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The Oncologist, Vol. 10, No. 7, 518-527, August 2005; doi:10.1634/theoncologist.10-7-518
© 2005 AlphaMed Press

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 Rhabdomyosarcoma: New Windows of Opportunity
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Rhabdomyosarcoma: New Windows of Opportunity

Philip P. Breitfelda, William H. Meyerb

a Duke University Medical Center, Durham, North Carolina, USA; b University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA

Correspondence: William H. Meyer, M.D., University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA. Telephone: 405-271-5311; Fax: 405-271-3756; e-mail: william-meyer{at}ouhsc.edu


   LEARNING OBJECTIVES
Top
 Learning Objectives
Abstract
 Introduction
 Future Directions
 Disclosure of Potential...
 References
 
After completing this course, the reader will be able to:

  1. Interpret the histologic findings of rhabdomyosarcoma and differentiate rhabdomyosarcoma from other small round cell neoplasms.
  2. Define the extent of disease using the Intergroup Rhabdomyosarcoma Study stage and group systems and apply these systems to predict prognosis.
  3. Discuss the multidisciplinary nature of therapy for rhabdomyosarcoma.
  4. Evaluate the most appropriate risk-based therapy alternatives for rhabdomyosarcoma.

Access and take the CME test online and receive 1 hour of AMA PRA category 1 credit at CME.TheOncologist.com


   ABSTRACT
Top
 Learning Objectives
 Abstract
Introduction
 Future Directions
 Disclosure of Potential...
 References
 
Rhabdomyosarcoma is a highly malignant, small blue cell tumor characterized by muscle differentiation. With modern treatment, more than 70% of children and adolescents with this disease are cured. Adequate biopsy to obtain sufficient tissue for accurate diagnosis and molecular characterization is critical. Patients must be assessed for tumor extent; the Intergroup Rhabdomyosarcoma Study (IRS) clinical group and Staging system is universally applied in North America. Multidisciplinary therapy is necessary to maximize cure rates. Local control relies on complete surgical excision when possible; those whose tumors are not completely excised and those with alveolar histology tumors require local irradiation to maximize local control. In North America, vincristine (Oncovin®; Eli Lilly and Company, Indianapolis, http://www.lilly.com), dactinomycin (Cosmegen®; Merck & Co., Inc., Whitehouse Station, NJ, http://www.merck.com), and cyclophosphamide are the standard chemotherapy agents. The IRS has used therapeutic window studies to confirm the predictive nature of preclinical xenograft models and to identify several new single agents and combinations of agents with activity in high-risk patient groups. Despite these efforts, the outcome for these high-risk patients remains poor. The next generation of Children’s Oncology Group studies will evaluate the efficacy of topoisomerase-I inhibitors and dose-compression therapy approaches. New advances in molecular characterization of tumors, including gene-expression analysis, may identify new therapeutic targets that can be exploited by expanded preclinical drug discovery efforts, and hold the promise of revolutionizing risk-based therapies.

Key Words. Rhabdomyosarcoma • Child • Therapy • Radiotherpy • Sarcoma • Soft-tissue neoplasms • Antineoplastic agents • Human


   INTRODUCTION
Top
 Learning Objectives
 Abstract
 Introduction
Future Directions
 Disclosure of Potential...
 References
 
Rhabdomyosarcoma (RMS) is the most common soft-tissue sarcoma occurring in childhood and adolescence. Approximately 350 new cases occur each year in the U.S. [1]. Cure rates have improved substantially in the past three decades; with modern multidisciplinary therapy, at least 70% of children and adolescents with RMS are cured [2, 3]. The most common sites of presentation are: genitourinary (GU) (29%), parameningeal (24%), extremity (15%), retroperitoneal (13%), orbit (8%), other head and neck (7%), and miscellaneous other sites (4%) (Fig. 1Go). Most often, RMS presents as a rapidly enlarging mass lesion, although often the manifestations of tumor growth depend on the primary tumor site. For example, tumors in the nasopharynx often present with facial pain or cranial nerve dysfunction; primary GU tumors may present with vaginal bleeding and/or signs of urinary obstruction. Most tumors occur sporadically, with no predisposing associated risk factors. However, in a few cases, RMS has developed in children with neurofibromatosis [4, 5], Li-Fraumeni syndrome [6–9], Costello syndrome [10, 11], Noonan’s syndrome [12, 13], Beckwith-Wiedemann syndrome [14, 15], and a variety of congenital anomalies [16]. RMS has also been associated with parental use of cocaine and marijuana [17].



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  		Figure 1. Distribution of common primary tumor sites.

 
Pathology
RMS is one of the small round blue cell tumors that occur in children, and it must be distinguished from neuroblastoma, Ewing’s sarcoma, and lymphoma. The correct identification of RMS is a substantial challenge. Using a central review mechanism for patients enrolled in Intergroup Rhabdomyosarcoma Study Group (IRS) studies, up to 20% of children enrolled are found to be incorrectly diagnosed with RMS or have their histologic subtype reclassified. Adequate biopsy is critical for accurate diagnosis and to provide tissue for special histochemical stains and molecular studies; fine-needle aspirates are never appropriate. Malignant skeletal muscle differentiation distinguishes RMS from the other round blue cell neoplasms. On light microscopy, cross striations and rhabdomyoblasts may been seen; typically, immunohistochemical staining is required (tumors typically are positive for one or more muscle-specific markers, including myogenin, MyoD1, muscle-specific actin, myoglobin, and/or desmin) [18, 19]. Tumors are classified using the modified International Classification of Rhabdomyosarcoma [20, 21]. The two common histiotypes in children and adolescents are a favorable group comprising embryonal rhabdomyosarcoma (ERMS) and its variants and an unfavorable group comprising alveolar rhabdomyosarcoma (ARMS). Historically, cooperative group trials have included undifferentiated sarcoma in this unfavorable group [22]; however, future Children’s Oncology Group (COG) RMS trials will exclude these tumors.

Embryonal tumors comprise more than half of all RMS cases. These tumors tend to occur in younger children and at more favorable sites. ERMSs are characterized by primitive spindle cells, often with a myxoid background. The botryoid variant of ERMS typically develops as a grape-like protrusion in mucosa-lined hollow organs (vagina, bladder, or nasopharynx) and demonstrates subepithelial condensation (cambium layer). No specific genetic marker is diagnostic for ERMS. ARMS tumors are less common, occurring more often in the extremities and in adolescents. Histologically, these tumors are characterized by loose, noncohesive, round or oval tumor cell aggregates, separated by a fibrous septal framework [23]. A solid variant of ARMS is also recognized [24]. The definition of alveolar histology has been recently refined so that any amount of alveolar component establishes the diagnosis of ARMS [21]. Unique gene fusions of PAX3 or PAX7 (on chromosomes 2 and 1, respectively) and the FOXO1a (FKHR) gene on chromosome 13 specifically identify ARMS, although some ARMS tumors (<25%) are translocation negative [25–29]. Both PAX fusion transcripts can be detected by polymerase chain reaction–based and fluorescence in situ hybridization assays, which may be helpful in the diagnosis and detection of minimal disease [30].

Staging
Determining the extent of disease is critical for treatment planning and estimating outcome. Appropriate staging workup includes evaluation of the primary tumor for location, size, invasiveness, and anatomic boundaries, using magnetic resonance imaging (MRI) or computerized tomography (CT) scanning, and assessment of metastatic disease using CT scanning of the lungs, a bone scan, bilateral bone marrow aspirates/biopsies, and imaging of regional lymph nodes. Regional lymphatic spread often occurs in extremity [31–33] and paratesticular [34–37] tumors, particularly in patients over the age of 10 years. In these two patient groups, lymph node sampling with histologic assessment of the regional draining nodes is required for adequate staging [38, 39]. At this time, positron emission tomography (PET) is not considered a standard staging tool for RMS.

Since its inception, the IRS has devised and has continued to use a staging system that classifies these tumors by IRS Group, which is determined by the extent of the initial tumor resection (Table 1Go) [40, 41]. Since the early 1990s, the IRS has also used a modification of the tumor-node-metastasis staging system that is based on the pretreatment assessment of tumor site and size and regional and systemic tumor spread (Table 2Go) [42, 43]. Those with group I and group II embryonal histology tumors have the best outcomes; those with advanced group and stage alveolar tumors, particularly those with metastatic disease, fare the poorest. In the most recent series of COG cooperative group studies, patients were assigned to one of three risk groups. Recent European cooperative group studies have used a four-tier risk system [44, 45]. Low-risk patients comprise about one third of the total patient population. This subset is restricted to those with localized embryonal histology tumors. Most patients in this stratum have resected (group I or group II) tumors, although those with group III tumors arising in favorable sites (stage 1) are also enrolled in the low-risk study. Based on data from the IRS-IV study, the predicted 5-year failure-free survival (FFS) and overall survival rates for low-risk patients are 88% and 95%, respectively. Those with ERMS that are group III, stage 2 and stage 3, and all those with nonmetastatic ARMS are eligible for the intermediate-risk trial; this group comprises almost one half of patients with RMS. The predicted outcomes at 5 years for this group are a 70% FFS rate and a 75% overall survival rate. Children and adolescents with metastatic RMS have the poorest overall outcome (5-year FFS and overall survival rates of 25% and 27%, respectively) and are eligible for the high-risk study. This group comprises slightly less than 20% of the entire population.


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  		Table 1. IRS clinical grouping classification
 

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  		Table 2. IRS-modified TNM pretreatment staging classification
 
Treatment
All patients with RMS are presumed to have micrometastatic disease at diagnosis, thus the rationale for multidisciplinary therapy. All require chemotherapy. Most require specific management directed at control of the primary site. Typically, this is either primary (or occasionally delayed) complete surgical excision or local irradiation. Europeans have treated some children without any local control modality, accepting a higher risk for local recurrence in the hopes of minimizing the morbidity of local therapy in selected children [46, 47].

Radiation Therapy
The use of radiation therapy to achieve control of local and regional disease is a mainstay of therapy for RMS [48]. Since their inceptions, the IRS (now Soft Tissue Sarcoma [STS] Committee of the COG) and the European cooperative groups have lead the effort to provide a standardized dose, field size, and timing of radiation therapy in the context of their clinical trials [2, 49]. Their research strategy over the past 15 years has mainly been one of measuring the effect of empiric changes in the use of radiation. We learned in the context of the IRS-I through IRS-III trials that patients with group I disease have an excellent outcome without the use of radiation therapy, with the exception of patients with alveolar histology; those patients fare better with the addition of radiation [50]. In the IRS-IV study, because of the concern that local and regional control was not achieved in up to one-third of group III patients in the IRS-II study [51], a randomized trial was conducted to determine if the use of hyperfractionated radiation therapy could improve the local control rate in group III patients. The overall local control rate improved to 87% but was not influenced by the type of radiation therapy [52]. In Europe, the use of radiation therapy tailored to the initial response to chemotherapy in group III patients has been empirically tested [53], making it possible to avoid radiation exposure in some patients [47].

Surgery
Surgery remains an important treatment modality for RMS. This has been made evident with the observation that, for most anatomic sites, achieving clinical group I status by complete excision of the tumor prior to the initiation of chemotherapy improves outcome. This goal may need to be compromised if surgery is likely to lead to impairment of function. For example, over the past 15 years, there has been a trend to preserve bladder function by avoiding initial cystectomy [54–58] and to avoid surgery in many patients with vaginal RMS [46, 59, 60]. Second, surgery is an important tool for staging the extent of lymph node involvement, especially in extremity and paratesticular RMS. In the IRS-IV trial, CT was used to determine the extent of retroperitoneal lymph node involvement for paratesticular primaries. The results of that study indicated that this was a safe method for children under 10 years of age, but for those over the age of 10 years, group I patients did not do as well as group II patients [39]. This indicates that CT may underestimate clinically important disease in the retroperitoneum, at least in children over the age of 10 years. The current recommendation is to perform staging retroperitoneal lymph node sampling of the ipsilateral chain in such patients. Likewise, CT and physical exams appear to underestimate nodal disease in extremity RMS [33]. Thus, surgical exploration of regional nodes (or a sentinel lymph node procedure [61]) in patients with extremity tumors is now standard care. Determining the presence of regional lymph node spread is of importance, since such patients require regional radiation therapy.

Chemotherapy
In nonmetastatic patients, the IRS studies have established vincristine (Oncovin®; Eli Lilly and Company, Indianapolis, http://www.lilly.com) and dactinomycin (Cosmegen®;Merck & Co., Inc., Whitehouse Station, NJ, http://www.merck.com) (VA), and often VA plus cyclophosphamide (VAC), for selected patients as the standard chemotherapy regimen in North America. For the more favorable subset of low-risk patients (subset A in Table 3Go), IRS studies have demonstrated that prolonged VA therapy is associated with a nearly 95% overall survival rate [2]. A subset of low-risk patients (subset B in Table 3Go) appears to benefit from the addition of cyclophosphamide [3], achieving a 5-year FFS rate of 84% in the IRS-IV trial with VAC, compared with an only 70% FFS rate in the IRS-III trial on VA therapy. In group III intermediate-risk patients, the substitution of either vincristine/ifosfamide (Ifex®; Bristol-Myers Squibb, Princeton, NJ, http://www.bms.com)/etoposide (Etopophos®, VePesid®; Bristol-Myers Squibb) or vincristine/dactinomycin/ifosfamide for VAC chemotherapy was not superior to VAC therapy based on a randomized comparison in the IRS-IV trial [3]. Ifosfamide is substituted for cyclophosphamide in most European studies [45, 53]. The dose of cyclophosphamide in IRS studies has varied, with the dose increasing to 2.2g/m2 in the IRS-IV trial [3] and the current studies. Although the IRS has explored the dose escalation of cyclophosphamide [62, 63], a recent reanalysis of the IRS-IV trial compared with the IRS-II trial failed to demonstrate that intermediate-risk patients benefited from this dose increase. In addition, associated with this dose of cyclophosphamide, the IRS has identified that veno-occlusive disease is a specific risk in patients exposed to VAC therapy and found that this risk was independently associated with children <3 years of age [64]. This led to specific dosing guidelines for current IRS studies for infants and children <3 years of age. In metastatic RMS, using an upfront window design, IRS studies have established the activity of many agents in newly diagnosed patients, including ifosfamide/doxorubicin (Adriamycin®; Bedford Laboratories, Bedford, OH, http://www.bedfordlabs.com) [65], ifosfamide/etoposide [66], melphalan (Alkeran®; Glaxo SmithKline, Philadelphia, http://www.gsk.com)/vincristine [66], topotecan (Hycamtin®; GlaxoSmithKline) [67], topotecan/cyclophosphamide [68], and irinotecan (Camptostar®; Pfizer Pharmaceuticals, New York, http://www.pfizer.com) [69]. Nevertheless, the overall survival of the high-risk metastatic group has remained disappointingly low and no better than the outcomes seen in the IRS-III trial (James R. Anderson and Philip P. Breitfeld, personal communication). In these patients, the European cooperative groups have demonstrated prospectively that consolidation using a high-dose chemotherapy regimen with hematopoietic stem cell rescue has no impact on overall outcome [70]. A retrospective analysis of published reports demonstrated similar findings [71].


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  		Table 3. Protocol assignment of low-risk patient subsets

 

   FUTURE DIRECTIONS
Top
 Learning Objectives
 Abstract
 Introduction
 Future Directions
Disclosure of Potential...
 References
 
Refining Risk Assessment
Better tools for assessing the risk of treatment failure will permit better tailoring of appropriate treatment and protocol assignments. The COG low-risk studies have defined two subsets of low-risk patients, providing more aggressive therapy for the more advanced group/stage (Fig. 2). An updated analysis of these subgroups indicated that small numbers of patients, defined as subset B in the previous low-risk study (D9602), that is, those who are stage 1, group IIB and group IIC, or stage 2, group 2, had excellent outcomes in the IRS-III study, treated only with extended VA therapy. To minimize the exposure to alkylator therapy for these children and to simplify the risk assignment in the new low-risk RMS study, ARST0331, these patients are now included as part of the subset 1 study population.

Refinements in pathologic and biologic assessments also may lead to improvements in risk assignment. A small proportion of RMS tumors show anaplastic histologic changes, with diffuse anaplasia associated with a poorer prognosis. Continued evaluation is ongoing to determine whether this morphologic change will be independently prognostic. An analysis of the IRS-IV ARMS cases demonstrated an inferior outcome for patients with metastatic disease whose tumors had PAX3 fusions compared with those whose tumors had PAX7 fusions; this will be prospectively evaluated in the new high-risk study [72]. A recent study has noted an increased N-myc copy number and expression in a proportion of ARMS patients, correlating this finding with adverse outcomes [73].

Gene-expression analysis of RMS holds the promise for both better prognostic assessment and the definition of new therapeutic targets. In small series of patients, gene-expression profiling has clearly demonstrated unique differences among the histologic subtypes of RMS, although translocation-negative ARMS tumors have gene profiles that are similar to those of ERMS tumors [74, 75]. In addition, expression of several tyrosine kinases and G protein–coupled receptors were found, suggesting possible new therapeutic targets. A much larger analysis of RMS from the IRS-IV study is now under way. It is hoped that this analysis will aid in the biologic characterization of RMS, provide independent prognostic information beyond clinical and pathologic factors, and define new therapeutic targets.

Improving Imaging Assessments
Contemporary CT and MRI have permitted a better assessment of primary tumor extent and the presence of metastatic disease. In large part due to better assessment of tumor extent, successive IRS studies have permitted a reduction in radiotherapy ports, particularly for parameningeal tumors [76–79]. However, better methods of assessment are needed to measure tumor response and evaluation of residual changes at the end of therapy. A recent analysis of IRS-IV data showed that response, as measured by routine imaging modalities, does not correlate with outcome [80]. Some patients with residual masses at the end of therapy do not have active tumors and do not develop recurrent disease. Whether biopsy of such masses at the end of therapy is useful or clinically indicated is not known. PET imaging holds the promise for better definition of active disease after therapeutic interventions and will be explored in the next series of COG studies.

Local Control Measures
Nodal metastases are frequent in those with extremity primaries and those over the age of 10 years with paratesticular tumors. Ipsilateral lymph node dissection is required for accurate staging; for such patients, sentinel node biopsy may be of value. Positive nodal sites must be included in radiotherapy ports. Newer radiotherapy techniques should be considered to spare normal tissues. For selected patients, brachytherapy may be considered [81]. Three-dimensional conformal radiotherapy results in excellent local tumor control and is routinely used in many centers [82]. The present intermediate-risk COG trial (D9803) is evaluating selected radiotherapy dose reductions depending on the initial tumor response and resectability. The long-term results from that trial will not be available for several years. In the next COG RMS studies, the use of early irradiation and radiation sensitization with irinotecan will be tested. Patients at intermediate risk for treatment failure all will receive local irradiation beginning at week 4, based on the successful use of early irradiation in previous IRS/COG studies for those with parameningeal disease.

Chemotherapy
For the COG studies, VAC continues to be the standard therapy against which other chemotherapy approaches are measured. Previous analyses of IRS data suggested a possible dose-response relationship for cyclophosphamide. Based on those analyses, a pilot dose-intensification study tested increasing doses of cyclophosphamide in combination with vincristine and dactinomycin. Dose escalation resulted in substantially greater toxicity and no apparent therapeutic benefit [63]. Subsequent analyses of IRS data show that when higher-risk patients receiving only VA therapy were excluded from the analysis, no dose-response relationship of cyclophosphamide was detectable. Consequently, in the next series of COG RMS trials, cyclophosphamide will be administered at a 1.2-g/m2 dose for all patients in all risk categories.

The new COG low-risk trial opened in 2004. That study identifies two subsets of patients (Fig. 1Go), and prescribes different chemotherapy, dependent on the anticipated risk of recurrence. All enrolled patients receive four cycles of VAC chemotherapy, based on detailed analyses of mature data from the IRS-III and IRS-IV trials that show an improvement in the 5-year FFS rate for all low-risk subsets of patients with the addition of cyclophosphamide. However, to avoid the late complications of repetitive cycles of high-dose cyclophosphamide, the trial limits the total cumulative exposure to 4.8 g/m2, which should minimize the risk for infertility. The lowest-risk subset (subset 1) receives a substantially shorter total therapy (only 24 weeks), in part based on data from European studies [45]. Subset 2 patients also receive four cycles of VAC followed by 36 weeks of VA therapy. This represents significantly less total cyclophosphamide exposure, compared with the D9602 study, with the intent of maintaining excellent outcome while decreasing the morbidity of therapy. The lower dose radiotherapy guidelines used in the D9602 trial for local control of group II and group III patients continue in the new study.

The present intermediate-risk study, D9803, will reach its accrual target in September 2005. Based on the activity of topotecan in RMS, used alone [67,83] and in combination with cyclophosphamide [68, 84], that study prospectively compares VAC therapy with VAC plus topotecan/cyclophosphamide. The study is also testing whether a reduction in radiotherapy dose, dependent on initial chemotherapy response, is safe. The earliest results of that trial will not be available until mid-2006.

Planning for subsequent intermediate- and high-risk studies is well under way, with anticipated activations later in 2005. Both studies are based in part on data from the recently completed high-risk trial, D9802, that demonstrated very high response rates for irinotecan [69] and irinotecan/vincristine [85].

The new intermediate-risk trial will prospectively randomize patients to receive either VAC chemotherapy (using the lower dose of cyclophosphamide) or VAC plus irinotecan/vincristine. All patients will receive earlier administration of local radiotherapy (beginning at week 4), based in part on the successful use of early radiotherapy for parameningeal primary tumors. Early use of radiotherapy will also permit randomization of patients with parameningeal disease, a large group that was excluded from randomization in the previous intermediate-risk trial. The study will also evaluate concurrent irradiation and irinotecan, based on the potential radiosensitizing activity of irinotecan. The study also will address a number of secondary aims, in particular, assessing novel methods to evaluate tumor response.

The next high-risk study will build on the success of D9802, continuing the use of irinotecan/vincristine. However, since patients treated in the IRS/STS window trials had no better outcome than those treated in the IRS-III trial, and since no candidate novel agents are ready for phase II testing, we will exploit this as an opportunity to evaluate a different strategy in this patient group at high risk for treatment failure. Following initial exposure to irinotecan/vincristine, the study will test whether dose-compressed treatment with alternating combinations of vincristine/doxorubicin/cyclophosphamide and ifosfamide/etoposide (among the most active combinations from prior window trials) will improve outcome. The trial will also evaluate the safety of irinotecan radiosensitization in the context of this aggressive multiagent chemotherapy regimen.

Most patients who develop tumor recurrence have a dismal prognosis [86]. The ongoing relapse study, ARST0121, is a randomized comparison of two different schedules of irinotecan administration (both administered with vincristine). After the initial window evaluation, patients receive alternating vincristine/doxorubicin/cyclophosphamide (VDC) and ifosfamide/etoposide cycles, administered in standard 3-week cycles. These combinations were selected because both have substantial activity in RMS and none of the active front-line studies use these combinations. Patients whose tumors fail to respond to irinotecan/vincristine and those not receiving the window also receive tirapazamine (Tirazone®; Sanofi-Synthelabo Inc., New York, http://www.sanofi-synthelabo.us) [87, 88] with VDC cycles. As the new high-risk study is implemented, new strategies for patients relapsing after that trial will be needed.

New treatment strategies are clearly needed, particularly for higher-risk, newly diagnosed patients and for those who develop recurrent tumors, where there has been little improvement in outcome. The promise of identification of new treatment targets through gene-expression analyses is looming, and efforts are underway to expand the availability of tumor tissue for these analyses. Such targeted therapy holds great promise for new treatments in RMS and other childhood solid tumors. The new National Cancer Institute Pediatric Preclinical Testing Program, led by Dr. Peter Houghton, promises to identify new agents. This is of particular importance for RMS, where single-institution and IRS/COG studies have amply demonstrated the ability of such preclinical drug testing models to predict clinical activity [89–93]. This and other ongoing efforts, including studies of CpG oligopeptides [94], oncolytic herpes simplex virus tumor injections [95, 96], rapamycin analogs [97], vaccines against small peptide fragments that span the PAX3-FKHR fusion [98], epidermal growth factor receptor tyrosine kinase inhibitors, and tumor necrosis factor alpha–related apoptosis–inducing ligands (TRAILs) [99], promise to provide opportunities for novel interventions for patients with RMS.


   DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST
Top
 Learning Objectives
 Abstract
 Introduction
 Future Directions
 Disclosure of Potential...
References
 
The authors indicate no potential conflicts of interest.


   REFERENCES
Top
 Learning Objectives
 Abstract
 Introduction
 Future Directions
 Disclosure of Potential...
 References
 

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Received March 17, 2005; accepted for publication June 8, 2005.




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