eMedicine Specialties > Pediatrics: General Medicine > Oncology
Nonrhabdomyosarcoma Soft Tissue Sarcomas: Treatment & Medication
Updated: Dec 3, 2008
- Overview
- Differential Diagnoses & Workup
- Treatment & Medication
- Follow-up
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.
Adult
45-75 mg/m2/dose IV given over 48 h
Pediatric
Administer as in adults
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
Documented hypersensitivity; myocardial damage; cumulative dose >450 mg/m2 (relative contraindication)
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.
Adult
2.2 g/m2/dose IV
Pediatric
Administer as in adults
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
Documented hypersensitivity; severely depressed bone-marrow function
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.
Adult
1.8 g/m2/d IV for 5 d or 3 g/m2/d IV for 3 d
Pediatric
Administer as in adults
Phenobarbital, phenytoin, chloral hydrate, and other drugs that interfere with cytochrome P450 (CYP) activity may alter effects
Documented hypersensitivity; depressed bone marrow function
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.
Adult
60-120 mg/m2 IV
Pediatric
Administer as in adults
Increases toxicity of bleomycin and ethacrynic acid
Documented hypersensitivity; preexisting renal insufficiency; myelosuppression; hearing impairment
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.
Adult
100 mg/m2 IV on days 1-5
Pediatric
Administer as in adults
May prolong effects of warfarin and increase clearance of methotrexate; has additive effects with cyclosporine in cytotoxicity of tumor cells
Documented hypersensitivity
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.
Adult
2 mg IV bolus
Pediatric
1.5 mg/m2 IV bolus; not to exceed 2 mg/dose
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
Documented hypersensitivity; IT administration (may cause death)
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.
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
Increases risk of hepatotoxicity with enflurane or halothane
Documented hypersensitivity; chicken pox; herpes zoster; concomitant radiation
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.
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)
None reported
Documented hypersensitivity
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.
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
Although CYP inducers (eg, barbiturates, rifampin, carbamazepine, phenytoin) may change half-life and clearance, dosage adjustment not usually required
Documented hypersensitivity
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.
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
CYP3A substrate; CYP3A inducers (eg, phenobarbital) may decrease effects, whereas inhibitors (eg, erythromycin, clarithromycin) may increase toxicity
Documented hypersensitivity to granisetron or other 5-HT3 antagonists (eg, dolasetron [Anzemet], ondansetron [Zofran])
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.
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
May increase warfarin affect, adjust dosage according to target international normalized ratio (INR)
Documented hypersensitivity
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
More on Nonrhabdomyosarcoma Soft Tissue Sarcomas |
| Overview: Nonrhabdomyosarcoma Soft Tissue Sarcomas |
| Differential Diagnoses & Workup: Nonrhabdomyosarcoma Soft Tissue Sarcomas |
 Treatment & Medication: Nonrhabdomyosarcoma Soft Tissue Sarcomas |
| Follow-up: Nonrhabdomyosarcoma Soft Tissue Sarcomas |
| References |
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Further Reading
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
