Treatment statement for Health professionals

Childhood Rhabdomyosarcoma Treatment (PDQ®)

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Purpose of This PDQ Summary
General Information
Cellular Classification
Stage Information
Treatment Option Overview
Previously Untreated Childhood Rhabdomyosarcoma
Recurrent Childhood Rhabdomyosarcoma
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Changes to This Summary (12/10/2009)
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Purpose of This PDQ Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of childhood rhabdomyosarcoma. This summary is reviewed regularly and updated as necessary by the PDQ Pediatric Treatment Editorial Board.

Information about the following is included in this summary:

Cellular classification.
Stage information.
Treatment options.

This summary is intended as a resource to inform and assist clinicians and other health professionals who care for pediatric cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Pediatric and Adult Treatment Editorial Boards use a formal evidence ranking system in developing their level-of-evidence designations. Based on the strength of the available evidence, treatment options are described as either “standard” or “under clinical evaluation.” These classifications should not be used as a basis for reimbursement determinations.

This summary is also available in a patient version, which is written in less technical language, and in Spanish.

General Information

The National Cancer Institute (NCI) provides the PDQ pediatric cancer treatment information summaries as a public service to increase the availability of evidence-based cancer information to health professionals, patients, and the public.

Cancer in children and adolescents is rare. Children and adolescents with cancer should be referred to medical centers that have a multidisciplinary team of cancer specialists with experience treating the cancers that occur during childhood and adolescence. This multidisciplinary team approach incorporates the skills of the primary care physician, pediatric surgical subspecialists, radiation oncologist, pediatric oncologist/hematologist, rehabilitation specialists, pediatric nurse specialists, social workers, and others to ensure that children receive treatment, supportive care, and rehabilitation that will achieve optimal survival and quality of life. (Refer to the PDQ summary on Pediatric Supportive Care for specific information about supportive care for children and adolescents with cancer.)

Guidelines for pediatric cancer centers and their role in the treatment of pediatric patients with cancer have been outlined by the American Academy of Pediatrics. [1] At these pediatric cancer centers, clinical trials are available for most types of cancer that occur in children and adolescents, and the opportunity to participate in these trials is offered to most patients/families. Clinical trials for children and adolescents with cancer are generally designed to compare potentially better therapy with therapy that is currently accepted as standard. Most of the progress made in identifying curative therapies for childhood cancers has been achieved through clinical trials. Information about ongoing clinical trials is available from the NCI Web site.

In recent decades, dramatic improvements in survival have been achieved for children and adolescents with cancer. Childhood and adolescent cancer survivors require close follow-up because cancer therapy side effects may persist or develop months or years after treatment. (Refer to the PDQ summary on Late Effects of Treatment for Childhood Cancer for specific information about the incidence, type, and monitoring of late effects in childhood and adolescent cancer survivors.)

Childhood rhabdomyosarcoma, a soft tissue malignant tumor of skeletal muscle origin, accounts for approximately 3.5% of the cases of cancer among children aged 0 to 14 years and 2% of the cases among adolescents and young adults aged 15 to 19 years. [2] [3] It is usually curable in most children with localized disease who receive combined modality therapy, with more than 70% surviving 5 years after diagnosis. [4] [5] [6] Relapses are uncommon after 5 years of disease-free survival, with a 9% late-event rate at 10 years. Relapses, however, are more common for patients who have gross residual disease in unfavorable sites following initial surgery and those who have metastatic disease at diagnosis. [7] The most common primary sites for rhabdomyosarcoma are the head and neck (e.g., parameningeal head and neck, orbit, pharynx), the genitourinary tract, and the extremities. [4] [5] Other less common primary sites include the trunk, chest wall, perineal/anal region, and abdomen including the retroperitoneum and biliary tract.

Most cases of rhabdomyosarcoma occur sporadically, with no recognized predisposing factor or risk factor, [8] though a small proportion are associated with genetic conditions. These conditions include Li-Fraumeni cancer susceptibility syndrome (with germline p53 mutations), [9] [10] [11] neurofibromatosis type I, [12] Costello syndrome (with germline HRAS mutations), [13] [14] [15] Beckwith-Wiedemann syndrome (with which Wilms tumor and hepatoblastoma are more commonly associated), [16] [17] and Noonan syndrome. [18]

The prognosis for a child or adolescent with rhabdomyosarcoma is related to the age of the patient, site of origin, widest diameter of the tumor, resectability, presence of metastases, number of metastatic sites or tissues involved, presence or absence of regional lymph node involvement, histopathologic subtype (alveolar vs. embryonal), and delivery of radiation therapy (RT) in selected cases, [4] [5] [19] [20] [21] [22] [23] [24] [25] [26][Level of evidence: 3iiiA] as well as unique biological characteristics of rhabdomyosarcoma tumor cells. [27] Response to induction chemotherapy, as judged by anatomic imaging, does not appear to correlate with the likelihood of survival in patients with rhabdomyosarcoma. [28] Examples of both clinical and biological factors with proven or possible prognostic significance are briefly described below.

Children younger than 1 year and older children do not tolerate aggressive therapy, including full-dose radiation and appropriate chemotherapy on schedule as well as older children; therefore, outcome may be adversely affected. [6] [29] Children aged between 1 and 9 years have the best overall survival rates. [20]

Primary sites with more favorable prognoses include the orbit and nonparameningeal head and neck, paratestis, vulva, vagina, uterus (nonbladder, nonprostate genitourinary tract), and biliary tract. [4] [5] [30] [31] [32]

Tumor burden at diagnosis has prognostic significance. Patients with smaller tumors (<5 cm) have improved survival compared with children with larger tumors. [4] [30] A retrospective review of soft tissue sarcomas in children and adolescents suggests that the 5 cm cutoff used for adults with soft tissue sarcoma may not be ideal for smaller children, especially infants. The review identified an interaction between tumor diameter and body surface area (BSA). [33][Level of evidence: 3iiA] Children with metastatic disease at diagnosis have the poorest prognosis. The prognostic significance of metastatic disease is modified by tumor histology (embryonal is more favorable than alveolar) and by the number of metastatic sites. [21] Similarly, patients with metastatic genitourinary (nonbladder, nonprostate) primary tumors have a more favorable outcome than do patients with metastatic disease from primary tumors at other sites. [34] In addition, patients with otherwise localized disease but with proven regional lymph node involvement have a poorer prognosis than do patients without regional nodal involvement. [24] [25]

The extent of disease following the primary surgical procedure (i.e., the Surgico-pathologic Group, formerly called the Clinical Group) is also correlated with outcome. [4] In the Intergroup Rhabdomyosarcoma Study Group (IRSG) Protocol III, patients with localized, gross residual disease after initial surgery (Surgico-pathologic Group III) had a 5-year survival rate of approximately 70% compared with a more than 90% 5-year survival rate for patients with no residual tumor after surgery (Group I) and an approximate 80% 5-year survival rate for patients with microscopic residual tumor following surgery (Group II). [4] [19]

The alveolar subtype is more prevalent among patients with less favorable clinical features (e.g., younger than 1 year or older than 10 years, extremity primary tumors, and metastatic disease), and is generally associated with a worse outcome. In the IRSG Protocol I and IRSG Protocol II studies, the alveolar subtype was associated with a less favorable outcome even in patients whose primary tumor was completely resected (Group I). [31] Statistically significant differences in survival for histopathologic subtype were not noted when all patients with rhabdomyosarcoma were analyzed, [35] [36] and differences were not noted by histologic subtype in a large group of German children with rhabdomyosarcoma. [30] In the IRSG Protocol III study, outcome for patients with Group I alveolar subtype tumors was similar to that for other patients with Group I tumors, but the patients with alveolar subtype tumors received more intensive therapy. [4]

Patients with undifferentiated sarcomas were treated in trials coordinated by the IRSG from 1972 until 2006, [37] but they are currently eligible for the nonrhabdomyosarcoma soft tissue sarcoma protocol using agents active in adult soft tissue sarcoma, ifosfamide and doxorubicin (COG-ARST0332). (Refer to the PDQ summary on Childhood Soft Tissue Sarcoma for more information.)

Because treatment and prognosis depend, in part, on the histology and molecular genetics of the tumor, it is necessary that the tumor tissue be reviewed by pathologists and cytogeneticists/molecular geneticists with experience in the evaluation and diagnosis of tumors in children. Additionally, the diversity of primary sites, the distinctive surgical and RT treatments for each primary site, and the subsequent site-specific rehabilitation underscore the importance of treating children with rhabdomyosarcoma in medical centers with appropriate experience in all therapeutic modalities.

References:

Cellular Classification

Rhabdomyosarcoma can be divided into several histologic subsets: embryonal rhabdomyosarcoma, which has embryonal, botryoid, and spindle cell subtypes; alveolar rhabdomyosarcoma; and pleomorphic rhabdomyosarcoma. [1] [2]

Embryonal Rhabdomyosarcoma

The embryonal subtype is the most frequently observed subtype in children, accounting for approximately 60% to 70% of rhabdomyosarcomas of childhood. [1] Tumors with embryonal histology typically arise in the head and neck region or in the genitourinary tract, although they may occur at any primary site.

Botryoid and spindle cell subtypes

Botryoid tumors represent about 10% of all rhabdomyosarcoma cases and are embryonal tumors that arise under the mucosal surface of body orifices such as the vagina, bladder, nasopharynx, and biliary tract. The spindle cell variant of embryonal rhabdomyosarcoma is most frequently observed at the paratesticular site. [3] Both the botryoid and the spindle cell subtypes are associated with very favorable outcomes. [2]

Alveolar Rhabdomyosarcoma

Approximately 20% of children with rhabdomyosarcoma have the alveolar subtype. An increased frequency of this subtype is noted in adolescents and in patients with primary sites involving the extremities, trunk, and perineum/perianal region. [1]

Pleomorphic (Anaplastic) Rhabdomyosarcoma

Pleomorphic rhabdomyosarcoma occurs predominantly in patients aged 30 to 50 years and is rarely seen in children. In children, the term pleomorphic has been replaced by the term anaplastic. [4] In a retrospective review of a prospective cohort of patients, anaplasia did not have a statistically significant association with either failure-free survival or overall survival. [5][Level of evidence: 3iiA]

Chromosomal and Molecular Characteristics

The embryonal and alveolar histologies have distinctive molecular characteristics that have been used for diagnostic confirmation and that may be useful in the future for monitoring minimal residual disease during treatment. [6] [7] [8] [9] [10] Unique translocations between the FKHR gene on chromosome 13 and either the PAX3 gene on chromosome 2 or the PAX7 gene on chromosome 1 are characteristic of alveolar rhabdomyosarcoma. [6] [11] Translocations involving the PAX3 gene occur in approximately 59% of alveolar rhabdomyosarcoma cases, while the PAX7 gene appears to be involved in about 19% of cases. [6] Patients with solid variant alveolar histology have a lower incidence of PAX-FKHR gene fusions than do patients showing classical alveolar histology. [12] Alveolar cases associated with the PAX7 gene, with or without metastases, appear to occur in patients at a younger age, and they may have longer event-free survival rates than those associated with PAX3 gene rearrangements. [13] [14] [15] [16] In alveolar cases associated with the PAX3 gene, patients are older and have a higher incidence of invasive tumor (T2). Around 22% of cases have no detectable PAX gene translocation. [10] [12] Embryonal tumors, on the other hand, often show loss of specific genomic material from the short arm of chromosome 11. [11] [17] [18] The consistent loss of genomic material from the chromosome 11p15 region in embryonal tumors suggests the presence of a tumor suppressor gene, though no such gene has yet been identified. Breakpoints involving the 1p11-1q11 region are relatively common (36%) in embryonal rhabdomyosarcoma. [19] Gene expression arrays identify a cluster of genes that correlate with rhabdomyosarcomas that contain the PAX-FKHR translocation. Tumors with alveolar histology that lack the translocation have a gene expression profile more similar to embryonal rhabdomyosarcomas than to alveolar rhabdomyosarcomas. [20] It is controversial whether translocation-negative rhabdomyosarcomas with some histologic features of alveolar rhabdomyosarcoma should be classified as embryonal based on gene expression profile rather than classified as alveolar by light microscopy findings.

References:

Stage Information

Before a biopsy of a suspected tumor mass is performed, imaging studies of the mass and baseline laboratory studies should be obtained. After the diagnosis of rhabdomyosarcoma has been made, an extensive evaluation to determine the extent of the disease should be done prior to instituting therapy. This evaluation should include a chest x-ray, computed tomography (CT) scan of the chest, bilateral bone marrow aspirates and biopsies, bone scan, magnetic resonance imaging of the base of the skull and brain (for parameningeal primary tumors only), and CT scan of the abdomen and pelvis (for lower extremity or genitourinary primary tumors).

A CT scan of regional lymph nodes should be considered. Enlarged lymph nodes should be biopsied. One study has demonstrated that sentinel lymph node biopsies can be safely performed in children with rhabdomyosarcoma, and tumor-positive biopsies may alter the treatment plan. [1] Positron emission tomography (PET) with fluorine-18-fluorodeoxyglucose (FDG) scans can identify areas of possible metastatic disease not seen by other imaging modalities. [2] However, the efficacy of these two procedures for identifying involved lymph nodes or other sites is under evaluation, and these procedures are not required by current treatment protocols.

Terms used in this summary section are defined below in Table 1.

Table 1. Definition of Terms

Term	Definition
Favorable site	Orbit; nonparameningeal head and neck; genitourinary tract excluding kidney, bladder, and prostate; biliary tract.
Unfavorable site	Any site other than favorable.
T1	Tumor confined to anatomic site of origin.
T2	Tumor extension and/or fixation to surrounding tissue.
a	Tumor ≤5 cm in maximum diameter.
b	Tumor >5 cm in maximum diameter.
N0	No clinical regional lymph node involvement.
N1	Clinical regional lymph node involvement.
NX	Regional lymph nodes not examined; no information.
M0	No metastatic disease.
M1	Metastatic disease.

Staging of rhabdomyosarcoma is relatively complex. The process includes the following steps:

Assigning a stage (consider site, size, Surgico-pathologic Group, and presence/absence of metastases).

Assigning a local tumor Surgico-pathologic Group (status postsurgical resection/biopsy, with pathologic assessment of the tumor margin).

Assigning a Risk Group (classified by Stage, Group, and histology).

As noted previously, prognosis for children with rhabdomyosarcoma depends on the primary site, tumor size, Group, and histologic subtype. Favorable prognostic groups were identified in previous Intergroup Rhabdomyosarcoma Study Group (IRSG) studies, and treatment plans were designed on the basis of assignment of patients to different treatment groups according to prognosis. Several years ago, the IRSG merged with the National Wilms Tumor Study Group and with the two large cooperative pediatric cancer treatment groups to form the Children's Oncology Group (COG). New protocols for children with soft tissue sarcoma are developed by the Soft Tissue Sarcoma Committee of the COG (COG-STS).

Current COG-STS protocols for rhabdomyosarcoma use a TNM-based pretreatment staging system that incorporates the Surgico-pathologic Group, primary tumor site, regional lymph node status, and the presence or absence of metastases. This staging system is described in Table 2 below. [3] [4]

Table 2. COG-STS Pretreatment Staging System

Stage	Sites of Primary Tumor	T Stage	Tumor Size	Regional Lymph Nodes	Distant Metastasis
I	Favorable sites	T1 or T2	Any size	N0 or N1 or NX	M0
II	Unfavorable sites	T1 or T2	a, ≤ 5 cm	N0 or NX	M0
III	Unfavorable sites	T1 or T2	a, ≤ 5 cm	N1	M0
b, > 5 cm	N0 or N1 or NX
IV	Any site	T1 or T2	Any size	N0 or N1 or NX	M1
M0 = absence of metastatic spread; M1 = presence of metastatic spread beyond the primary site; N0 = absence of nodal spread; N1 = presence of nodal spread beyond the primary site; X = unknown N status.

The IRSG Protocol I, IRSG Protocol II, and IRSG Protocol III studies prescribed treatment plans based on the Surgico-pathologic Group system. In this system, Groups are defined by the extent of disease and by the extent of initial surgical resection after pathologic review of the tumor specimen(s). The definitions for these Groups are shown in Table 3 below. [5] [6]

Table 3. COG-STS Surgico-pathologic Group System

Group	Definition
I (Approximately 13% of all patients are in this group.)	A localized tumor that is completely removed with pathologically clear margins and no regional lymph node involvement.
II (Approximately 20% of all patients are in this group.)	A localized tumor that is grossly removed with (a) microscopic disease at the margin, (b) involved, grossly removed regional lymph nodes, or (c) both (a) and (b).
III (Approximately 48% of all patients are in this group.)	A localized tumor with gross residual disease after incomplete removal or biopsy only.
IV (Approximately 18% of all patients are in this group.)	Distant metastases are present at diagnosis.

After patients are categorized by Stage and Surgico-pathologic Group, a Risk Group is assigned. This takes into account Stage, Group, and histology. Patients are classified for protocol purposes as having a low risk, intermediate risk, or high risk of disease recurrence. [7] [8] Treatment assignment is based on Risk Group, as shown in Table 4.

Table 4. COG-STS Rhabdomyosarcoma Risk Group Classification

Risk Group	Histology	Stage	Group
Low risk	Embryonal	1	I, II, III
Embryonal	2, 3	I, II
Intermediate risk	Embryonal	2, 3	III
Alveolar	1, 2, 3	I, II, III
High risk	Embryonal or Alveolar	4	IV

Since 2006, patients with undifferentiated sarcomas are treated on the COG-STS protocol for non-rhabdomyosarcomatous soft tissue sarcoma. Refer to the PDQ summary on Childhood Soft Tissue Sarcoma for more information.

References:

Treatment Option Overview

All children with rhabdomyosarcoma require multimodality therapy with systemic chemotherapy, in conjunction with either surgery, radiation therapy (RT), or both modalities for local tumor control. [1] [2] [3] This treatment entails surgical resection, if feasible without major functional/cosmetic impairment, followed by chemotherapy. Some patients with initially unresected tumors may undergo second-look surgery to remove residual tumor. Because rhabdomyosarcoma is sensitive to chemotherapy and RT, surgery is delayed if it will result in disfigurement or if it will interfere with organ function. Chemotherapy and possibly RT are administered in advance with the hope that subsequent surgical resection will be successful without undesirable side effects. RT is indicated for patients with microscopic residual (Group II) disease and gross residual (Group III) disease. It is also recommended for Group I patients with alveolar histology. The discussion of treatment options for children with rhabdomyosarcoma is therefore divided into separate sections describing surgery, chemotherapy, and RT.

The treatment of rhabdomyosarcoma by the Children's Oncology Group and in Europe—as exemplified by trials from the Intergroup Rhabdomyosarcoma Study Group (IRSG), the Children's Oncology Group Soft Tissue Sarcoma Committee (COG-STS), and the International Society of Pediatric Oncology Malignant Mesenchymal Tumor (MMT)—differs in management and overall treatment philosophy. [2] In the MMT trials, a primary objective is to reduce the use of local therapy, relying on initial chemotherapy followed by alternate chemotherapy in the event of a poor response to initial therapy. Local therapy focused on surgical resection is then administered, reserving RT for use only after incomplete resection, documented regional lymph node involvement, or a poor clinical response to initial chemotherapy. This approach is designed to avoid major surgical procedures and especially RT, with their attendant morbidities. Overall survival (OS) is the primary end point, accepting the possibility of an inferior event-free survival (EFS) that might accompany nonaggressive local therapy when compared with more routine and earlier use of surgery and RT. The necessity of second-line salvage therapy for those who relapse is accepted in these trials. Conversely, the primary COG-STS objective has been to employ local therapy soon after initial chemotherapy, using RT for patients with residual disease after initial operation or biopsy only, and for patients with alveolar histology. EFS is the target end point, attempting to avoid relapse and salvage therapy. Results of these two approaches confirm that the IRSG trials resulted in superior EFS and better OS than the most recently published MMT 89 therapy. In some subsets of patients defined by primary site, the survival differences were greater (extremities, nonparameningeal head and neck); in others, the results were largely similar (genitourinary tract). Nevertheless, the overall impression is that survival for most patient subsets is superior with the use of early local therapy, including RT. However, in the MMT trials, some patients are spared aggressive local therapy, which may reduce the potential for morbidities associated with such therapy. [1] [2] [3]

References:

Previously Untreated Childhood Rhabdomyosarcoma

Note: Some citations in the text of this section are followed by a level of evidence. The PDQ Editorial Boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence.)

Surgical Management Treatment Options

The basic principle for the initial surgical treatment of children with rhabdomyosarcoma is complete resection of the primary tumor with a surrounding margin of normal tissue, along with sampling lymph nodes in the draining nodal basin, provided that major functional/cosmetic impairment will not result. [1][Level of evidence: 3iii] Important exceptions to the rule of normal margin exist (e.g., tumors of the orbit and of the genitourinary region). [2] [3] The principle of wide and complete resection of the primary tumor is less applicable to patients known to have metastatic disease at the initial operation, but it is a reasonable concept if easily accomplished. Patients with microscopic residual tumor following their initial excisional procedure appear to have improved prognoses if a second operative procedure to re-excise the primary tumor bed before beginning chemotherapy can achieve complete removal of tumor. [4] There is little evidence that debulking surgery that leaves macroscopic residual tumor improves outcome, compared with biopsy alone. [5][Level of evidence: 2A] Because rhabdomyosarcoma can arise from multiple sites, surgical care must be tailored to the unique aspects of each site. Surgical management of the more common primary sites is provided below.

Head and neck

If the tumors are parameningeal (in the middle ear/mastoid, nasopharynx/nasal cavity, paranasal sinus, parapharyngeal region, or pterygopalatine/infratemporal fossa), a magnetic resonance imaging (MRI) scan with contrast of the primary site and brain should be obtained to check for presence of base-of-skull erosion and possible extension through the dura. If skull erosion and/or transdural extension is equivocal, a computed tomography (CT) scan of the same regions with contrast is indicated. If there is any suspicion of extension down the spinal cord, an MRI scan with contrast of the entire cord should be obtained. The cerebrospinal fluid (CSF) should be examined for malignant cells in all patients with parameningeal tumors. Despite its parameningeal site, middle ear rhabdomyosarcoma has a favorable prognosis. [6]

Rhabdomyosarcomas of the orbit should not undergo exenteration, but biopsy is needed for diagnosis. [7] [8] Biopsy is followed by chemotherapy and RT, with orbital exenteration reserved for the small number of patients with locally persistent or recurrent disease. [9] [10]

For superficial and nonorbital head and neck tumors, wide excision of the primary tumor (when feasible) and ipsilateral neck lymph node sampling of clinically involved nodes are appropriate. [11] Narrow resection margins (<1 mm) are acceptable because of anatomic restrictions. Cosmetic and functional factors should always be considered, but with modern techniques, complete resection in patients with superficial tumors need not be inconsistent with good cosmetic and functional results. Specialized, multidisciplinary surgical teams also have performed resections of anterior skull-based tumors in areas previously considered inaccessible to definitive surgical management, including the nasal areas, paranasal sinuses, and temporal fossa. These procedures should only be considered, however, in children with recurrent locoregional disease or residual disease following chemotherapy and radiation therapy (RT). For patients with head and neck primary tumors that are considered unresectable, chemotherapy and RT are the mainstay of primary management. [6] [9] [12] [13] [14] [15]

Extremity sites

The definitive surgical procedure involves wide local excision with en bloc removal of a cuff of normal tissue. [2] Primary re-excision may be appropriate in patients whose initial surgical procedure leaves microscopic residual disease that is resectable by a second procedure. [4] Because of the significant incidence of nodal spread for extremity primary tumors (often without clinical evidence of involvement) and because of the prognostic and therapeutic implications of nodal involvement, extensive pretreatment assessment for regional nodal involvement is warranted. [16] [17] [18] [19] The Children's Oncology Group Soft Tissue Sarcoma Committee (COG-STS) recommends systematic aggressive axillary node sampling for patients with upper-extremity primary tumors, even with clinically and radiographically negative nodes. The COG-STS also recommends inguinal and femoral triangle node sampling for patients with lower-extremity primary tumors, even with clinically and radiographically negative nodes. If clinically positive nodes are present, biopsy of more proximal nodes is recommended prior to sampling of the involved nodal region. Sentinel lymph node (SLN) mapping is employed at some centers to identify the regional nodes that are the most likely to be involved. The contribution of SLN mapping is not yet clearly defined in pediatric patients. [19] [20] [21] [22]

Truncal sites

The surgical management of patients with lesions of the chest wall or abdominal wall should follow the same guidelines as those used for lesions of the extremities (i.e., wide local excision and an attempt to achieve negative microscopic margins). These resections may require use of prosthetic materials. Very large truncal masses should be biopsied before chemotherapy, with or without RT, is administered and should be removed secondarily to achieve negative margins followed by reconstruction. Most patients who present with large tumors in these sites have localized disease that becomes amenable to complete resection with negative margins after preoperative therapy and is therefore associated with excellent long-term survival. [23] [24] [25] [26]

Intrathoracic or intraabdominal sarcomas may not be resectable at diagnosis because of the massive size of the tumor and extension into vital organs or vessels. [27] For patients with initially unresectable retroperitoneal/pelvic tumors, complete surgical removal following chemotherapy offers a significant survival advantage (73% vs. 34% to 44% without removal). [27]

With rhabdomyosarcoma of the biliary tree, total resection is rarely feasible. Outcome is good despite residual disease after surgery. External biliary drains significantly increase the risk of postoperative infectious complications. Thus, external biliary drainage is not warranted. [28]

Patients with rhabdomyosarcoma arising from tissue around the perineum or anus usually have advanced disease. These patients have a high likelihood of regional lymph node involvement, and about half of the tumors have alveolar histology. The current recommendation is to sample the lymph nodes. When feasible, without unacceptable morbidity, removing all gross tumor before chemotherapy is begun improves the likelihood of cure. In Intergroup Rhabdomyosarcoma Study Group (IRSG) Protocols I through IV, the overall survival (OS) after aggressive therapy for tumors in this location was 49%. [29]

Genitourinary system

Primary sites for childhood rhabdomyosarcoma within the genitourinary system include the paratesticular area, bladder, prostate, kidney, vagina, uterus, and vulva. Specific considerations for the surgical management of tumors arising at each of these sites are discussed in the paragraphs below.

Lesions occurring adjacent to the testis or spermatic cord and up to the internal inguinal ring should be removed by orchiectomy with resection of the entire spermatic cord, utilizing an inguinal incision with proximal vascular control (i.e., radical orchiectomy). [30] Resection of hemiscrotal skin is required when there is tumor fixation or invasion, or when a previous transscrotal biopsy has been performed. Paratesticular tumors have been found to have a relatively high incidence of lymphatic spread (26% in IRSG Protocol I and IRSG Protocol II ), [16] and all patients with paratesticular primary tumors should have thin-cut abdominal and pelvic CT scans with contrast to evaluate nodal involvement. For patients who are younger than 10 years and who have Group I disease, and whose CT scans show no evidence of lymph node enlargement, retroperitoneal node biopsy/sampling is unnecessary, but a repeat CT scan every 3 months is recommended. [31] [32] For patients with suggestive or positive CT scans, retroperitoneal lymph node sampling (but not formal node dissection) is recommended, and treatment is based on the findings of this procedure. [3] [33] [34] A staging ipsilateral retroperitoneal lymph node dissection is currently required for all children 10 years and older with paratesticular rhabdomyosarcoma on IRSG and COG-STS studies. Node dissection is not routine in Europe for adolescents with resected paratesticular rhabdomyosarcoma. European investigators tend to rely on radiographic rather than surgico-pathologic assessment of retroperitoneal lymph node involvement. [30] [31] It appears, however, that the ability of the CT scan to predict the presence of lymph node involvement needs further study. [35] For patients with incompletely removed paratesticular tumors which require radiation therapy, temporarily repositioning the contralateral testicle into the adjacent thigh prior to scrotal radiation therapy may preserve hormone production. [36][Level of evidence: 3iiiC]

Bladder salvage is a major goal of therapy for patients with tumors arising in the prostate and bladder. An important review providing information about historical, current, and future treatment approaches for prostate and bladder rhabdomyosarcomas has been published. [37] In rare cases, the tumor is confined to the dome of the bladder and can be completely resected. Otherwise, to preserve a functional bladder in patients with gross residual disease, chemotherapy and RT have been used to reduce tumor bulk, [38] [39] followed, when necessary, by a more limited surgical procedure such as partial cystectomy. [40] Early experience with this approach was disappointing, with only 20% to 40% of patients with bladder/prostate tumors remaining alive and with functional bladders 3 years following diagnosis (3-year OS was 70% in IRSG Protocol II). [40] [41] The more recent experience from IRSG Protocol III and IRSG Protocol IV, which used more intensive chemotherapy and RT, showed 55% of patients alive with functional bladders at 3 years postdiagnosis, with 3-year OS exceeding 80%. [39] [42] [43] Thus, this approach to therapy remains generally accepted, with the belief that more effective chemotherapy and RT will continue to increase the frequency of bladder salvage. The initial surgical procedure in most patients consists of a biopsy, which often can be performed using ultrasound guidance or cystoscopy, or by a direct-vision transanal route. For patients with biopsy-proven, residual malignant tumor following chemotherapy and RT, appropriate surgical management may include partial cystectomy, prostatectomy, or exenteration (usually approached anteriorly with preservation of the rectum). Very few studies have objective long-term assessments of bladder function, and urodynamic studies are important to obtain accurate evaluation of bladder function. [44]

In patients who have been treated with chemotherapy and RT for rhabdomyosarcoma arising in the bladder/prostate region, the presence of well-differentiated rhabdomyoblasts in surgical specimens or biopsies obtained after treatment does not appear to be associated with a high risk of recurrence and is not an indication for a surgical procedure such as total cystectomy. [42] [45] [46] One study suggested that in patients with residual bladder tumors with histologic evidence of maturation, additional courses of chemotherapy should be given before cystectomy is considered. [42] Surgery should be considered only if malignant tumor cells do not disappear over time following initial chemotherapy and RT. Because of very limited data, it is unclear whether this situation is analogous for patients with rhabdomyosarcoma arising in other parts of the body.

For patients with genitourinary primary tumors of the vagina/vulva/uterus, the initial surgical procedure is usually a transvaginal biopsy. Initial radical surgery is not indicated for rhabdomyosarcoma of the vagina/vulva/uterus. [3] Conservative surgical intervention for vaginal rhabdomyosarcoma, with primary chemotherapy and adjunctive radiation when necessary, appears to result in excellent disease-free survival. [47] Because of the smaller number of patients with uterine rhabdomyosarcoma, it is difficult to make a definitive treatment decision, but chemotherapy or RT is also effective. [47] [48] Exenteration is usually not required for primary tumors at these sites, but if needed it may be done, with rectal preservation possible in most cases.

Unusual primary sites

Rhabdomyosarcoma occasionally arises in sites other than those discussed above. Patients with localized primary rhabdomyosarcoma of the brain can occasionally be cured using a combination of tumor excision, RT, and chemotherapy. [49][Level of evidence: 3iiiDiii]

Patients with laryngeal rhabdomyosarcoma will usually be treated with chemotherapy and RT after biopsy in an attempt to preserve the larynx. [50]

Patients with diaphragm tumors often have locally advanced disease that is not grossly resectable initially because of fixation to adjacent vital structures such as the lung, great vessels, pericardium, and/or liver. In such circumstances, chemotherapy should be initiated after diagnostic biopsy, with the intent to try to remove residual tumor at a later date. [51]

The kidney is occasionally the primary site for rhabdomyosarcoma or undifferentiated sarcoma; ten cases have been identified from among 5,746 eligible patients (0.17%) enrolled on IRSG protocols. The tumors were large (median diameter, 12 cm) and anaplasia was present in 60% of patients. Six patients with grossly complete tumor removal at diagnosis survived; the four with incomplete removal and gross or metastatic disease died of infection or metastatic tumor. [52]

Two well-documented cases of primary ovarian rhabdomyosarcoma (one stage III and one stage IV) have been reported to supplement the eight previously reported patients. These two cases were alive at 20 and 8 months after diagnosis. Six of the previously reported eight patients had died of their disease. [53][Level of evidence: 3iiiDiii] Treatment with combination chemotherapy followed by removal of the residual mass or masses can sometimes be successful. [53]

Metastatic sites

Primary resection of metastatic disease is rarely indicated. [54] Persistent metastatic disease in the lung following RT and chemotherapy should be resected when possible to render patients disease free, provided that adequate pulmonary function can be preserved.

Chemotherapy Treatment Options

All children with rhabdomyosarcoma should receive chemotherapy. The intensity and duration of the chemotherapy are dependent on the Risk Group assignment. [55] See Table 4 in the Staging Information section for more information on Risk Groups.

Low-risk patients

Standard treatment options

Low-risk patients have a localized (nonmetastatic) embryonal histology tumor in a favorable site, or a localized embryonal rhabdomyosarcoma in an unfavorable site that has been grossly resected (Surgico-pathologic Groups I and II). (See Table 3 in the Staging Information section of this summary.) Certain subgroups of low-risk patients have achieved survival rates higher than 90% by undergoing two-drug chemotherapy with vincristine and dactinomycin (VA) plus RT for residual tumor. See Table 5 below.

Table 5. Characteristics of Low-Risk Patients with High Survival Rates Using Two-Drug Therapy with VA ± RT

Site	Size	Group	Nodes
Favorable	Any	I, IIA	N0
Orbital	Any	I, III	N0
Unfavorable	≤ 5 cm	I, IIA	N0

Other subgroups of low-risk patients have achieved survival rates higher than 90% by undergoing three-drug chemotherapy with VA and cyclophosphamide (VAC) plus RT for residual tumor. The total cyclophosphamide dose used in recently completed COG protocols was 28.6 g/M². See Table 6 below:

Table 6. Characteristics of Low-Risk Patients with High Survival Rates Using Three-Drug Therapy with VAC ± RT

Site	Size	Group	Nodes
Favorable (orbital or non-orbital)	Any	IIB, IIC, III	N0, N1
Unfavorable	≤ 5 cm	II	N0
Unfavorable	> 5 cm	I, II	N0, N1

Treatment options under clinical evaluation

The following are examples of national and/or institutional clinical trials that are currently being conducted. Information about ongoing clinical trials is available from the NCI Web site.

COG-ARST0331: The current COG low-risk embryonal rhabdomyosarcoma regimen includes four initial courses of cyclophosphamide given every 3 weeks, using a historically modest dose of 1.2 g/M²/per course (total dose, 4.8 g/M²), with vincristine, and dactinomycin, followed by RT at week 13 for patients with microscopic, locoregional, or gross residual tumor. Subsequently, patients receive 4 or 12 further courses of VA, depending on the tumor stage and Group. The protocol is designed to increase efficacy of treatment while shortening the duration of treatment for a subset of low-risk patients and reducing both acute toxicity (myelosuppression) and long-term toxicity (impaired fertility) from cyclophosphamide.

Intermediate-risk patients

Standard treatment options

Intermediate-risk patients have survival rates ranging from 55% to 70%. This category includes patients with embryonal rhabdomyosarcoma at unfavorable sites who have gross residual disease (i.e., group III), and patients with nonmetastatic alveolar rhabdomyosarcoma at any site. For intermediate-risk patients, vincristine, dactinomycin, and cyclophosphamide (VAC) is the standard chemotherapy treatment. [56] [57] [58] The IRSG Protocol IV randomly assigned patients to receive either standard VAC therapy or one of two other chemotherapy regimens. One regimen combined vincristine and dactinomycin with ifosfamide (VAI), [59] based on the activity of ifosfamide against rhabdomyosarcoma. [60] [61] The other regimen combined vincristine with ifosfamide and etoposide. [62] The combination of ifosfamide and etoposide had previously demonstrated substantial activity against rhabdomyosarcoma in phase II trials. [63] In the IRSG Protocol IV, there was no difference in outcome between these three treatments, confirming that VAC remains the standard chemotherapy combination for children with intermediate-prognosis rhabdomyosarcoma. [34]
A comparison of survival in patients with tumors of embryonal histology treated on IRSG Protocol IV (who received higher doses of alkylating agents) compared with similar patients treated on IRSG Protocol III (who received lower doses of alkylating agents) suggested a benefit with the use of higher doses of cyclophosphamide for certain groups of intermediate-risk patients. These included patients with tumors at favorable sites and positive lymph nodes, patients with gross residual disease, or patients with tumors at unfavorable sites who underwent grossly complete resections, but not patients with unresected embryonal rhabdomyosarcoma at unfavorable sites. [64] For other groups of intermediate-risk patients, an intensification of cyclophosphamide was feasible but did not improve outcome. [65]

The COG has also evaluated whether the addition of topotecan and cyclophosphamide to standard VAC therapy improves outcome for children with intermediate-risk rhabdomyosarcoma. Topotecan was prioritized for evaluation on the basis of its preclinical activity in rhabdomyosarcoma xenograft models as well as its single agent activity in previously untreated children with rhabdomyosarcoma, particularly those with alveolar rhabdomyosarcoma. [66] [67] Furthermore, the combination of cyclophosphamide and topotecan demonstrated substantial activity both in the recurrent disease setting and in newly diagnosed patients with metastatic disease. [68] [69] The recent COG clinical trial for newly diagnosed patients with intermediate-risk disease randomly assigned patients to receive either VAC therapy or VAC therapy with additional courses of topotecan and cyclophosphamide. However, patients who received topotecan and cyclophosphamide fared no better than those treated with VAC alone. [70]

In a limited-institution pilot study, a combination of vincristine/doxorubicin/cyclophosphamide (VDC) alternating with ifosfamide/etoposide (IE) was used to treat patients with intermediate-risk rhabdomyosarcoma. The relative efficacy of this approach versus the standard approach would require further investigation. [71][Level of evidence: 3iiiA]

Treatment options under clinical evaluation

The following are examples of national and/or institutional clinical trials that are currently being conducted. Information about ongoing clinical trials is available from the NCI Web site.

COG-ARST0531: The new COG intermediate-risk rhabdomyosarcoma protocol will compare standard VAC chemotherapy versus VAC alternating with vincristine and irinotecan (VI). RT will commence at week 4 in conjunction with VI to determine the potential benefit of early local therapy in this group of patients.

High-risk patients

Standard treatment options

High-risk patients have metastatic disease in one or more sites at diagnosis (stage IV). These patients continue to have a relatively poor prognosis (5-year survival rate of 50% or lower) with current therapy, and new approaches to treatment are needed to improve survival in this group. [58] [72] [73] In a pooled analysis of high-risk rhabdomyosarcoma patients treated with multiagent chemotherapy (all chemotherapy regimens used a cyclophosphamide or ifosfamide plus dactinomycin and vincristine-based backbone with variation as to the use of additional chemotherapy agents) followed by local therapy (surgery with or without RT) within 3 to 5 months of starting chemotherapy, adverse prognostic factors in patients presenting with metastatic disease included: age younger than 1 year or age 10 years or older, unfavorable primary site, bone and/or bone marrow involvement, and three or more metastatic sites. The event-free survival (EFS) rate at 3 years was 50% for patients without any of these adverse prognostic factors. The EFS rates were 42% for patients with one adverse prognostic factor, 18% for patients with two adverse prognostic factors, 12% for patients three adverse prognostic factors, and 5% for patients with four adverse prognostic factors. [74][Level of evidence: 3iiiA]
The standard systemic therapy for children with metastatic rhabdomyosarcoma is the three-drug combination of VAC. Despite many clinical trials attempting to improve outcome by adding additional agents to standard VAC chemotherapy (or substituting new agents for one or more components of VAC chemotherapy), to date, no chemotherapy regimens have been shown to be more effective than VAC. For example, in the IRSG Protocol IV, three combinations of drug pairs were studied in an up-front window: IE, vincristine/melphalan (VM), [75] and ifosfamide/doxorubicin (ID). [76] These patients received VAC after the up-front window agents were evaluated at weeks 6 and 12. OS for patients treated with IE and ID was comparable (31% and 34%, respectively) and better than those treated with VM (22%). [76] However, results with VAC chemotherapy for stage IV rhabdomyosarcoma in the North American experience are similar. Results from a phase II window trial of patients with metastatic disease at presentation and treated with topotecan and cyclophosphamide showed activity for this two-drug combination, but survival was not different from that seen with previous regimens. [68] [69] An up-front window trial of topotecan in previously untreated children and adolescents with metastatic rhabdomyosarcoma gave similar results. [67] Irinotecan and irinotecan with vincristine [77] have also been evaluated as up-front windows by the COG-STS; the response rates were better when irinotecan was administered with vincristine than without it, but again, survival in a preliminary analysis was not improved over prior experience. [77] In a French study, 20 patients with metastatic disease at diagnosis received window therapy with doxorubicin for two courses. Thirteen of 20 patients responded to therapy, and 4 patients had progressive disease. [78]

Alternative Therapies

High-dose chemotherapy with stem cell rescue has been evaluated in a limited number of patients with rhabdomyosarcoma [79] [80] [81] [82] [83][Level of evidence: 3iiiA] but has failed to improve the prognosis of patients with high-risk rhabdomyosarcoma.

Treatment options under clinical evaluation

The following are examples of national and/or institutional clinical trials that are currently being conducted. Information about ongoing clinical trials is available from the NCI Web site.

COG-ARST0431: The COG high-risk trial is closed and results are pending. This trial was for all patients with rhabdomyosarcoma and metastatic disease, regardless of age and histology. The trial evaluated an intensified treatment regimen that began with two courses of vincristine and irinotecan in conjunction with RT. Continuation therapy included cycles of vincristine/doxorubicin/cyclophosphamide and IE using interval dose compression. The regimen also included VAC pulses. The feasibility and toxicity of combining VI with RT was also evaluated.

The NCI's intramural Pediatric Oncology Branch conducted a study of consolidative immunotherapy incorporating T-cell reconstitution followed by a dendritic-cell plus tumor-peptide vaccine that could be given with little toxicity to patients with translocation-positive metastatic or recurrent Ewing sarcoma and alveolar rhabdomyosarcoma. [84][Level of evidence: 3iiiA] This treatment approach is still under clinical evaluation.

Radiation Therapy Management Options

RT is an effective method for achieving local control of tumor for patients with microscopic or gross residual disease following biopsy, initial surgical resection, or chemotherapy. Patients with completely resected tumors (Group I) of embryonal histology do well without RT, [56] [57] but RT benefits patients with group I tumors with alveolar or undifferentiated histology. [85] A review of European trials conducted by the Cooperative Soft Tissue Sarcoma Study Group between 1981 and 1998 in which RT was omitted for some Group II patients demonstrated a benefit to using RT as a component of local tumor control for all Group II patient subsets (defined by tumor histology, tumor size, and tumor site). [86] Local failure is the predominant type of relapse for patients with Group III disease. Patients with tumor-involved regional lymph nodes at diagnosis have a higher risk of local and distant failure compared with patients whose lymph nodes are negative. [87] As with the surgical management of patients with rhabdomyosarcoma, recommendations for RT depend on the site of primary tumor and on the amount of residual disease, if any, following surgical resection. For patients with head and neck rhabdomyosarcoma, four studies reported excellent local control in patients treated with intensity-modulated radiation therapy (IMRT) or fractionated stereotactic RT and chemotherapy over a 4-year period. Further study is needed, but the use of IMRT and chemotherapy in patients with head and neck rhabdomyosarcoma may result in less severe late effects. [88] [89] [90] [91] [92][Level of evidence: 3iiiA]

For optimal care of pediatric patients undergoing radiation treatments, it is imperative to have a radiation oncologist, radiation technicians, and nurses who are experienced in treating children. An anesthesiologist may be necessary to help sedate and immobilize young patients. The facility should be equipped with a linear accelerator and have the capabilities to administer electron beam therapy. Computerized treatment planning with a three-dimensional planning system should be available. Techniques to deliver radiation specifically to the tumor while sparing normal tissue (e.g., conformal radiation, IMRT, proton-beam therapy, or brachytherapy) should be considered (see below). [93] [94] [95]

Standard treatment options

The RT dose depends predominantly on the amount of residual disease, if any, following the primary surgical resection. In general, patients with microscopic residual disease (Group II) receive RT to approximately 41 Gy, [85] [96] though doses from 30 Gy to 40 Gy may be adequate in patients receiving effective multiagent chemotherapy. [97] IRSG Protocol II patients with gross residual disease (Group III) who received 40 Gy to more than 50 Gy had locoregional relapse rates greater than 30%; higher doses of radiation (>60 Gy) have been associated with unacceptable long-term toxic effects. [98] [99] Group III patients on the IRSG Protocol IV standard treatment arm received 50.4 Gy. [100]

The treated volume should be determined by the extent of tumor at diagnosis prior to surgical resection and prior to chemotherapy. A margin of 2 cm is generally used, including clinically involved regional lymph nodes. [85] While the volume irradiated may be modified on the basis of guidelines for normal tissue tolerance, gross residual disease at the time of radiation should receive full-dose treatment.

The timing of RT generally allows for chemotherapy to be given for 1 to 3 months before RT is initiated. In recent COG protocols, patients with parameningeal disease who have evidence of intracranial extension start radiation therapy at the beginning of treatment. [57] [101] [102] A prospective trial of 26 patients with group III parameningeal rhabdomyosarcoma achieved good local control and survival with RT administered at the conventional time. [103] RT is usually given for 5 to 6 weeks (e.g., 1.8 Gy per day for 28 treatment days), during which time chemotherapy is usually modified to avoid the radiosensitizing agents dactinomycin and doxorubicin.

The IRSG conducted a randomized study within the IRSG Protocol IV protocol and showed that giving RT twice a day, 6 to 8 hours apart, at 1.1 Gy per dose (hyperfractionated schedule), 5 days per week was feasible but difficult to accomplish in small children who required sedation twice daily. Patients with localized, gross residual tumors were randomly assigned to receive conventional RT (50.4 Gy vs. 59.4 Gy) given by the twice-daily hyperfractionated schedule. There was no demonstrated advantage in terms of local control. [104] Therefore, conventional RT remains the standard for treating patients with rhabdomyosarcoma and gross residual disease. [34]

Among the modifications of RT for specific primary sites recommended for IRSG Protocol IV patients were the following: [34] [100]

For patients with orbital tumors, precautions should be taken to limit the dose to the lens, cornea, lacrimal gland, and optic chiasm.

Patients with bladder/prostate primary tumors who present with a large pelvic mass resulting from a distended bladder caused by outlet obstruction receive treatment to a volume defined by imaging studies following initial chemotherapy.

Girls with genitourinary primary tumors should have their ovaries shielded or possibly moved, in an effort to preserve fertility when they are receiving RT to the lower abdomen and pelvis. In the COG-ARST0331 study, there was an unacceptably high rate of local recurrence in girls with Group III vaginal tumors who did not receive RT. The COG-STS is now recommending that RT be administered to subsequent patients with residual viable vaginal tumor, beginning at week 24.

Patients with parameningeal disease with intracranial extension in contiguity with the primary tumor, and/or cranial base bone erosion, and/or cranial nerve palsy do not require whole-brain irradiation or intrathecal therapy, unless tumor cells are present in the CSF at diagnosis. [101] Patients should receive RT to the site of primary tumor with a 2-cm margin to include the meninges adjacent to the primary tumor [102] and the region of intracranial extension, if present, again with a 2-cm margin. Patients with intracranial extension should begin receiving RT within 2 weeks after diagnosis. [102]

Rarely, children can present with tumor cells in the CSF, have other evidence of diffuse meningeal disease, and/or have multiple intraparenchymal brain metastases from a distant primary tumor. They should be treated with central nervous system-directed irradiation in addition to chemotherapy/RT for the primary tumor. Spinal irradiation may also be indicated.

Very young children (age < 36months or younger) diagnosed with rhabdomyosarcoma pose a therapeutic challenge because of their increased risk for treatment-related morbidity. Recent experience [105] supports using a somewhat reduced dose of RT in settings where surgery alone is insufficient to provide a high likelihood of local control. For children with initially unresectable tumors, delayed gross total resection followed by 36 Gy beam RT provides an excellent likelihood of local control. For infants with unresectable tumors, higher doses of RT remain appropriate. Radiation techniques are designed to maximize normal tissue sparing, and should include conformal approaches, often with intensity modulated techniques.

Treatment options under clinical evaluation

The following are examples of national and/or institutional clinical trials involving RT that are currently being conducted. Information about ongoing clinical trials is available from the NCI Web site.

Brachytherapy, using either intracavitary or interstitial implants, is another method of local control and has been used in selected situations for children with rhabdomyosarcoma, especially those with primary tumors at vaginal or vulvar sites, [106] [107] [108] [109] [110] and selected bladder/prostate sites. [92] In small series from one or two institutions, this treatment approach was associated with a high survival rate and with retention of a functional organ or tissue in most patients. [107] [111] Other sites, especially head and neck, have also been treated with brachytherapy. [112] Patients with initial Group III disease who later have microscopic residual disease after chemotherapy with or without delayed surgery are likely to achieve local control with RT at doses of 40 Gy or more. [113]

Current Clinical Trials

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with previously untreated childhood rhabdomyosarcoma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

References:

Recurrent Childhood Rhabdomyosarcoma

Although patients with recurrent or progressive rhabdomyosarcoma sometimes achieve complete remission with secondary therapy, the long-term prognosis is usually poor. [1] [2] The prognosis is most favorable (50% to 70% 5-year survival rates) for children who initially present with stage I or Group I disease and embryonal histology, and who have smaller tumors or present with a local or regional recurrence. [1] [2] [3] The small number of children with botryoid histology who relapse have a similarly favorable prognosis. [1] Most other children who relapse have an extremely poor prognosis. [1] A retrospective review of rhabdomyosarcoma patients from German soft tissue sarcoma trials identified time to recurrence as an important independent prognostic factor. Shorter time to recurrence was associated with higher risk of mortality from recurrent rhabdomyosarcoma. [4][Level of evidence: 3iiB]

The selection of further treatment depends on many factors, including the site(s) of recurrence, previous treatment, and individual patient considerations. Treatment for local or regional recurrence may include wide local excision or aggressive surgical removal of tumor, particularly in the absence of widespread bony metastases. [5] Some survivors have also been reported after surgical removal of only one or a few metastases in the lung. [5] RT should be considered for patients who have not already received RT in the area of recurrence, or rarely for those who have received RT but for whom surgical excision is not possible. Previously unused, active, single agents or combinations of drugs may also enhance the likelihood of disease control.

The following standard chemotherapy regimens have been used to treat recurrent rhabdomyosarcoma:

Carboplatin/etoposide. [6]

Ifosfamide, carboplatin, and etoposide. [7] [8]

Cyclophosphamide/topotecan. [9]

Irinotecan with or without vincristine. [10] [11] [12] [13]

Treatment options under clinical evaluation for recurrent rhabdomyosarcoma:

On the basis of historical relapse data from the Intergroup Rhabdomyosarcoma Study Group, [1] the Children’s Oncology Group is currently analyzing a risk-based approach to salvage treatment for rhabdomyosarcoma patients experiencing a first relapse or progressive disease. Relapsed patients with a favorable prognosis received doxorubicin/cyclophosphamide alternating with ifosfamide/etoposide. For patients with a poor prognosis and measurable disease, a randomized study of two administration schedules of irinotecan (five daily doses for 1 week vs. five daily doses for 2 weeks) in combination with vincristine preceded treatment with doxorubicin/cyclophosphamide alternating with ifosfamide/etoposide. Poor-prognosis patients without measurable disease received doxorubicin/cyclophosphamide with the addition of an investigational agent, tirapazamine, alternating with ifosfamide/etoposide.

Intensive chemotherapy followed by autologous bone marrow transplantation. Very intensive chemotherapy followed by autologous bone marrow reinfusion is also under investigation for patients with recurrent rhabdomyosarcoma. A review of the published data did not determine a significant benefit for patients who underwent this salvage treatment approach. [14]

Single-agent vinorelbine. [15]

Combination vinorelbine and low-dose cyclophosphamide. [16]

Rapamycin. [17]

Topotecan, vincristine, and doxorubicin. [18][Level of evidence: 3iiiDiii]

New agents under clinical evaluation in phase I and phase II trials should be considered for relapsed patients.

Current Clinical Trials

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with recurrent childhood rhabdomyosarcoma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

References:

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Changes to This Summary (12/10/2009)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

Cellular Classification

Revised text to state that alveolar cases associated with the PAX7 gene, with or without metastases, appear to occur in patients at a younger age (cited Krsková et al. as reference 14).

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- Treatment options for adult cancers.
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- Treatment options for childhood cancers.
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Date last modified: 2009-12-10

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