP3A inducers (eg, phenobarbital) may decrease effects, whereas inhibitors (eg, erythromycin, clarithromycin) may increase toxicity
Contraindications
Documented hypersensitivity to granisetron or other 5-HT3 antagonists (eg, dolasetron [Anzemet], ondansetron [Zofran])
Precautions
Pregnancy
B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions
Commonly causes abdominal pain, constipation, diarrhea, headache, lack or loss of strength, unusual tiredness, weakness, or vomiting; caution in liver disease
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.
Mesna (Mesnex)
Inactivates acrolein and prevents urothelial toxicity without affecting cytostatic activity.
Dosing
Adult
Dosage depends on dosage of ifosfamide or cyclophosphamide and is typically 60-100% of dosage for antineoplastic agent; may be administered as initial bolus then continuous or intermittent IV infusions before and after chemotherapy regimen
Pediatric
Administer as in adults
Interactions
May increase warfarin affect, adjust dosage according to target international normalized ratio (INR)
Contraindications
Documented hypersensitivity
Precautions
Pregnancy
B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions
Monitor morning urine for hematuria before ifosfamide or cyclophosphamide dose; common adverse effects include hypotension, headache, GI toxicity, and limb pain
Follow-up
Further Inpatient Care
- Inpatient care of patients with nonrhabdomyosarcoma soft tissue sarcomas (NRSTS) 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.
- CBC counts should be assessed once or twice a week while patients are receiving granulocyte-colony stimulating factor (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 (Perform annual ECG and echocardiography.)
Complications
The long-term effects of NRSTS treatment in children are many.
- Surgical treatments may cause marked permanent functional deficits, depending on the location and extent of surgery.
- The use of chemotherapy has been associated with numerous late effects. Doxorubicin can cause life-threatening cardiomyopathy. Ifosfamide can cause permanent renal impairment, hemorrhagic cystitis, infertility, gonadal failure, and an increased risk of secondary malignancies. Radiation therapy can also have lifelong debilitating effects. The effects of radiation depend on the location irradiated and the amount of radiation given to the site. Common effects can include growth plate arrest, pulmonary fibrosis, development of muscle fibrosis and contractures, and development of a secondary cancer in the radiation field.
Prognosis
Prognostic factors for children with NRSTS include the presence of metastatic disease, ability to achieve local control, tumor size and invasiveness, and tumor histologic grade.
- According to IRS groups, survival rates are as follows:
- Group I - 82%
- Group II - 67%
- Group III - 12%
- Group IV - 5
- Tumor, node, and metastases (TNM) stage 4 ( the presence of metastasis) correlates with an extremely poor prognosis of (<20%).
- Many factors contribute to survival, but the degree of resectability at the time of diagnosis is the most important factor identified to date.
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Keywords
nonrhabdomyosarcoma soft tissue sarcoma, NRSTS, tumor, fibrosarcoma, malignant peripheral nerve sheath tumor, malignant fibrous histiocytoma, synovial sarcoma, alveolar soft part sarcoma, leiomyosarcoma, liposarcoma, dermatofibrosarcoma protuberans, epithelioid sarcoma, desmoplastic small round cell tumor, infantile fibrosarcoma, IFS, nodular fasciitis, myositis ossificans, neurofibromatosis type I, NF1, human immunodeficiency virus, Epstein-Barr virus, EBV, hemangiopericytomas, hypoglycemia, hypophosphatemic rickets, hyperglycemia, Li-Fraumeni syndrome, Gorlin syndrome
Contributor Information and Disclosures
Author
Noah C Federman, MD, Assistant Professor of Pediatrics, Division of Pediatric Hematology/Oncology, Mattel Children's Hospital, David Geffen School of Medicine; Director, Pediatric Bone and Soft Tissue Sarcoma Program, University of California at Los Angeles
Noah C Federman, MD is a member of the following medical societies: American Academy of Pediatrics, American Society of Hematology, and Connective Tissue Oncology Society
Disclosure: Nothing to disclose.
Coauthor(s)
Kathleen M Sakamoto, MD, PhD, Professor and Chief, Division of Hematology-Oncology, Vice-Chair of Research, Mattel Children's Hospital at UCLA; Department of Pathology and Laboratory Medicine, Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA and California Nanosystems Institute and Molecular Biology, UCLA
Kathleen M Sakamoto, MD, PhD is a member of the following medical societies: American Society of Hematology, American Society of Pediatric Hematology/Oncology, New York Academy of Sciences, Society for Pediatric Research, and Western Society for Pediatric Research
Disclosure: Nothing to disclose.
Gary D Crouch, MD, Program Director of Pediatric Hematology-Oncology Fellowship, Department of Pediatrics, Associate Professor, Uniformed Services University of the Health Sciences
Gary D Crouch, MD is a member of the following medical societies: American Academy of Pediatrics and American Society of Hematology
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
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
Paul D Petry, DO, FACOP, FAAP, Consulting Staff, Freeman Pediatric Care, Freeman Health System
Paul D Petry, DO, FACOP, FAAP is a member of the following medical societies: American Academy of Osteopathy, American Academy of Pediatrics, American College of Osteopathic Pediatricians, and American Osteopathic Association
Disclosure: Nothing to disclose.
Chief Editor
Robert J Arceci, MD, PhD, King Fahd Professor of Pediatric Oncology, Department of Oncology, Division of Pediatric Oncology, Johns Hopkins University School of Medicine
Robert J Arceci, MD, PhD is a member of the following medical societies: American Association for Cancer Research, American Association for the Advancement of Science, American Pediatric Society, American Society of Hematology, and American Society of Pediatric Hematology/Oncology
Disclosure: Nothing to disclose.
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