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Childhood Rhabdomyosarcoma Treatment (PDQ®): Treatment - Health Professional Information [NCI]
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Childhood Rhabdomyosarcoma Treatment
General Information
Fortunately, cancer in children and adolescents is rare, although the overall incidence of childhood cancer has been slowly increasing since 1975.[1] 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.[2] 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.
Dramatic improvements in survival have been achieved for children and adolescents with cancer.[1] Between 1975 and 2002, childhood cancer mortality has decreased by more than 50%. For rhabdomyosarcoma, the 5-year survival rate has increased over the same time from 53% to 65% for children younger than 15 years and from 30% to 47% for adolescents aged 15 to 19 years.[1] 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.)
Incidence and Epidemiology
Childhood rhabdomyosarcoma, a soft tissue malignant tumor of mesenchymal 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.[3,4] The incidence is 4.5 per 1 million children and 50% of cases are seen in the first decade of life.[5]
Incidence may depend on the histologic subtype of rhabdomyosarcoma:
- Embryonal: Patients with embryonal rhabdomyosarcoma are predominantly male (M:F = 1.5) and peaks in the 0 to 4 year age group at approximately 4 cases per 1 million children, with a lower rate in adolescents, approximately 1.5 cases per 1 million adolescents.[5]
- Alveolar: The incidence of alveolar rhabdomyosarcoma does not vary by gender and is constant from ages 0 to 19 years at approximately 1 case per 1 million children and adolescents.[5]
- Undifferentiated sarcoma: Compared with older patients, infants younger than 1 year have a higher incidence of undifferentiated sarcoma and tumors of the trunk and abdomen and a lower incidence of parameningeal tumors.[6]
The most common primary sites for rhabdomyosarcoma are the head, the genitourinary tract, and the extremities.[7,8] Within extremity tumors, tumors of the hand and foot occur more often in older patients and have an alveolar histology; these tumors also have a higher rate of metastatic spread.[9] 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.[10] For patients with embryonal tumors, high birth weight and large size for gestational age are associated with an increased incidence of rhabdomyosarcoma.[11] Genetic conditions associated with rhabdomyosarcoma include Li-Fraumeni cancer susceptibility syndrome (with germline p53 mutations),[12,13,14] neurofibromatosis type I,[15] Costello syndrome (with germline HRAS mutations),[16,17,18] Beckwith-Wiedemann syndrome (with which Wilms tumor and hepatoblastoma are more commonly associated),[19,20] and Noonan syndrome.[21]
Prognostic Factors
The prognosis for a child or adolescent with rhabdomyosarcoma is related to the age of the patient, site of origin, tumor size (widest diameter), 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 in selected cases,[7,8,22,23,24,25,26,27,28]; [29][Level of evidence: 3iiiA] as well as unique biological characteristics of rhabdomyosarcoma tumor cells.[30] It is unclear whether response to induction chemotherapy, as judged by anatomic imaging, correlates with the likelihood of survival in patients with rhabdomyosarcoma, as one study found an association and another study did not.[31,32][Level of evidence: 3iiA]
Rhabdomyosarcoma is usually curable in most children with localized disease who receive combined-modality therapy, with more than 70% surviving 5 years after diagnosis.[7,8,33] 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.[34]
Examples of both clinical and biological factors with proven or possible prognostic significance include the following:
-
Age: Children aged 1 to 9 years have the best prognosis, while those younger and older fare less well. In recent Intergroup Rhabdomyosarcoma Study Group (IRSG) trials, 5-year failure-free survival (FFS) was 57% for patients younger than 1 year, 81% for patients aged 1 to 9 years, and 68% for patients older than 10 years. Five-year survival for these groups was 76%, 87%, and 76%, respectively.[6] Historical data show that adults fare worse than children (5-year overall survival (OS) rates, 27% ± 1.4% and 61% ± 1.4%, respectively; P < .0001).[35]
- Infants may do poorly because their bone marrow is less tolerant of chemotherapy doses that older children can receive, thus infants are relatively underdosed compared with older patients. In addition, infants younger than 1 year may be less likely to receive radiation therapy for local control, because of concern about the high incidence of complications in this age group. [23,33,36] Thus, they have a relatively high rate of local failure.
- In older children, vincristine and dactinomycin have upper dosage limits based on body surface area, and these patients may also require reduced vincristine doses because of neurotoxicity.[23,37]
- Adolescents: A report from the AIEOP (Italian) Soft Tissue Sarcoma Committee suggests that adolescents may have more frequent unfavorable tumor characteristics, including alveolar histology, regional lymph node involvement, and metastatic disease involvement, accounting for their poor prognosis. This study also found that 5-year OS and progression-free survival rates were somewhat lower in adolescents compared with children, but the differences among age groups younger than 1 year and aged 10 to 19 years at diagnosis were significantly worse than those in the group aged 1 to 9 years.[38]
-
Site of origin: Primary sites with more favorable prognoses include the following:[7,8,39,40]
- Orbit and nonparameningeal head and neck.
- Paratestis, vulva, vagina, uterus (nonbladder, nonprostate genitourinary tract).
- Biliary tract.
-
Diameter of the tumor: Patients with smaller tumors (≤5 cm) have improved survival compared with children with larger tumors.[7] Both tumor volume and maximum tumor diameter are associated with outcome.[32][Level of evidence: 3iiA]
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).[41] This was not confirmed by a Children's Oncology Group study of patients with intermediate-risk rhabdomyosarcoma.[42] This relationship requires prospective study to determine the therapeutic implications of the observation.
-
Metastases and regional lymph node involvement: Children with metastatic disease at diagnosis have the worst prognosis. The prognostic significance of metastatic disease is modified by tumor histology (embryonal is more favorable than alveolar), the site of metastatic disease, and the number of metastatic sites.[24,43,44] 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.[45]
Patients with otherwise localized disease but with proven regional lymph node involvement have a worse prognosis than do patients without regional nodal involvement.[27,28]
- Resectability: The extent of disease following the primary surgical procedure (i.e., the Surgical-pathologic Group, formerly called the Clinical Group) is also correlated with outcome.[7] In the IRS-III study, patients with localized, gross residual disease after initial surgery (Surgical-pathologic Group III) had a 5-year survival rate of approximately 70% compared with a more than 90% 5-year survival rate for patients without residual tumor after surgery (Group I) and an approximately 80% 5-year survival rate for patients with microscopic residual tumor following surgery (Group II).[7,22] Regardless, outcome is primarily related to the use of multimodality therapy; all patients require chemotherapy and at least 85% also benefit from radiation therapy, with favorable outcome even for those patients with nonresectable disease. In IRS-IV, the Group III patients with unresectable disease who were treated with chemotherapy and radiation therapy had a 5-year FFS of about 75%.[46]
-
Histopathologic subtype: 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 at diagnosis), and is generally associated with a worse outcome than in similar patients with embryonal rhabdomyosarcoma. In the IRS-I and IRS-II studies, the alveolar subtype was associated with a less favorable outcome even in patients whose primary tumor was completely resected (Group I).[39] A statistically significant difference in 5-year survival by histopathologic subtype (82% for embryonal rhabdomyosarcoma vs. 65% for alveolar rhabdomyosarcoma), was not noted when 1,258 IRS-III and IRS-IV patients with rhabdomyosarcoma were analyzed.[47] In the IRS-III study, outcome for patients with Group I alveolar subtype tumors was similar to that for other patients with Group I tumors, but the alveolar patients received more intensive therapy.[7]
Patients with alveolar rhabdomyosarcoma who have regional lymph node involvement have significantly worse outcomes (5-year FFS, 43%) than patients who do not have regional lymph node involvement (5-year FFS, 73%).[48]
Anaplasia has been observed in 13% of cases of rhabdomyosarcoma and its presence may adversely influence clinical outcome in patients with intermediate-risk embryonal rhabdomyosarcoma. However, anaplasia was not shown to be an independent prognostic variable in a multivariate analysis (P = .081).[49]
- Biological characteristics: Refer to the Molecular Classification section of this summary for more information.
Adult patients with rhabdomyosarcoma have a high incidence of pleomorphic histology (19%). Pleomorphic histology is extremely rare in children and young adults with rhabdomyosarcoma. Adults also have a higher incidence of tumors in unfavorable sites compared with children.[35]
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 radiation therapy 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]
For current trials developed by the Soft Tissue Sarcoma Committee of the Children's Oncology Group, to be designated as alveolar, the tumor must have greater than 50% alveolar elements; if the alveolar component is 50% or less, the tumor is considered embryonal. In some earlier studies (the D series, 1997–2005), any alveolar focus was sufficient, but that criterion was later abandoned.
Pleomorphic (Anaplastic) Rhabdomyosarcoma
Pleomorphic rhabdomyosarcoma occurs predominantly in adults aged 30 to 50 years and is rarely seen in children.[4] In adults, pleomorphic rhabdomyosarcoma is associated with a worse prognosis. In children, the term anaplasia is preferred.[5] In a retrospective review of 546 pediatric patients, the presence of anaplasia was only associated in univariate analysis with inferior clinical outcome in patients with intermediate-risk rhabdomyosarcoma.[6]
Molecular Classification
The embryonal and alveolar histologies have distinctive molecular characteristics that have been used for diagnostic confirmation, and may be useful for assigning therapy and monitoring residual disease during treatment.[7,8,9,10,11]
-
Alveolar histology: Unique translocations between the FOXO1 (previously called FKHR) gene on chromosome 13 and either the PAX3 gene on chromosome 2 (t(2;13)(q35;q14)) or the PAX7 gene on chromosome 1 (t(1;13)(p36;q14)) are found in 70% to 80% of patients with alveolar histology tumors.[7,12] 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.[7] Patients with solid-variant alveolar histology have a lower incidence of PAX-FOXO1 gene fusions than do patients showing classical alveolar histology.[13]
Alveolar cases associated with the PAX7 gene, with or without metastases, appear to occur in patients at a younger age, and may be associated with longer event-free survival (EFS) rates than those associated with PAX3 gene rearrangements.[14,15,16,17] Alveolar cases associated with the PAX3 gene are older and have a higher incidence of invasive tumor (T2). Around 22% of cases showing alveolar histology have no detectable PAX gene translocation.[11,13]
- Embryonal histology: Embryonal tumors often show loss of specific genomic material from the short arm of chromosome 11.[12,18,19] The consistent loss of genomic material at the chromosome 11p15 region in embryonal tumors suggests the presence of a tumor suppressor gene, although no such gene has yet been identified. Breakpoints involving the 1p11-1q11 region are relatively common (36%) in embryonal rhabdomyosarcoma.[20]
These findings highlight the important differences between embryonal and alveolar tumors. There are data that alveolar tumors carrying either a t(1;13) or a t(2;13) translocation (translocation-positive) are biologically and clinically different from alveolar tumors that do not have a translocation (translocation-negative) and from embryonal tumors.[11,21,22,23] In a study of Intergroup Rhabdomyosarcoma Study Group (IRSG) cases, the outcome for patients with translocation-negative alveolar rhabdomyosarcoma was better than that observed for translocation-positive cases and was similar to that seen in patients with embryonal rhabdomyosarcoma, suggesting that fusion status is a critical factor for risk stratification in pediatric rhabdomyosarcoma.[22] However, a German study of 121 patients with alveolar rhabdomyosarcoma found no significant difference in EFS at 5 years among patients who were PAX-FOXO1–positive compared with those who were translocation-negative.[24]
A study suggests that metagene expression analyses can classify patients with rhabdomyosarcoma into the three distinct risk groups and may be particularly helpful in identifying intermediate-risk patients with poor-risk features. Further studies are needed to confirm these findings.[21]
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 (MRI) 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 or MRI scan of regional lymph nodes should be considered. Abnormal-appearing lymph nodes should be biopsied when possible. 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.[2,3,4] However, the efficacy of these two procedures for identifying involved lymph nodes or other sites is currently under investigation, 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 other than kidney, bladder, and prostate; biliary tract. |
| Unfavorable site | Any site other than favorable. |
| T1 | Tumor confined to anatomic site of origin (noninvasive). |
| T2 | Tumor extension and/or fixation to surrounding tissue (invasive). |
| 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:
| 1. | Assigning a Stage: Determined by primary site, tumor size (widest diameter), and presence or absence of regional lymph node and/or distant metastases. |
|---|---|
| 2. | Assigning a local tumor Group: Determined by status postsurgical resection/biopsy, with pathologic assessment of the tumor margin and of lymph node disease. |
| 3. | Assigning a Risk Group: Determined by Stage, Group, and histology. |
As noted previously, prognosis for children with rhabdomyosarcoma depends predominantly 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 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 the TNM-based pretreatment staging system that incorporates the primary tumor site, presence or absence of tumor invasion of surrounding tissues, tumor size, regional lymph node status, and the presence or absence of metastases. This staging system is described in Table 2 below.[5,6]
Table 2. Soft Tissue Sarcoma Committee of the Children's Oncology Group: Pretreatment Staging System
| Stage | Sites of Primary Tumor | T Stage | Tumor Size | Regional Lymph Nodes | Distant Metastasis |
| N0 = absence of nodal spread; N1 = presence of regional nodal spread beyond the primary site; X = unknown N status; M0 = absence of metastatic spread; M1 = presence of metastatic spread beyond the primary site and regional lymph nodes; T1 = tumor confined to anatomic site of origin (noninvasive); T2a = tumor extension and/or fixation to surrounding tissue (invasive), tumor ≤5 cm in maximum diameter; T2b = tumor extension and/or fixation to surrounding tissue (invasive), tumor >5 cm in maximum diameter. | |||||
| 1 | Favorable sites | T1 or T2 | Any size | N0 or N1 or NX | M0 |
| 2 | Unfavorable sites | T1 or T2 | a, ≤ 5 cm | N0 or NX | M0 |
| 3 | Unfavorable sites | T1 or T2 | a, ≤ 5 cm | N1 | M0 |
| b, > 5 cm | N0 or N1 or NX | ||||
| 4 | Any site | T1 or T2 | Any size | N0 or N1 or NX | M1 |
The IRS-I, IRS-II, and IRS-III studies prescribed treatment plans based on the Surgical-pathologic Group system. In this system, Groups are defined by the extent of disease and by the completeness or extent of initial surgical resection after pathologic review of the tumor specimen(s). The definitions for these Groups are shown in Table 3 below.[7,8]
Table 3. Soft Tissue Sarcoma Committee of the Children's Oncology Group: Surgical-pathologic Group System
| Group | Incidence | Definition |
| I | Approximately 13% | Localized tumor, completely removed with microscopically clear margins and no regional lymph node involvement. Lymph node biopsy or sampling is encouraged if lymph nodes are clinically or radiologically suspicious. |
| II | Approximately 20% | Localized tumor, completely removed with: (a) microscopic disease at the margin, (b) regional disease with involved, grossly removed regional lymph nodes without microresidual disease,or(c) regional disease with involved nodes, grossly removed but with microscopic residual and/or histologic involvement of the most distal node from the primary tumor. |
| III | Approximately 48% | Localized tumor, incompletely removed with gross, residual disease after: (a) biopsy only,or(b) gross major resection of the primary tumor (>50%). |
| IV | Approximately 18% | Distant metastases are present at diagnosis. This category includes: (a) radiographically identified evidence of tumor spread,and(b) positive tumor cells in cerebral spinal fluid, pleural, or peritoneal fluids, or implants in these regions. |
After patients are categorized by Stage and Surgical-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.[9,10] Treatment assignment is based on Risk Group, as shown in Table 4. To be designated as alveolar, the tumor must have greater than 50% alveolar elements; if the alveolar component is 50% or less, the tumor is considered embryonal.
Table 4. Soft Tissue Sarcoma Committee of the Children's Oncology Group: 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 nonrhabdomyosarcomatous 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 to maximize local tumor control.[1,2,3] Surgical resection may be performed prior to chemotherapy if it will not result in disfigurement, substantial functional compromise, or organ dysfunction. In most cases, this is not possible, and therefore, only an initial biopsy is performed. The majority of patients have Group III (gross residual) disease. After initial chemotherapy, Group III patients receive definitive RT for control of the primary tumor. Some patients with initially unresected tumors may undergo second-look surgery (delayed primary excision) to remove residual tumor. This is most appropriate if the delayed excision is deemed feasible with acceptable functional/cosmetic outcome, and if a modest reduction in radiation dose is expected to significantly reduce the risk of long-term adverse effects. RT is given to clinically suspicious lymph nodes (detected by palpation or imaging) unless the suspicious lymph nodes are biopsied and shown to be free of rhabdomyosarcoma.
The discussion of treatment options for children with rhabdomyosarcoma is therefore divided into separate sections describing the following local control options:
- Surgery.
- RT.
- Chemotherapy.
The treatment of rhabdomyosarcoma by the Children's Oncology Group (COG) and in Europe (as exemplified by trials from the Intergroup Rhabdomyosarcoma Study Group [IRSG], the Soft Tissue Sarcoma Committee of the COG [COG-STS], and the International Society of Pediatric Oncology Malignant Mesenchymal Tumor [MMT] Group) differs in management and overall treatment philosophy.[2] In the MMT trials, the main objective is to reduce the use of local therapies using initial front-line chemotherapy followed by second-line therapy in the presence of poor response. Subsequent surgical resection is preferred over RT, which is used 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 long-term damaging effects from RT. Conversely, the primary COG-STS objective has been to employ local therapy soon after the initial operation or biopsy (except in patients with metastatic disease), using RT for patients with residual disease. Event-free survival (EFS) is the target endpoint, attempting to avoid relapse and subsequent salvage therapy.[3] The MMT Group approach led to an overall survival (OS) rate of 71% in the European MMT89 study compared with an OS rate of 84% in the IRS-IV study. Similarly, EFS rates at 5 years were 57% in the MMT89 study versus 78% in the IRS-IV study. Differences in outcome were most striking for patients with extremity and head and neck nonparameningeal tumors, whereas results were similar for patients with genitourinary tumors. 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]
Patients with undifferentiated sarcomas were treated in trials coordinated by the IRSG from 1972 until 2006,[4] and more recently were eligible for the nonrhabdomyosarcoma soft tissue sarcoma protocol using agents active in adult soft tissue sarcoma, ifosfamide and doxorubicin (COG-ARST0332). However, this trial has now been closed.
References:
Previously Untreated Childhood Rhabdomyosarcoma
Local Control Management: Surgery
In recent years, the predominant site of treatment failure in patients with initially localized rhabdomyosarcoma has been local recurrence. Both surgery and radiation therapy are primarily measures taken to produce local control, but each has risks, as well as benefits. Surgical removal of the entire tumor should be considered initially, but only if major functional/cosmetic impairment will not result.[1] With that proviso, complete resection of the primary tumor with a surrounding margin of normal tissue and sampling possibly involved lymph nodes in the draining nodal basin is recommended. Important exceptions to the rule of normal margins 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 (primary re-excision) to resect the primary tumor bed before beginning chemotherapy can achieve complete removal of the tumor.[4]
Clinical and/or imaging evaluation of regional lymph nodes is an important part of pretreatment staging. Pathologic evaluation of regional nodes is currently required for all patients with extremity primary rhabdomyosarcoma and boys aged 10 years and older with paratesticular rhabdomyosarcoma, because microscopic tumor is often documented even when the nodes are not enlarged. (Refer to the Regional and in-transit lymph nodes section of this summary for more information.)
There is little evidence that debulking surgery (i.e., expected to leave macroscopic residual tumor) improves outcome, compared with biopsy alone.[5][Level of evidence: 2A] Second-look procedures (also known as delayed primary excision) can identify viable tumor that remains after initial chemotherapy; patients with viable tumor had shorter event-free survival (EFS) rates than did those without viable tumor, but there was no effect on overall survival (OS).[6] Thus, the exact role of delayed primary excision remains undefined in rhabdomyosarcoma and is most appropriate if it is anticipated that a complete resection is possible and that the modest reduction in radiation dose will substantially decrease the risk for late effects.
Because rhabdomyosarcoma can arise from multiple sites, surgical care decisions and radiotherapeutic options must be tailored to the specific aspects of each site, and should be discussed with a multidisciplinary team including representatives of those specialties, as well as pediatric oncologists. Surgical management of the more common primary sites is provided in the Local Control Management with Surgery and RT by Primary Sites of Disease section of this summary.
Local Control Management: Radiation Therapy (RT)
Only 15% of patients present with Group I, completely resected disease, so RT is used in the majority of cases.
RT is an effective method for achieving local control of the tumor for patients with microscopic or gross residual disease following biopsy, initial surgical resection, or chemotherapy. Patients with completely resected embryonal rhabdomyosarcoma (Group I) do well without RT.[7] An earlier study of Group I patients with alveolar rhabdomyosarcoma and undifferentiated soft tissue sarcoma found that omission of RT was followed by decreased local control.[8] A subsequent review of patients with only alveolar rhabdomyosarcoma found that the improvement in outcome with RT did not reach statistical significance for patients with Stage 1 and 2 tumors. There were very few patients (n = 4) with large tumors (Stage 3, >5 cm) who did not receive RT, but their outcome was poor.[9][Level of evidence: 3iiiDii]
In more than 50% of Group II rhabdomyosarcoma patients, local recurrence was due to noncompliance with guidelines or omission of RT.[10] A review of European trials conducted by the German Cooperative Weichteilsarkom Studien (CWS) 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, as defined by tumor histology, tumor size, and tumor site.[11]
The predominant type of relapse for patients with Group III disease is local failure. Patients with tumor-involved regional lymph nodes at diagnosis also have a higher risk of local and distant failure compared with patients whose lymph nodes are uninvolved.[12] As with the surgical management of patients with rhabdomyosarcoma, recommendations for RT depend on the site of primary tumor, the postsurgical (if performed) amount of residual disease (none vs. microscopic vs. macroscopic), and the presence of involved lymph nodes.
For optimal care of pediatric patients undergoing radiation treatments, it is imperative to have available a radiation oncologist, radiation technicians, and nurses who are experienced in treating children. An anesthesiologist may be necessary to sedate and immobilize young patients. 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 therapy, intensity-modulated radiation therapy [IMRT], proton-beam therapy [charged-particle radiation therapy], or brachytherapy) are appropriate.[13,14,15] Comparison of proton-beam and IMRT treatment plans has shown that proton-beam radiation can spare more normal tissue adjacent to the targeted volume than IMRT.[16,17] Follow-up remains relatively short, and there are no data available to determine if the reduction in dose to adjacent tissue will result in improved functional outcome or reduce the risk of secondary malignancy. Because patient numbers are small, it is not possible to determine if the risk of local recurrence might be increased by reducing radiation dose in tissue adjacent to the primary tumor.
Standard RT of children with rhabdomyosarcoma includes the following:
- 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 36 Gy if they do not have involved lymph nodes and 41 Gy in the presence of involved nodes.[8,18,19]IRS-II patients with gross residual disease (Group III) who received 40 Gy to more than 50 Gy had locoregional relapse rates greater than 30% but higher doses of radiation (>60 Gy) were associated with unacceptable long-term toxic effects.[20,21] Group III patients on the IRS-IV standard treatment arm received 50.4 Gy, with 5-year progression-free survival of 55% to 75%.[22] Experience supports using a somewhat reduced dose of RT in patients with Group III disease who have delayed gross total resection with negative margins. In the recent COG-D9602 study, these patients had a greater than 85% likelihood of local control with 36 Gy.[23]
- 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.[8] 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. RT is usually given over 5 to 6 weeks (e.g., 1.8 Gy once per day), during which time chemotherapy is usually modified to avoid the radiosensitizing agents dactinomycin and doxorubicin.
The IRS-IV trial included a randomized study that reported the administration of 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, once-daily RT (total dose of 50.4 Gy) versus the twice-daily hyperfractionated schedule (total dose of 59.4 Gy). There was no demonstrated advantage in terms of local control.[24] Conventional RT remains the standard for treating patients who have rhabdomyosarcoma with gross residual disease.[25]
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 [26,27,28,29,30] and selected bladder/prostate sites.[31][Level of evidence: 3iiiA] 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.[27,32] Other sites, especially head and neck, have also been treated with brachytherapy.[33] Patients with initial Group III disease, who subsequently have microscopic residual disease following chemotherapy with or without delayed surgery are likely to achieve local control with RT at doses of 40 Gy or more.[34]
Very young children (aged ≤36 months) diagnosed with rhabdomyosarcoma pose a therapeutic challenge because of their increased risk for treatment-related morbidity.[23] As suggested above, in older children, reduced radiation doses may be appropriate if delayed surgery can provide negative margins. However, for infants who are unable to undergo surgical resection, higher doses of RT remain appropriate.[35] Radiation techniques are designed to maximize normal tissue sparing, and should include conformal approaches, often with intensity-modulated techniques.
Local Control Management with Surgery and RT by Primary Sites of Disease
Head and neck
Rhabdomyosarcomas of the orbit should not undergo exenteration, but biopsy is needed for diagnosis.[36,37] Biopsy is followed by chemotherapy and RT, with orbital exenteration reserved for the small number of patients with locally persistent or recurrent disease.[38,39] RT and chemotherapy are the standard of care, with survival in excess of 90% to 95%. For patients with orbital tumors, precautions should be taken to limit the RT dose to the lens and cornea.
If the tumors are nonorbital and cranial parameningeal (arising 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 onto or through the dura.[40,41,42] If skull erosion and/or transdural extension is equivocal, a computed tomography (CT) scan with contrast of the same regions is indicated. Also, 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. Because complete removal of these tumors is difficult, owing to their location, the initial surgical procedure for these patients is usually only a biopsy for diagnosis.
Nonorbital cranial parameningeal tumors are optimally managed by conformal RT and chemotherapy. 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.[40] Patients should receive RT to the site of primary tumor with a 1.5 cm margin to include the meninges adjacent to the primary tumor and the region of intracranial extension, if present, with a 1.5 cm margin.[41] In a retrospective trial, starting radiation therapy within 2 weeks of diagnosis for patients with signs of meningeal impingement was associated with lower rates of local failure. When no signs of meningeal impingement were present, delay of radiation therapy for more than 10 weeks did not impact local failure rates.[41]
Children who present with tumor cells in the CSF (Stage 4) may or may not have other evidence of diffuse meningeal disease and/or distant metastases. In a review of experience from IRSG Protocols II though IV, eight patients had tumor cells in the CSF at diagnosis; three of four without other distant metastases were alive at 6 to 16 years after diagnosis, as was one of four who had concomitant metastases elsewhere.[43] Patients may also have multiple intraparenchymal brain metastases from a distant primary tumor. They may be treated with central nervous system-directed RT in addition to treatment with chemotherapy/RT for the primary tumor. Spinal RT may also be indicated.[44,45]
For nonparameningeal 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.[46] 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 RT.
For patients with head and neck primary tumors that are considered unresectable, chemotherapy and RT with organ preservation are the mainstay of primary management.[38,42,47,48,49,50] Several studies have reported excellent local control in patients with rhabdomyosarcoma of the head and neck treated with IMRT, fractionated stereotactic radiation therapy, or protons and chemotherapy. 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.[51,52,53]; [54][Level of evidence: 3iiiA]
Extremity sites
Intensity-modulated radiation therapy (IMRT) can be used to spare the bone, yet provide optimal soft tissue coverage, and is used for the management of extremity rhabdomyosarcoma. Complete primary tumor removal from the hand or foot is not feasible in most cases because of functional impairment.[55][Level of evidence: 3iiA] For children presenting with a primary tumor of the hands or feet, Children's Oncology Group (COG) studies have shown 100% 10-year local control using RT along with chemotherapy, avoiding amputation in these children.[56][Level of evidence: 3iiiA]
Primary re-excision prior to beginning chemotherapy (i.e., not delayed) may be appropriate in patients whose initial surgical procedure leaves microscopic residual disease that is deemed resectable by a second procedure.[4]
Regional and in-transit lymph nodes
The Soft Tissue Sarcoma Committee of the COG (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 mapping is employed at some centers to identify the regional nodes that are the most likely to be involved.[57,58,59,60] However, the contribution of sentinel lymph node mapping is not yet clearly defined in pediatric patients.
Because of the significant incidence of regional nodal spread in patients with extremity primary tumors (often without clinical evidence of involvement) and because of the prognostic and therapeutic implications of nodal involvement, extensive pretreatment assessment of regional (and possibly in-transit) nodes is warranted.[57,61,62,63,64]; [65][Level of evidence: 3iiDi] In-transit nodes are defined as epitrochlear and brachial for upper-extremity tumors and popliteal for lower-extremity tumors. Regional lymph nodes for those tumor sites are axillary/infraclavicular nodes and inguinal/femoral nodes, respectively. In a review of 226 patients with primary extremity rhabdomyosarcoma, 5% had tumor-involved in-transit nodes, and over 5 years, the rate of in-transit node recurrence was 12%. Very few patients (n = 11) underwent in-transit node examination at diagnosis, but five of them, all with alveolar rhabdomyosarcoma, had tumor-involved nodes. However, the EFS rates were not significantly different among those evaluated initially and those not evaluated initially for in-transit nodal disease.[65]
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 initially. Chemotherapy, with or without RT, is then given. Initial surgery is performed if there is a realistic expectation of achieving negative margins. However, most patients who present with large tumors in these sites have localized disease that becomes amenable to complete resection with negative margins after preoperative chemoradiotherapy and those patients may have excellent long-term survival.[66,67,68,69]
Intrathoracic or intra-abdominal sarcomas may not be resectable at diagnosis because of the massive size of the tumor and extension into vital organs or vessels.[70] For patients with initially unresectable retroperitoneal/pelvic tumors, complete surgical removal following chemotherapy, with or without RT, offers a significant survival advantage (73% vs. 34%–44% without removal).[70]
With rhabdomyosarcoma of the biliary tree, total resection is rarely feasible and standard treatment includes chemotherapy and RT. Outcome for patients with this primary site 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.[71]
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 regional lymph nodes. When feasible and without unacceptable morbidity, removing all gross tumor prior to chemotherapy improves the likelihood of cure. In Intergroup Rhabdomyosarcoma Study Group (IRSG) Protocols I through IV, the OS rate after aggressive therapy for 71 patients with tumors in this location was 49%, best for patients in Stage 2 (small tumors, negative regional nodes), intermediate for those in Stage 3, and worst for those in Stage 4 at diagnosis.[72] However, with the goal of organ preservation, patients with tumors of the perineum/anus are preferentially managed with chemotherapy and RT without aggressive surgery, which may result in loss of sphincter control.
Genitourinary system
Primary sites for childhood rhabdomyosarcoma within the genitourinary system include the paratesticular area, bladder, prostate, kidney, vulva, vagina, and uterus. Specific considerations for the surgical and radiotherapeutic management of tumors arising at each of these sites are discussed in the paragraphs below.[73]
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 spermatic cord, utilizing an inguinal incision with proximal vascular control (i.e., radical orchiectomy).[74] Resection of hemiscrotal skin is required when there is tumor fixation or invasion, or when a previous transscrotal biopsy has been performed. For patients with incompletely removed paratesticular tumors that require RT, temporarily repositioning the contralateral testicle into the adjacent thigh prior to scrotal radiation therapy may preserve hormone production.[75][Level of evidence: 3iiiC]
Paratesticular tumors have a relatively high incidence of lymphatic spread (26% in IRS-I and IRS-II),[61] 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 have Group I disease, are younger than 10 years, and in whom 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.[76,77] 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.[3,25,78] A staging ipsilateral retroperitoneal lymph node dissection is currently required for all children 10 years and older with paratesticular rhabdomyosarcoma on COG-STS studies. However, node dissection is not routine in Europe for adolescents with resected paratesticular rhabdomyosarcoma. Many European investigators rely on radiographic rather than surgical-pathologic assessment of retroperitoneal lymph node involvement.[74,76] It appears, however, that the ability of the CT scan to predict the presence of lymph node involvement needs further study.[79]
Bladder preservation is a major goal of therapy for patients with tumors arising in the bladder and/or prostate. Two important reviews provide information about the historical, current, and future treatment approaches for patients with bladder and prostate rhabdomyosarcomas.[80,81]
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,[82,83] followed, when necessary, by a more limited surgical procedure such as partial cystectomy.[84] 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 IRS-II).[84,85] The later experience from IRS-III and IRS-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%.[83,86,87] Patients with a primary tumor of the bladder/prostate who present with a large pelvic mass resulting from a distended bladder caused by outlet obstruction at diagnosis receive RT to a volume defined by imaging studies following initial chemotherapy to relieve outlet obstruction. 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. In selected cases in one series, bladder-conserving surgery plus brachytherapy for boys with prostate or bladder-neck rhabdomyosarcoma led to excellent survival, bladder preservation, and short-term functional results.[31][Level of evidence: 3iiiB] 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.[88]
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 major surgical procedure such as total cystectomy.[86,89,90] 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.[86] 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.
The kidney is occasionally the primary site for rhabdomyosarcoma; six cases were identified from among 5,746 eligible patients enrolled on IRSG protocols. The tumors were large (mean widest diameter, 12.7 cm), and anaplasia was present in four (67%) patients. Three patients with grossly complete tumor removal at diagnosis survived; the three with incomplete removal and gross or metastatic disease died of infection or metastatic tumor.[91]
For patients with genitourinary primary tumors of the vulva/vagina/uterus, the initial surgical procedure is usually a vulvar or transvaginal biopsy. Initial radical surgery is not indicated for rhabdomyosarcoma of the vulva/vagina/uterus.[3] Conservative surgical intervention for vaginal rhabdomyosarcoma, with primary chemotherapy and adjunctive radiation (often brachytherapy) for residual disease (Group II or III), results in excellent disease-free survival.[92,93]
In the COG-ARST0331 study, there was an unacceptably high rate of local recurrences in girls with Group III vaginal tumors who did not receive RT.[93][Level of evidence: 3iiiDiii]
Because of the smaller number of patients with uterine rhabdomyosarcoma, it is difficult to make a definitive treatment decision, but chemotherapy with or without RT is also effective.[92,94] 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.
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.
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.[95][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.[96]
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 and RT should be initiated after diagnostic biopsy, with the intent to consider removal of residual tumor at a later date if feasible.[97]
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 patients were alive at 20 and 8 months after diagnosis. Six of the previously reported eight patients had died of their disease.[98][Level of evidence: 3iiiDiii] Treatment with combination chemotherapy followed by removal of the residual mass or masses can sometimes be successful.[98]
Metastatic sites
Primary resection of metastatic disease at diagnosis (Stage 4, M1, Group IV) is rarely indicated.
The CWS Group reviewed four consecutive trials and identified 29 patients with M1 embryonal rhabdomyosarcoma and metastasis limited to the lung at diagnosis. They reported approximately 38% 5-year EFS for the cohort and did not identify any benefit for local control of pulmonary metastasis, whether by lung irradiation (n = 9), pulmonary metastasectomy (n = 3), or no targeted pulmonary therapy (n = 19).[99][Level of evidence: 3iiiA]
The IRSG reviewed 46 IRS-IV (1991–1997) patients with metastatic disease at diagnosis confined to the lungs. Only 11 (24%) had a biopsy of the lung, including six at the time of primary diagnosis. They were compared with 234 patients with single non-lung metastatic sites or multiple other sites of metastases. The lung-only patients were more likely to have embryonal rhabdomyosarcoma and parameningeal primary tumors than the larger group of 234 patients, and were less likely to have regional lymph node disease at diagnosis. Failure-free survival (FFS) and OS rates at 4 years were 35% and 42%, respectively, better than for those with two or more sites of metastases (P = .005 and .002, respectively). Being younger than 10 years at diagnosis was also a favorable prognostic factor. Lung irradiation was recommended by the protocols for the lung-only group, but many did not receive it. Those who did receive lung irradiation had better FFS and OS at 4 years than those who did not (P = .01 and P = .039, respectively).[100][Level of evidence: 3iiiB]
Chemotherapy Treatment Options
All children with rhabdomyosarcoma should receive chemotherapy. The intensity and duration of the chemotherapy are dependent on the Risk Group assignment.[101] See Table 4 in the Stage Information section for more information about Risk Groups.
Adolescents treated with therapy for rhabdomyosarcoma experience less hematologic toxicity and more peripheral nerve toxicity than do younger patients.[102]
Low-risk patients
Standard treatment options
- Low-risk patients have localized (nonmetastatic) embryonal histology tumors in favorable sites that have been grossly resected (Groups I and II), embryonal tumors in the orbit that have not been completely resected (Group III), and localized tumors in an unfavorable site that have been grossly resected (Groups I and II). (See Table 3 in the Stage Information section of this summary.) Certain subgroups of low-risk patients have achieved survival rates higher than 90% when treated with a two-drug chemotherapy regimen that includes 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 Vincristine and Dactinomycin With or Without Radiation Therapy (Subset A)
| Site | Size | Group | Nodes |
| N0 = absence of nodal spread. | |||
| Favorable | Any | I, IIA | N0 |
| Orbital | Any | I, II, III | N0 |
| Unfavorable | ≤5 cm | I | N0 |
The COG-D9602 study stratified 388 patients with low-risk embryonal rhabdomyosarcoma into two groups.[103] Treatment for subgroup A patients (n = 264; Stage 1 Group I/IIA, Stage 2 Group I, and Stage 1 Group III orbit) consisted of VA with or without RT for 48 weeks. Patients with subgroup B disease (n = 78; Stage 1 Group IIB/C, Stage I Group III nonorbit, Stage 2 Group II, and Stage 3 Group I/II disease) received VA plus cyclophosphamide (total cumulative dose of 28.6 g/m2). Radiation doses were reduced from 41.4 Gy to 36 Gy for Stage 1 Group IIA patients and from 50 Gy or 59 Gy to 45 Gy for Group III orbit patients. For subgroup A patients, the 5-year overall FFS rate was 88% and the OS rate was 97%. For subgroup B patients, the 5-year FFS rate was 85% and the OS rate was 93%.
Other subgroups of low-risk patients have achieved survival rates of at least 90% with three-drug chemotherapy with VA and cyclophosphamide ([VAC], total cyclophosphamide dose of 28.6 g/m2) plus RT for residual tumor. See Table 6 below.
Table 6. Characteristics of Low-Risk Patients with High Survival Rates Using Three-Drug Therapy with Vincristine, Dactinomycin, and Cyclophosphamide With or Without Radiation Therapy (Subset B)
| Site | Size | Group | Nodes |
| N0 = absence of nodal spread; N1 = presence of regional nodal spread beyond the primary site. | |||
| Favorable (orbital or non-orbital) | Any | IIB, IIC, III | N0, N1 |
| Unfavorable | ≤5 cm | II | N0 |
| Unfavorable | >5 cm | I, II | N0, N1 |
Intermediate-risk patients
Standard treatment options
- In IRS-IV, intermediate-risk patients had survival rates at 3 years from 84% to 88%. This category includes patients with embryonal rhabdomyosarcoma at unfavorable sites (Stages 2 and 3) with gross residual disease (i.e., Group III), and patients with nonmetastatic alveolar rhabdomyosarcoma (Stages 2 and 3) at any site (Groups I, II, and III). The IRS-IV study randomly assigned intermediate-risk patients to receive either standard VAC therapy or one of two other chemotherapy regimens using ifosfamide as the alkylating agent. Outcomes with VAC were as good as the other two regimens and easier to administer. Because there was no difference in outcome between these three treatments, confirming VAC as the standard chemotherapy combination for children with intermediate-risk rhabdomyosarcoma.[25]
A comparison of survival in patients with tumors of embryonal histology treated on IRS-IV (who received higher doses of alkylating agents) compared with similar patients treated on IRS-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.[104] For other groups of intermediate-risk patients, an intensification of cyclophosphamide was feasible but did not improve outcome.[105]
- The COG has also evaluated whether the addition of topotecan and cyclophosphamide to standard VAC therapy improved 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.[106,107] Furthermore, the combination of cyclophosphamide and topotecan demonstrated substantial activity both in patients with recurrent disease and in newly diagnosed patients with metastatic disease.[108,109] The COG-D9803 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; 4-year FFS was 73% with VAC and 68% with VAC/VTC (vincristine, topotecan, and cyclophosphamide).[108][Level of evidence: 1iiA] Thus, VAC is still the standard form of multiagent chemotherapy for intermediate-risk patients.
- 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.[110][Level of evidence: 3iiiA]
- Approximately 20% of Group III patients will have a residual mass at the completion of therapy. The presence of a residual mass had no adverse prognostic significance.[111,112] Aggressive alternative therapy may not be warranted for rhabdomyosarcoma patients with a residual mass at the end of planned therapy. For Group III patients, best response to initial chemotherapy had no impact on overall outcome.[112] While induction chemotherapy is commonly administered for 9 to 12 weeks, 2.2% of patients with intermediate-risk rhabdomyosarcoma on the IRS-IV and COG-D9803 studies were found to have early disease progression and did not receive their planned course of RT.[113] COG investigators are now studying the value of early administration of RT in patients of intermediate risk.
Treatment options under clinical evaluation
The following is an example of a national and/or international clinical trial that is currently being conducted. Information about ongoing clinical trials is available from the NCI Web site.
- COG-ARST0531 (Combination Chemotherapy and Radiation Therapy in Treating Patients With Newly Diagnosed Rhabdomyosarcoma): The COG intermediate-risk rhabdomyosarcoma protocol is comparing standard VAC chemotherapy versus VAC alternating with vincristine and irinotecan (VI). RT begins 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.[100,114,115] Two retrospective studies have looked at patients who present with metastases limited to the lungs;[99,100] results are summarized in the Metastatic sites section of this summary.
A pooled analysis of 788 high-risk rhabdomyosarcoma patients treated with multiagent chemotherapy (all regimens used cyclophosphamide or ifosfamide plus dactinomycin and vincristine with or without additional chemotherapeutic agents), followed by local therapy (surgery with or without RT) within 3 to 5 months of starting chemotherapy, identified several adverse prognostic factors. These were age younger than 1 year, age 10 years or older, unfavorable primary site, bone and/or bone marrow involvement, and three or more different metastatic sites. The 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 (P < .0001).[116][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, including the following:
- In the IRS-IV study, three combinations of drug pairs were studied in an up-front window —IE, vincristine/melphalan (VM),[117] and ifosfamide/doxorubicin (ID).[118] These patients received VAC after the up-front window agents were evaluated at weeks 6 and 12. OS rates for patients treated with IE and ID were comparable (31% and 34%, respectively) and better than for those treated with VM (22%).[118] 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.[108,109] An up-front window trial of topotecan in previously untreated children and adolescents with metastatic rhabdomyosarcoma gave similar results.[107]
- Irinotecan and irinotecan with vincristine [119] 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.[119]
- 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 four patients had progressive disease.[120]
- A study from the International Society of Pediatric Oncology (SIOP) demonstrated continued poor outcome for patients with high-risk features such as age 10 years and older or bone/bone marrow involvement. This study compared a standard six-drug combination followed by vincristine, doxorubicin, cyclophosphamide (VDC) maintenance versus an arm that evaluated a window of single-agent doxorubicin or carboplatin followed by sequential high-dose monotherapy courses including cyclophosphamide, etoposide, and carboplatin followed by maintenance VAC. No benefit was seen for the high-dose therapy arm.[121]
Alternative Therapies
- High-dose chemotherapy with stem cell rescue has been evaluated in a limited number of patients with rhabdomyosarcoma.[122,123]; [124][Level of evidence: 3iiiA] The use of high-dose chemotherapy with stem cell rescue has failed to improve the outcome of patients with newly diagnosed or recurrent 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-ARST08P1 (Temozolomide, Cixutumumab [IMC-A12], and Combination Chemotherapy in Treating Patients With Metastatic Rhabdomyosarcoma): COG-ARST08P1 evaluates the addition of novel therapeutic agents to the intensive chemotherapy used in the COG study COG-ARST0431. Newly diagnosed patients with metastatic rhabdomyosarcoma (excluding patients younger than 10 years with embryonal rhabdomyosarcoma) who have an expected FFS of less than 20% are eligible. The study consists of the following three sequential pilots:
- Pilot 1 assesses the feasibility of adding IMC-A12, a fully human IgG1 monoclonal antibody targeting the insulin-like growth factor-1 receptor (IGF-1R), to most known effective chemotherapy agents in rhabdomyosarcoma.
- Pilot 2 assesses the feasibility of adding temozolomide, an alkylating agent, to vincristine/irinotecan cycles, based on synergistic activity of temozolomide when added to irinotecan.
- Pilot 3 will assess the feasibility of adding both agents to the COG-ARST0431 backbone, provided that pilot studies 1 and 2 have not shown unexpected toxicity.
- 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 was given with little toxicity to patients with translocation-positive metastatic or recurrent Ewing sarcoma and alveolar rhabdomyosarcoma.[125][Level of evidence: 3iiiA]
Current Clinical Trials
Check for U.S. clinical trials from NCI's list of cancer clinical trials 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 1 or Group I disease and embryonal histology and who have small tumors, and for those who have a local or regional nodal 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] European investigators performed a retrospective review of patients with rhabdomyosarcoma enrolled on cooperative group trials who experienced recurrence. They identified metastatic (as opposed to local) recurrence, prior radiation therapy, initial tumor size (>5 cm), and time to relapse (<18 months) as unfavorable prognostic features for survival after recurrence.[5]
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.[6,7] Some survivors have also been reported after surgical removal of only one or a few metastases in the lung.[6] Radiation therapy should be considered for patients who have not already received radiation therapy in the area of recurrence, or rarely for those who have received radiation therapy 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.[8]
- Ifosfamide, carboplatin, and etoposide.[9,10]
- Cyclophosphamide/topotecan.[11]
- Irinotecan with or without vincristine.[12,13,14,15] A Children's Oncology Group (COG) prospective, randomized, up-front window trial, COG-ARST0121, showed no difference between vincristine plus irinotecan (20 mg/m2 /d) daily × 5 days for 4 weeks per 6-week treatment cycle (Regimen 1A) and irinotecan (50 mg/m2 /d) daily × 5 days for 2 weeks per 6-week treatment cycle (Regimen 1B) in poor-risk patients with relapsed or progressive rhabdomyosarcoma. At 1 year after initiation of treatment for recurrence, the failure-free survival (FFS) rate was 37% and the overall survival rate (OS) was 55% for Regimen 1A; the FFS rate was 38% and OS rate was 60% for Regimen 1B. The Soft Tissue Sarcoma Committee of the COG recommended the more convenient Regimen 1B for further investigation.[16][Level of evidence: 1iiA]
- Single-agent vinorelbine. In one phase II trial, four of eleven patients with recurrent rhabdomyosarcoma responded to single-agent vinorelbine.[17] In another trial, 6 of 12 young patients (aged 9–29 years) had a partial response.[18]
- Vinorelbine and cyclophosphamide. In a pilot study, three patients (N = 9) with rhabdomyosarcoma had an objective response.[19]
- Gemcitabine and docetaxel. In a single institution trial, two patients (N = 5) with recurrent rhabdomyosarcoma achieved an objective response.[20]
- Rapamycin.[21]
- Topotecan, vincristine, and doxorubicin.[22][Level of evidence: 3iiiDiv]
Treatment options under clinical evaluation for recurrent rhabdomyosarcoma:
- COG-ARST0921 (Vinorelbine Ditartrate and Cyclophosphamide in Combination With Bevacizumab or Temsirolimus in Treating Patients With Recurrent or Refractory Rhabdomyosarcoma): A randomized phase II trial for patients experiencing their first relapse or progression of rhabdomyosarcoma. The goals of this study are to determine the feasibility of administering bevacizumab or temsirolimus with a chemotherapy regimen of intravenous vinorelbine and cyclophosphamide and to compare the event-free survival of patients treated with vinorelbine/cyclophosphamide plus temsirolimus and those treated with vinorelbine/cyclophosphamide plus bevacizumab.
- COG-ADVL1121 (Sorafenib Tosylate in Treating Younger Patients With Relapsed or Refractory Rhabdomyosarcoma, Wilms Tumor, Liver Cancer, or Thyroid Cancer): A phase II study of sorafenib, a Raf kinase and receptor tyrosine kinase inhibitor, for children and young adults with relapsed/refractory rhabdomyosarcoma, Wilms tumor, hepatocellular carcinoma, and papillary thyroid carcinoma. The goal of this study is to determine the objective response rate of sorafenib in children with refractory or relapsed rhabdomyosarcoma. Patients must be aged 2 to 30 years.
- 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. However, a review of the published data did not determine a significant benefit for patients who underwent this salvage treatment approach.[23,24,25]
- 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 list of cancer clinical trials 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:
Changes to This Summary (08 / 17 / 2012)
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.
General Information
Revised text to state that childhood rhabdomyosarcoma is a soft tissue malignant tumor of mesenchymal origin.
Revised text about the incidence of each histologic subtype of rhabdomyosarcoma.
Added text to state that infants younger than 1 year, who may be less likely to receive radiation therapy for local control, have a relatively high rate of local failure.
Added Gupta et al. as reference 37.
Added text about a report from the AIEOP Soft Tissue Sarcoma Committee that suggested that adolescents may have more frequent unfavorable tumor characteristics including alveolar histology, regional lymph node involvement, and metastatic disease involvement, accounting for their poor prognosis when compared with children (cited Bisogno et al. as reference 38).
Revised text to state that a statistically significant difference in 5-year survival by histopathologic subtype (82% for embryonal rhabdomyosarcoma vs. 65% for alveolar rhabdomyosarcoma), was not noted when 1,258 IRS-III and IRS-IV patients with rhabdomyosarcoma were analyzed.
Added text to state that anaplasia was not shown to be an independent prognostic variable in a multivariate analysis.
Cellular Classification
Added text to state that in some earlier studies, any alveolar focus was sufficient, but that criterion was later abandoned.
Revised text to state that unique translocations between the FOXO1 (previously called FKHR) gene on chromosome 13 and either the PAX3 gene on chromosome 2 (t(2;13)(q35;q14)) or the PAX7 gene on chromosome 1 (t(1;13)(p36;q14)) are found in 70% to 80% of patients with alveolar histology tumors.
Stage Information
Revised text about the process of assigning a Stage, Group, and Risk Group for rhabdomyosarcoma.
Revised text to state that current Soft Tissue Sarcoma Committee of the Children's Oncology Group (COG-STS) protocols for rhabdomyosarcoma use the TNM-based pretreatment staging system that incorporates the primary tumor site, presence or absence of tumor invasion of surrounding tissues, tumor size, regional lymph node status, and the presence or absence of metastases.
Revised Table 2 to include the definitions for T1, T2a, and T2b staging.
Revised Table 3 to update the definition for each surgical-pathologic Group.
Treatment Option Overview
Revised text to state that surgical resection may be performed prior to chemotherapy if it will not result in disfigurement, substantial functional compromise, or organ dysfunction. Also added text to state that the majority of patients have Group III (gross residual) disease; after initial chemotherapy, Group III patients receive definitive radiation therapy (RT) for control of the primary tumor.
Added text to state that the primary COG-STS objective has been to employ local therapy soon after the initial operation or biopsy (except in patients with metastatic disease), using RT for patients with residual disease. Event-free survival is the target endpoint, attempting to avoid relapse and subsequent salvage therapy.
Added text to state that the COG-ARST0332 trials has now been closed.
Previously Untreated Childhood Rhabdomyosarcoma
Added text to state that clinical and/or imaging evaluation of regional lymph nodes is an important part of pretreatment staging. Pathologic evaluation of regional nodes is currently required for all patients with extremity primary rhabdomyosarcoma and boys aged 10 years and older with paratesticular rhabdomyosarcoma, because microscopic tumor is often documented even when the nodes are not enlarged.
Added text to state that an earlier study of Group I patients with alveolar rhabdomyosarcoma and undifferentiated soft tissue sarcoma found that omission of RT was followed by decreased local control. A subsequent review of patients with only alveolar rhabdomyosarcoma found that the improvement in outcome with RT did not reach statistical significance for patients with Stage 1 and 2 tumors; there were very few patients with large tumors who did not receive RT, but their outcome was poor (cited Raney et al. as reference 9 and level of evidence 3iiiDii).
Revised text to state that as with the surgical management of patients with rhabdomyosarcoma, recommendations for RT depend on the site of primary tumor, the postsurgical amount of residual disease, and the presence of involved lymph nodes.
Added text about how treatment plans show that proton-beam radiation can spare more normal tissue adjacent to the targeted volume than intensity-modulated radiation therapy (IMRT); however, follow-up remains short and there are no data available to determine if the reduction in dose to adjacent tissue will result in improved functional outcome or reduce the risk of secondary malignancy (cited Cotter et al. and Childs et al. as references 16 and 17, respectively).
Revised text to state that in general, patients with microscopic residual disease (Group II) receive RT to 36 Gy if they do not have involved lymph nodes and 41 Gy in the presence of involved nodes. Also added text to state that experience supports using a somewhat reduced dose of RT in patients with Group III disease who have delayed gross total resection with negative margins. In the recent COG-D9602 study, these patients had a greater than 85% likelihood of local control with 36 Gy (cited Breneman et al. as reference 23).
Revised text to state that in older children, reduced radiation doses may be appropriate if delayed surgery can provide negative margins; however, for infants who are unable to undergo surgical resection, higher doses of RT remain appropriate.
Revised text to state that for patients with orbital tumors, precautions should be taken to limit the RT dose to the lens and cornea.
Added text to state that because complete removal of these tumors is difficult, owing to their location, the initial surgical procedure for patients with parameningeal tumors is usually only a biopsy for diagnosis.
Added text to state that in a retrospective trial, starting RT within 2 weeks of diagnosis for patients with signs of meningeal impingement was associated with lower rates of local failure. When no signs of meningeal impingement were present, delay of RT for more than 10 weeks did not impact local failure rates.
Added Wharam and Raney as references 44 and 45, respectively.
Revised text to state that several studies have reported excellent local control in patients with rhabdomyosarcoma of the head and neck treated with IMRT, fractionated stereotactic RT, or protons and chemotherapy.
Added text to state that primary re-excision prior to beginning chemotherapy may be appropriate in patients whose initial surgical procedure leaves microscopic residual disease that is deemed resectable by a second procedure.
Added text to state that two important reviews provide information about the historical, current, and future treatment approaches for patients with bladder and prostate rhabdomyosarcomas (cited Rodeberg et al. as reference 81).
Added text to state that adolescents treated with therapy for rhabdomyosarcoma experience less hematologic toxicity and more peripheral nerve toxicity than do younger patients (cited Gupta et al. as reference 102).
Recurrent Childhood Rhabdomyosarcoma
Added text to state that at 1 year after initiation of treatment for recurrence, the failure-free survival (FFS) rate was 37% and the overall survival (OS) rate was 55% for Regimen 1A; the FFS rate was 38% and OS was 60% for Regimen 1B. The COG-STS Committee recommended the more convenient Regimen 1B for further investigation.
Added text to state that in another trial investigating single-agent vinorelbine, 6 of 12 young patients had a partial response.
Added text to state that rapamycin and the combination of topotecan, vincristine, and doxorubicin are standard chemotherapy regimens that have been used to treat recurrent rhabdomyosarcoma.
This summary is written and maintained by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ NCI's Comprehensive Cancer Database pages.
About This PDQ Summary
Purpose of This Summary
This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of childhood rhabdomyosarcoma. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.
Reviewers and Updates
This summary is reviewed regularly and updated as necessary by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).
Board members review recently published articles each month to determine whether an article should:
- be discussed at a meeting,
- be cited with text, or
- replace or update an existing article that is already cited.
Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.
The lead reviewers for Childhood Rhabdomyosarcoma Treatment are:
- Louis S. Constine, MD (James P. Wilmot Cancer Center at University of Rochester Medical Center)
- Holcombe Edwin Grier, MD (Dana-Farber Cancer Institute/Boston Children's Hospital)
- Michael P. LaQuaglia, MD (Memorial Sloan-Kettering Cancer Center)
- Paul A. Meyers, MD (Memorial Sloan-Kettering Cancer Center)
- Alberto S. Pappo, MD (St. Jude Children's Research Hospital)
- R. Beverly Raney, MD (Consultant)
- Stephen J. Shochat, MD (St. Jude Children's Research Hospital)
Any comments or questions about the summary content should be submitted to Cancer.gov through the Web site's Contact Form. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.
Levels of Evidence
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 Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.
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National Cancer Institute: PDQ® Childhood Rhabdomyosarcoma Treatment. Bethesda, MD: National Cancer Institute. Date last modified <MM/DD/YYYY>. Available at: http://cancer.gov/cancertopics/pdq/treatment/childrhabdomyosarcoma/HealthProfessional. Accessed <MM/DD/YYYY>.
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Last Revised: 2012-08-17
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