Pediatric Rhabdomyosarcoma

Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children, accounting for 4.5% of all cases of childhood cancer. It is the third most common extracranial solid tumor of childhood.[4, 5] RMS is a malignant tumor of mesenchymal origin that is included in the group of small round blue cell tumors of childhood along with neuroblastoma, lymphoma and primitive neuroectodermal tumors. The name is derived from the Greek words rhabdo, which means rod shape, and myo, which means muscle. Although Weber first described rhabdomyosarcoma in 1854, a clear histologic definition was not available until 1946, when Stout recognized the distinct morphology of rhabdomyoblasts.[6] Stout described rhabdomyoblasts as appearing in round, strap, racquet, and spider forms. As its name suggests, the tumor is believed to arise from a primitive muscle cell. Rhabdomyoblasts sometimes have discernible muscle striations that are visible on specimens under light microscopy, although electron microscopy may be needed to detect subcellular elements. Cells are usually positive for intermediate filaments and other proteins typical of differentiated muscle cells, such as desmin, vimentin, myoglobin, actin, and transcription factor myoD.

An image depicting rhabdomyosarcoma can be seen below.

Axial CT scan of rhabdomyosarcoma in the left middle ear. Image provided by Suresh Muhkerji, MD, Department of Radiology, University of North Carolina Hospitals.

RMS is stratified into different histologic subtypes which influence management plans and patient outcome.[7]

Several distinct histologic groups have prognostic significance, including embryonal rhabdomyosarcoma (ERMS), which occurs in 55% of patients; the botryoid variant of ERMS, which occurs in 5% of patients; alveolar rhabdomyosarcoma (ARMS), which occurs in 20% of patients; and undifferentiated sarcoma (UDS), which occurs in 20% of patients.[8]  Similar to other pediatric malignancies, genomic sequencing studies show that RMS harbors a low DNA mutational burden.

Treatment responses and prognoses widely vary depending on location and histology. Studies of tumor biology and treatment in patients with rhabdomyosarcoma at a single institution, or even at regional centers, are not very feasible because of the variable nature and uncommon occurrence of the tumors. Therefore, most advances in knowledge and treatment have resulted from cooperative group studies.

The tumor is believed to arise from primitive muscle cells, but tumors can occur anywhere in the body; however, a primary bone rhabdomyosarcoma has not been reported. The most common sites are the head and neck (28%), extremities (24%), and genitourinary (GU) tract (18%). Other notable sites include the trunk (11%), orbit (7%), and retroperitoneum (6%). Rhabdomyosarcoma occurs at other sites in less than 3% of patients. The botryoid variant of ERMS arises in mucosal cavities, such as the bladder, vagina, nasopharynx, and middle ear. Lesions in the extremities are most likely to have an alveolar type of histology. Metastases are found predominantly in the lungs, bone marrow, bones, lymph nodes, breasts, and brain.

As with most tumors of childhood, the cause of rhabdomyosarcoma is unknown. The alveolar variant is so named because of the thin criss-crossing fibrous bands that appear as spaces between cellular regions of the tumor (reminiscent of lung alveoli). This variant is usually associated with 1 of 2 chromosomal translocations, namely, t(2;13) or t(1;13). These result in the fusion of the DNA-binding domain of the neuromuscular developmental transcription factors, encoded by PAX3 on chromosome 2 or PAX7 on chromosome 1[9] , to the transcriptional activation domain of a relatively ubiquitous transcription factor, FKHR (or FOXO1a), which is encoded on chromosome 13. Less common translocations involving the PAX genes have been found in some rare cases.[10]

The resulting hybrid molecule is a potent transcription activator. It is believed to contribute to the cancerous phenotype by abnormally activating or repressing other genes. The embryonal subtype usually has a loss of heterozygosity at band 11p15.5; this observation suggests the presence of a tumor suppressor gene. Other molecular aberrations that may provide clues to the origin of the tumor and that may be useful for future treatment strategies include TP53 mutations (which occur in approximately one half of patients), an elevated N-myc level (in 10% of patients with ARMS), and point mutations in N-ras and K-ras oncogenes (usually embryonal). In addition, levels of insulinlike growth factor-2 may be elevated, suggesting pathways involving autocrine and paracrine growth factors.[11]

The cause of rhabdomyosarcoma is unclear. Several genetic syndromes and environmental factors are associated with increased prevalence of rhabdomyosarcoma.[12]

• Genetic syndromes include the following:

  • Neurofibromatosis (4-5% risk of any one of numerous malignancies)

  • Li-Fraumeni syndrome (germline mutation of the tumor suppressor gene TP53)

  • Rubinstein-Taybi syndrome

  • Gorlin basal cell nevus syndrome

  • Beckwith-Wiedemann syndrome

  • Costello syndrome[13]

• A higher prevalence of congenital anomalies are observed in patients who later develop rhabdomyosarcoma with locations as follows:

  • Genitourinary (GU) tract

  • CNS (ie, Arnold-Chiari malformation)

  • GI tract

  • Cardiovascular system

• Environmental factors appear to influence the development of rhabdomyosarcoma, as follows:

  • Parental use of marijuana and cocaine

  • Intrauterine exposure to X-rays[14]

  • Previous exposure to alkylating agents

United States statistics

The incidence is 6 cases per 1,000,000 population per year (approximately 250 cases) in children and adolescents younger than 15 years.

International statistics

No notable geographic predilection is reported.

Race-, sex-, and age-related demographics

No racial predilection is obvious.

Overall, the male-to-female ratio is 1.2-1.4:1. Differences are observed according to the site of primary disease.

• GU tract: The male-to-female ratio is 3.3:1 in patients with bladder or prostate involvement and 2.1:1 in rhabdomyosarcoma of the GU tract without bladder or prostate involvement.

• Extremity: The male-to-female ratio is 0.79:1.

• Orbit: The male-to-female ratio is 0.88:1.

Approximately 87% of patients are younger than 15 years, and 13% of patients are aged 15-21 years. Rhabdomyosarcoma rarely affects adults. Age-related differences are observed for the different sites of primary disease. Two age peaks tend to be associated with different locations. Patients aged 2-6 years tend to have head and neck or GU tract primary tumors, whereas adolescents aged 14-18 years tend to have primary tumors in extremity, truncal, or paratesticular locations.

• GU tract: In patients with bladder or prostate involvement, 73% are younger than 5 years. In patients with rhabdomyosarcoma of the GU tract without bladder or prostate involvement, 27% are older than 15 years.

• Orbit: About 42% of patients with orbital rhabdomyosarcoma are aged 5-9 years.

Morbidity/mortality

In patients with localized disease, overall 5-year survival rates have improved to more than 80% with the combined use of surgery, radiation therapy, and chemotherapy.[1]  However, in patients with metastatic disease, little progress has been made in survival rates, with a 5-year event-free survival rate less than 30%. Those patients with metastatic disease without other high-risk factors, including unfavorable site, more than 3 sites, bone marrow involvement, and age younger than 1 year or older than 10 years, have a better prognosis (50% 3-y event-free survival) than those with 3-4 of these factors (12% and 5% 3-y event-free survival, respectively).[15]  The use of high-dose myeloablative therapy with autologous stem-cell rescue has not improved outcomes for these patients.[16]

In an analysis of data collected by the Surveillance, Epidemiology, and End Results (SEER) program, mortality was highly related to age, site, and histology.[17]  The 5-year survival was highest in children aged 1-4 years (77%) and was worst in infants and adolescents (47% and 48%, respectively). Orbital and GU sites were the most favorable (86% and 80%, respectively). Unfavorable sites included tumors of the extremities (50%), retroperitoneum (52%), and trunk (52%). Embryonal histology was best (67%) compared with alveolar histology (49%). Most patients with local recurrence are curable with salvage therapy, particularly if the recurrence is after initial therapy has been completed.

Complications

The treatment of rhabdomyosarcoma results in a multitude of potential long-term adverse effects.[18]  The most common findings include the following:

• Cardiomyopathy

  • In patients who receive an anthracycline, cardiac function must be monitored to assess for the development of cardiomyopathy.

  • Cardiomyopathy may also from cyclophosphamide use.

• Pulmonary failure

• Metabolic derangements: Ifosfamide use, in particular, can lead to renal electrolyte wasting (Fanconi syndrome).

• Secondary malignant neoplasms

  • Secondary malignant neoplasms may arise as a result of radiotherapy and chemotherapy, particularly with alkylating agents.

  • Etoposide markedly increases the risk for acute myelogenous leukemia, particularly when regimens with frequent dosing schedules are used.

  • Radiation therapy increases the risk of second malignancies, including skin and bone tumors.

Chemotherapy

Parents and patients (if appropriate) must undergo formal training to learn about the adverse effects of chemotherapy. They must know what is expected to happen as a result of the therapy and are encouraged to ask questions.

Central venous catheters

When patients have central venous catheters that exit the skin (eg, Hickman or Broviac catheters), the parents or the patient must learn to properly care for the line. This care usually involves daily heparin flushes.

Patients and parents must understand the limitations on activities because of central venous catheters. For example, swimming is not permitted.

Patients with subcutaneous catheters (eg, Mediport catheters) do not need to perform daily care, but they should learn to apply a topical anesthetic (eg, EMLA cream, or lidocaine-prilocaine cream) at least 1 hour before an anticipated needle stick.

Rhabdomyosarcoma (RMS) usually manifests as an expanding mass; symptoms depend on the location of the tumor. Pain may be present. If metastatic disease is present, symptoms of bone pain, respiratory difficulty (secondary to lung nodules or to pleural effusion), anemia, thrombocytopenia, and neutropenia may be present. Disseminated rhabdomyoblasts in the bone marrow may mimic leukemia, both in symptoms and light microscopic findings.

Typical presentations by the location of nonmetastatic disease are as follows:

• Orbit - Proptosis or dysconjugate gaze[2]

• Paratesticular - Painless scrotal mass

• Prostate - Bladder or bowel difficulties

• Uterus, cervix, bladder - Menorrhagia or metrorrhagia

• Vagina - Protruding polypoid mass (botryoid, meaning a grapelike cluster)

• Extremity - Painless mass

• Parameningeal (ear, mastoid, nasal cavity, paranasal sinuses, infratemporal fossa, pterygopalatine fossa) - Upper respiratory symptoms or pain[3]

Physical findings depend on the location of the tumor. Tumors in superficial locations may be palpable and detected relatively early, but those in deep locations (eg, retroperitoneum) may grow large before causing symptoms.

The following studies are indicated in rhabdomyosarcoma:

• CBC count: Anemia may be present because of inflammation, or pancytopenia may be present from bone marrow involvement.

• Liver function tests, including measurement of lactic acid dehydrogenase (LDH), aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase, and bilirubin levels: Metastatic disease of the liver may affect values of these proteins. Liver function must be assessed before chemotherapy.

• Renal function tests, including measurements of BUN and creatinine levels: Renal function must be assessed before chemotherapy.

• Urinalysis (UA): Hematuria may indicate involvement of the genitourinary (GU) tract.

• Blood electrolyte and chemistry, including evaluation of sodium, potassium, chlorine, carbon dioxide, calcium, phosphorous, and albumin values: Assess for abnormalities before chemotherapy.

Imaging studies that have been used in the workup include the following:

• Plain radiography: Radiography of the primary site and of the chest is helpful in determining the presence of calcifications and bone involvement of the primary tumor and to search for metastatic lung lesions.

• CT scanning

  • Obtain a chest CT scan to evaluate for metastases to the lungs. Chest CT scanning is best performed before surgery to avoid atelectasis, which can be confused with metastasis.

  • A CT scan of the primary site may also be helpful in evaluating for bone erosion, if present, and to follow up the patient's response to therapy.

  • Obtain a CT scan of the liver in patients with abdominal or pelvic primary tumors to assess for metastatic spread. Ultrasonography is an alternative.

• MRI: MRI improves definition of the mass and its invasion of adjacent organs, especially in orbital, paraspinal, or parameningeal regions. Obtain an MRI of the head if the patient is symptomatic at diagnosis.

• Bone scanning: Search for metastases to the bones.

• Ultrasonography: Obtain sonograms of the liver in patients with abdominal or pelvic tumors. CT scanning is an alternative.

• Echocardiography: Assess cardiac function before chemotherapy.

Procedures include the following:

• Biopsy: Open biopsy best enables adequate tissue sampling for diagnosis and molecular studies. Core needle biopsy is an alternative. Depending on the location, definitive surgery can be postponed to allow for neoadjuvant chemotherapy to shrink the tumor.

• Cytogenetics, fluorescent in situ hybridization (FISH)

  • This study helps in determining if the translocations t(1;13) or t(2;13), which are associated with the alveolar subtype, are present.

  • FISH also helps in the diagnosis to assess for break-apart of the FKHR gene, though this test will miss the rare variants that don’t involve FKHR.

  • FISH is most sensitive for these translocations and can be helpful in evaluating residual disease.

• Reverse transcriptase–polymerase chain reaction (RT-PCR) testing

  • When cytogenetic testing is unavailable (eg, culture failure) or when its results are uninformative, order a RT-PCR reaction to assess for the characteristic translocations associated with alveolar rhabdomyosarcoma (ARMS) and other small, round blue-cell tumors of childhood.

  • In many centers, the use of RT-PCR to screen for a panel of translocations associated with soft tissue sarcomas is becoming a routine adjunct to morphologic analysis to help ascertain the diagnosis.

• Bone marrow aspiration and biopsy: Assess for metastatic spread to bone marrow.

Rhabdomyosarcoma is one of the small, round blue-cell tumors of childhood. Occasionally, these types of tumors can be difficult to differentiate. Rhabdomyosarcoma cells tend to have variable differentiation along the myogenesis pathway and may appear as strap cells or myotubes that sometimes contain muscle cross-striations. Rhabdomyosarcoma cells may demonstrate positive immunohistochemical results for muscle-specific markers, such as myoglobin, actin, and desmin.[19]

Cells from the rhabdomyosarcoma subtypes have the following distinctive features:

• Botryoid: The cambium layer is characteristic, containing a condensation of loose tumor cells below an epithelial surface.

• Alveolar: Cells line up along membranes that may be imperceptibly thin or that may be obvious collagen bands resembling the lung alveoli. A tumor should be classified as this type if any portion of it appears to be alveolar.

• Undifferentiated: No evidence of myogenesis differentiation is usually present.

Balanced translocations between chromosomes (2;13) or (1;13) have been identified in approximately 80% of alveolar RMS.[20] The clinical behavior and molecular characteristics of alveolar RMS without a fusion gene are indistinguishable from embryonal cases and have been shown to be significantly different from fusion-positive alveolar cases, implying the critical role of fusion gene status in risk stratification of RMS.[21]

Recent research has been focused on performing whole genome, whole exome and transcriptome sequencing to characterize the landscape of somatic alterations. In addition to well recognized gene mutations that include the FGFR4/RAS/AKT pathway, novel recurrently mutated genes such as PTEN, GAB1, ROBO, FBXW7 and BCOR have been identified. These new findings provide potential new avenues for therapeutic intervention.[22, 23]

Treatment in patients with rhabdomyosarcoma (RMS) involves a combination of surgery, chemotherapy, and radiation therapy. Because the treatment plan is complicated and prolonged and because many medical issues are unique to pediatric oncology, all patients should be referred (at least initially) to a center with personnel who are skilled in caring for children with cancer.

At present, patients are categorized according to their risk, which takes into account the location of the tumor and the histologic and surgical results. Low-risk patients are those who have the best prognosis, whereas intermediate-risk or high-risk patients have an increased risk of having relapses and incurable disease. To separate the features into meaningful categories, patients are assigned to both a surgicopathologic clinical group (Roman numeral) and a stage (Arabic numeral). All patients with metastatic disease (group IV, stage 4) are considered high risk, except children and adolescents younger than 14 years with embryonal rhabdomyosarcoma (ERMS). In some studies, these patients appear to do better than others, for unknown reasons. Although all patients require chemotherapy, regimens vary depending on the stage and group.

• Surgicopathologic (clinical) group (Groups I-III are for localized disease).

  • Group I - Tumor completely removed

  • Group II - Microscopic residual tumor, involved regional nodes, or both

  • Group III - Gross residual tumor

  • Group IV - Distant metastatic disease

• Tumor, nodes, and metastases (TNM) staging system

  • Tumor - Confined to the site of origin (T1) or extends beyond the site of origin (T2)

  • Node - No regional node involvement (N0), regional node involvement (N1), or nodes unknown (NX)

  • Metastasis - No metastasis (M0), or metastases present at diagnosis (M1)

• RMS staging system

  • Stage 1 - Orbit, head, and/or neck (not parameningeal) involvement, and involvement of the GU tract (not bladder or prostate)

  • Stage 2 - Other locations, N0 or NX

  • Stage 3 - Other locations, N1 if the tumor is less than 5 cm or N0 or NX if the tumor more than 5 cm

  • Stage 4 - Any site with distant metastases

• Low-risk patients are those with the following embryonal histology:

  • Stages 1-3 in groups I-II (or III for only orbital involvement)

  • Stage 1 in group III

A study by Weigel et al that enrolled 109 patients, mostly 20 years of age or younger, with stage IV (metastatic) rhabdomyosarcoma, looked to improve outcome of patients with metastatic rhabdomyosarcoma by dose intensification with interval compression, use of the most active agents determined in phase II window studies, and use of irinotecan as a radiation sensitizer. The study reported a 3-year event-free survival (EFS) rate of 38%, and an overall survival rate of 56% which was below the primary objective to improve the 3-year EFS to 55%. Despite those setbacks, the study did find that patients with metastatic rhabdomyosarcoma with one or no Oberlin risk factor had an improved 3-year EFS of 69% on ARST0431 compared with a historical cohort from pooled European and US studies.[24, 25]

In a phase II trial of 87 patients with rhabdomyosarcoma who had experienced a first relapse or disease progression and whose prognosis was unfavorable, temsirolimus (Torisel) proved superior to bevacizumab (Avastin) as add-on therapy. At 6 months, event-free survival in these patients, whose prognosis was unfavorable, was 65% with temsirolimus versus 50% with bevacizumab, when these agents were added to a chemotherapy regimen of vinorelbine and cyclophosphamide.[26, 27]  At 6 months, the response rate also favored temsirolimus (47.4% vs 27.5%) as did the number of complete responses (5 vs 4) and the number of partial responses (13 vs 7). The rate of progressive disease was also better with temsirolimus (28% vs 10%).[26, 27]

In a second study of 461 children with intermediate-risk rhabdomyosarcoma, adding irinotecan to combination treatment with vincristine, dactinomycin, and cyclophosphamide (VAC) did not improve overall or event-free survival. However, the regimen containing irinotecan resulted in a lower rate of hematologic toxicity and cumulative dose of cyclophosphamide.[26, 28]

A randomized, controlled study by Bisogno et al demonstrated that the addition of 6 months of maintenance chemotherapy with low-dose vinorelbine/cyclophosphamide improved the 5-year overall survival rate for patients with high-risk RMS from 73.7% to 86.5%, or an absolute 13% increase. Over a 10-year period, 371 patients aged 6 months to 21 years were enrolled in the trial.[29, 30]

Surgical management of rhabdomyosarcoma varies depending on the location of the tumor. If feasible, remove tumors promptly and without unacceptable disfigurement or loss of function. Even if metastatic disease is present, surgical excision of the primary site should be performed, if possible. The surgical result helps determine the clinical grouping to be used for treatment stratification.

Surgical guidelines for the various sites can be found in the protocols of the Children's Oncology Group Soft Tissue Sarcoma Committee (formerly, Intergroup Rhabdomyosarcoma Study Group [IRSG]) and are beyond the scope of this article. However, common principles are noteworthy and described below.

• Primary tumor

  • Because relapses often occur at the site of the original primary tumor, adequate local control is essential.

  • Data from Europe suggest that chemotherapy alone can be effective for achieving adequate local control in some patients who have a complete response of the primary tumor. However, surgery and/or irradiation are needed for local control of residual disease.

  • If possible, complete excision of the lesion should be performed with a wide (2-cm) margin of healthy tissue. Wide margins of normal tissue often are impossible to achieve at certain sites, such as the head and neck. If margins are narrow, obtain several biopsy specimens from the surrounding tissue to assess for residual local disease.

  • For tumors that cannot be excised at diagnosis, a second-look procedure may be appropriate after a period of chemotherapy (usually 12 wk).

• Lymph nodes

  • Regional lymph nodes that appear to be clinically or radiographically involved should be sampled to determine the clinical group and the need for later radiation therapy.

  • Radical node dissection is not appropriate.

  • Axillary and femoral node sampling should be performed for lesions in the extremities, even if clinical findings are negative because of the high prevalence of metastatic disease arising from extremity lesions.

  • The use of sentinel node biopsy instead of lymph node sampling is being explored.[31]

The care of patients with rhabdomyosarcoma is complicated and extensive and touches all aspects of their lives. Initial evaluation and treatment should be undertaken at a center with a comprehensive program for children with cancer.

• Radiotherapist

  • Most patients with rhabdomyosarcoma require radiotherapy to achieve adequate local control, though radiotherapy is not usually performed until after initial surgical resection and the start of chemotherapy. Exceptions are patients with parameningeal primary tumors, for which initial radiotherapy has been shown to be beneficial.

  • A radiotherapist familiar with the requirements for clinical trials should be consulted at diagnosis for most patients in North America to determine if they have any special needs for treatment planning.

  • In initial studies, new techniques such as intensity-modulated radiotherapy (IMRT) and proton-beam radiotherapy appear to achieve adequate tumor control with reduced exposure to normal tissues.[32, 33]

  • There is a high risk of local recurrence in patients with group II disease (microscopic residual disease) if prescribed radiotherapy is omitted or reduced, as demonstrated by Million et al.[34] They noted that more than half the patients who relapsed at the original tumor site received nonstandard radiation therapy, and, of these, three quarters died of their disease.

• Psychosocial team: The psychosocial team is critical for helping patients and families cope with the stresses associated with the diagnosis and treatment of cancer. The social worker usually plays an intimate role in helping families navigate complicated insurance and financial issues.

• Dentist: A thorough dental evaluation is required to identify potential problems that may arise during chemotherapy.

• Pediatric therapists: Activities and therapy can be critical in helping the patient through the phases of medical therapy.

Diet

No specific dietary recommendations are needed. However, patients may require nasogastric feedings or parenteral nutrition during some phases of chemotherapy. This is especially true for patients with primary tumors in head and neck, who may have severe mucositis after radiation therapy.

Activity

No specific activity limitations are required. The patient's activity is restricted only as the location of the tumor and the adverse effects of treatment dictate.

Standard therapy for rhabdomyosarcoma (RMS) includes chemotherapy combined with surgical resection, radiotherapy, or both for local control, if necessary. These modalities have not improved survival rates in patients with metastatic disease; however, new agents active against rhabdomyosarcoma are being sought, and agents are being tested in phase I and II clinical trials. Novel therapies in development include oncolytic viruses[35] and immunotherapies, such as monoclonal antibodies[36] and dendritic-cell vaccines. In addition, evidence suggests that some targeted agents may be active in rhabdomyosarcoma, including proteosome inhibitors,[37] and anti-insulinlike growth factor receptor (IGFR) antibodies.[38] The role of oral maintenance therapy may be useful in controlling metastatic disease but has not been confirmed.[39]

Class Summary

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

The cell-division rate varies for different tumors. Tumors of most common cancers grow slowly compared with normal tissues, and the rate of growth may decrease further in large tumors. This difference allows normal cells to recover from chemotherapy more quickly than malignant cells can and is the rationale behind current cyclic dosing schedules.

Antineoplastic agents interfere with cell reproduction. Some agents are phase specific, whereas others (eg, alkylating agents, anthracyclines, cisplatin) are not. Cellular apoptosis (ie, programmed cell death) is a potential mechanism of many antineoplastic agents.[40] Those listed here are the standard active agents, although others, such as irinotecan, appear useful, are under investigation, and are now being included in all high-risk clinical trials.[41] The addition of agents known to be active in rhabdomyosarcoma, such as ifosfamide and topotecan, do not appear to provide additional benefit to intermediate-risk patients when added to the standard regimen of vincristine, actinomyocin, and cyclophosphamide.[5]

Vincristine (Oncovin)

Inhibits tubulin polymerization, targeting dividing cells. Acts as vesicant.

Dactinomycin (Cosmegen, actinomycin D)

Antibiotic derived from Streptomyces bacteria.

Cyclophosphamide (Cytoxan)

Alkylating agent believed to be cytotoxic to dividing cells by cross-linking cellular DNA. Processed in liver to active metabolites. Byproducts (eg, acrolein) accumulate in bladder and cause cystitis.

Etoposide (Toposar, VP16)

Inhibits topoisomerase II and therefore toxic to cells undergoing DNA replication.

Ifosfamide (Ifex)

Alkylating agent. Inhibits DNA and protein synthesis and therefore cell proliferation by causing DNA cross-linking and denaturation of double helix.

Irinotecan (Camptosar, CPT-11)

Topoisomerase I inhibitor. Use in RMS currently investigational.

Class Summary

Mesna is a prophylactic detoxifying agent used to inhibit hemorrhagic cystitis caused by ifosfamide and 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 to be responsible for urotoxicity.

Mesna (Mesnex)

Inactivates acrolein and prevents urothelial toxicity without affecting cytostatic activity. Sulfhydryl compound that accumulates in urine and inactivates toxic byproducts of cyclophosphamide and ifosfamide.

Class Summary

These agents act as hematopoietic growth factors that stimulate the development of granulocytes. They are used to treat or prevent neutropenia when patients are receiving myelosuppressive cancer chemotherapy and to reduce the period of neutropenia associated with bone marrow transplantation. They are also used to mobilize autologous peripheral blood progenitor cells for bone marrow transplantation and in the management of chronic neutropenia. They shorten the time to neutrophilic recovery after chemotherapy.

Filgrastim (Neupogen)

Granulocyte colony-stimulating factor (G-CSF) that activates and stimulates production, maturation, migration, and cytotoxicity of neutrophils. Better tolerated than alternative GM-CSF.

CBC count: Perform a CBC count twice each week in patients receiving therapy by using granulocyte-colony stimulating factor (G-CSF) so that G-CSF can be discontinued when the absolute neutrophil count has reached a predetermined level (usually 1 or 5 X 109/L [1000 or 5000/µL]). See the Absolute Neutrophil Count calculator.

Blood chemistry: Monitor blood chemistry results and liver function in patients receiving parenteral nutrition or in those who have a history of toxicity, especially if the patient continues to receive nephrotoxic or hepatotoxic antibiotics or other drugs.

Chemotherapy: Depending on the protocol, some chemotherapy regimens (eg, vincristine, dactinomycin in particular) can be administered on an outpatient basis.

Monitoring for recurrence: Continue to perform blood tests and radiographic scans on an outpatient basis, with the frequency decreasing over time. In general, patients should be examined every 3 months for the first year, every 6 months for the second and third years, and yearly thereafter.

Long-term follow-up care: At 5 or longer after the end of therapy, patients are considered to be long-term survivors. Patients should be examined annually at a late-effects clinic and monitored with appropriate studies depending on the type of therapy they received. Visits may include hormonal, psychosocial, and neurologic evaluations, as well as follow-up examinations by the radiotherapist.

Chemotherapy: Chemotherapy cycles are usually administered every 3 weeks (although vincristine is periodically given weekly) in patients with rhabdomyosarcoma (RMS), depending on recovery of the bone marrow. Patients receiving cycles that include cyclophosphamide, ifosfamide, and etoposide generally require inpatient admission for drug administration and monitoring.

Fever and neutropenia: Admission is required to administer intravenous (IV) antibiotics and to monitor patients.

Other reasons for inpatient care: Patients may require admission for a multitude of other medical problems during the chemotherapy phase of treatment, including varicella infection (to administer IV acyclovir and to monitor), mucositis (resulting from narcotics use), dehydration, meningitis, constipation, fungal pneumonia, and cystitis, among others.

Inpatient and outpatient medications include the following:

• Trimethoprim-sulfamethoxazole: Prophylaxis against pneumocystic pneumonia should continue until 6 months after the end of chemotherapy.

• Fluconazole: Systemic fungal prophylaxis is not necessary.

• Clotrimazole: Prophylactic therapy for thrush may be discontinued after chemotherapy is completed.

• Chlorhexidine mouth rinse: Prophylaxis against gingivitis and other mouth infections may be discontinued after chemotherapy is completed.

Although major cancer therapy should take place at a center with pediatric oncologists, the child's referring pediatrician or general practitioner should continue to play an important role in the child's care throughout treatment.

The referring physician can be critical in performing the first evaluation of an illness, particularly if the child lives far from an oncology center.