Optimal Management Strategies for Rhabdomyosarcoma in Children

Pediatr Drugs 2007; 9 (6): 391-400THERAPY IN PRACTICE 1174-5878/07/0006-0391/$44.95/0

© 2007 Adis Data Information BV. All rights reserved.

Optimal Management Strategies forRhabdomyosarcoma in ChildrenDavid Walterhouse and Andrea Watson

Division of Hematology/Oncology, Children’s Memorial Hospital, Northwestern University Feinberg School of Medicine,Chicago, Illinois, USA

Contents

Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3911. When Should Rhabdomyosarcoma Be Considered in the Differential Diagnosis? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3922. Establishing the Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3933. The Initial Evaluation of the Patient and Staging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3934. General Management Principles for Patients with Rhabdomyosarcoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 394

4.1 Surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3954.2 Radiotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3964.3 Chemotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 397

5. Outcomes for Patients with Rhabdomyosarcoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3986. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 399

Rhabdomyosarcoma is the most common sarcoma of childhood. Fortunately, the goal of cure is realistic forAbstractthe majority of patients with localized tumors. However, management of these patients remains challenging. Thefact that the tumor arises in a wide variety of primary sites, some of which are associated with specific patterns oflocal invasion, regional lymph node spread, and therapeutic response, requires physicians to be familiar withsite-specific staging and treatment details. In addition, rhabdomyosarcoma requires multimodality therapy thatcan be associated with significant acute toxicities and long-term effects, particularly when administered to youngchildren. These factors sometimes present a dilemma as to the best approach to optimize the chance of cure,minimize toxicity, and respect quality of life.

The purpose of this review is to discuss ‘optimal’ management of this complicated tumor. Since the tumor isrelatively rare, requires highly specialized care, and important management questions remain to be answered,optimal management of rhabdomyosarcoma includes enrollment in clinical trials whenever possible. Appropri-ate management begins with establishing the correct pathologic diagnosis, histologic subtype, primary site,extent of disease (International Society of Pediatric Oncology [SIOP]-TNM-Union Internationale Contre leCancer stage or Intergroup Rhabdomyosarcoma Study Group [IRSG] stage), and extent of resection (IRSGgroup). Cooperative groups throughout North America and Europe have defined risk-adapted treatment based onthese factors; this treatment requires a coordinated management plan that includes surgery, chemotherapy, andusually radiotherapy.

The surgical approach for rhabdomyosarcoma is to excise the primary tumor whenever possible withoutcausing major functional or cosmetic deficits. Wide excision is difficult in some primary sites and can becomplicated by the fact that the tumor grows in a locally infiltrative manner so that complete resection is oftenneither possible nor medically indicated. Incompletely resected tumors are generally treated with radiotherapy.The cooperative groups reduce the dose of radiation based on the response of the tumor to chemotherapy anddelayed primary resection to differing degrees. Response-adjusted radiation administration may reduce the long-

392 Walterhouse & Watson

term effects of radiotherapy, such as bone growth arrest, muscle atrophy, bladder dysfunction, and induction ofsecond malignant neoplasms; however, it may also be associated with an increased risk of tumor recurrence.

All patients with rhabdomyosarcoma require chemotherapy. A backbone of vincristine and dactinomycinwith either cyclophosphamide (VAC) or ifosfamide (IVA) has been established. Risk-adapted treatmentinvolves reducing or eliminating the alklyating agent for patients with the most favorable disease characteristcs.Clinical trials are ongoing to improve outcomes for higher risk patients; newer agents, such as topotecan oririnotecan, in combination with VAC or use of agents in novel ways are being investigated. Acute and long-termtoxicities associated with these chemotherapy regimens include myelosuppression, febrile neutropenia,hepatopathy, infertility, and second malignant neoplasms.

A 5-year survival rate >70% has been achieved in recent trials for patients with localized rhabdomyosarcoma.However, the outcome for patients who present with metastatic disease remains poor. In the future, risk-adaptedclassification of rhabdomyosarcoma will likely be based on biologic features, such as the presence ofchromosomal translocations or specific gene expression profiles. It is hoped that newer therapies directed atspecific molecular genetic defects will benefit all patients with rhabdomyosarcoma.

Rhabdomyosarcoma accounts for only 4–6% of all childhood Europe (the German Cooperativen Weichteilsarkom Studie[CWS] and the Italian Cooperative Group [ICG]). General treat-malignancies. However, it is the most common sarcoma in chil-ment principles and guidelines, exceptions that are warranted indren aged <15 years, accounting for approximately 50% of allsome situations, newer diagnostic tools and treatment approaches,pediatric soft tissue sarcomas.[1] Rhabdomyosarcoma consists ofand ongoing controversies are considered.malignant cells that demonstrate evidence of skeletal muscle

differentiation.1. When Should Rhabdomyosarcoma BeManagement of rhabdomyosarcoma can be challenging forConsidered in the Differential Diagnosis?physicians for several reasons. One of the main reasons is that this

sarcoma arises in a wide variety of primary sites, some of which Rhabdomyosarcoma should be considered in the differentialare associated with specific patterns of local invasion, regional diagnosis of any soft tissue mass, whether associated with pain orlymph node spread, and therapeutic response. This requires not, especially in the head and neck region (~40% of cases),clinicians to be familiar with site-specific staging and treatment genitourinary tract (~20% of cases), or extremities (~20% ofdetails, and to appropriately refine their evaluation and manage- cases) in the pediatric age group.[2,3] The only sites from whichment based on where the tumor arises. Fortunately, the goal of rhabdomyosarcoma does not seem to arise are the CNS and bones.cure is realistic today for many patients with localized rhabdomy- Typically, at the time of initial presentation the mass will haveosarcoma with the use of multimodality therapy. However, for been present for several weeks. Sometimes the tumor is notthese patients, optimal management also presents considerable detected on physical examination but becomes apparent by caus-challenges because of significant acute toxicities and long-term ing pain or a disturbance in function, such as a cranial nerve palsyeffects of current therapies particularly when administered to or urinary tract obstruction.young children. Indeed, there is still considerable controversy The peak age group for rhabdomyosarcoma is <5 years.[1]

surrounding the best approach to optimize outcome yet minimise Therefore, mild congenital anomalies and patterns or stigmata oftoxicity for these patients. Patients with metastatic disease at cancer predisposition syndromes that can be associated withdiagnosis or recurrent rhabdomyosarcoma continue to fare poorly rhabdomyosarcoma may have gone unnoticed prior to the patientwith current therapeutic approaches; optimal management strate- presenting with the tumor. Identification of these features maygies for these patients remain to be defined. provide important clues to the etiology of the tumor as well as

This article discusses ‘optimal’ management strategies for affect future management and follow-up. Indeed, it was throughrhabdomyosarcoma in children based primarily on results of stud- studies assessing cancer patterns in families of patients withies conducted by the Intergroup Rhabdomyosarcoma Study Group rhabdomyosarcoma that led to the description of the Li-Fraumeni(IRSG) in North America, now known as the Soft Tissue Sarcoma familial cancer syndrome, caused by germline p53 mutations andCommittee of the Children’s Oncology Group (STS COG), as well characterized by increased susceptibility to soft tissue sarcomas,as by the International Society of Pediatric Oncology (SIOP) brain tumors, adrenal cortical carcinoma, breast cancer, leukemia,Sarcoma Committee, and by the Soft Tissue Sarcoma Groups in and osteosarcoma in families, including multiple primaries and

© 2007 Adis Data Information BV. All rights reserved. Pediatr Drugs 2007; 9 (6)

Management Strategies for Rhabdomyosarcoma 393

tumors in young individuals.[4,5] Rhabdomyosarcoma has also sion profiles may provide a biologically relevant classificationbeen associated with neurofibromatosis type 1,[6] Beckwith- system that defines treatment. Submission of tumor samples at theWiedemann syndrome,[7] and Costello syndrome, a rare over- time of surgery to address research questions in clinical trialsgrowth syndrome for which the gene defect remains unknown.[8] represents a very important step toward developing biologicallyIn addition to these syndromes, congenital anomalies most com- based treatment.monly of the genitourinary tract or CNS have been described withincreased frequency in individuals with rhabdomyosarcoma.[6,9]

3. The Initial Evaluation of the Patient and StagingThis suggests that prenatal events resulting from in utero expo-sures or abnormalities in critical developmental regulatory genes It is important to define the primary site as precisely as possiblemay contribute to the development of both the birth defects and for all patients with rhabdomyosarcoma, using magneticrhabdomyosarcomas in these children. resonance imaging and/or CT imaging as well as input from

surgeons and pathologists. Tumor sites are generally divided into2. Establishing the Diagnosis seven main categories: orbit, parameningeal (the middle ear, nasal

cavity, paranasal sinuses, nasopharynx, infratemporal fossa, andThe definitive diagnosis of rhabdomyosarcoma requires a biop- pterygopalatine and parapharyngeal areas), non-parameningeal

sy that demonstrates spindle cell or small round blue cell morphol- head and neck, bladder/prostate, non-bladder/prostate genito-ogy, and expression of myogenic transcription factors, such as urinary, extremity, and others. Since the tumor grows in a locallymyogenin and its upstream regulator MyoD, by immunohisto- invasive manner, it is not always possible to distinguish the precisechemistry.[10] Controversy remains surrounding the use of needle site of origin from a neighboring site of invasion. When in doubt, itbiopsies versus open biopsies to obtain appropriate material to is important to recognize any unfavorable site that is involved anddefinitively establish the diagnosis in patients with unresectable classify the tumor according to the most unfavorable site so thattumors.[11] Sometimes the diagnosis is made from a tumor that has appropriately aggressive therapy can be administered.been resected; for staging purposes care should be taken by the The most common metastatic sites include the lungs, bone,pathologist and surgeon to clearly establish the size of the mass bone marrow, liver, and distant lymph nodes.[13] Therefore, theand whether there is any microscopic or gross residual tumor. metastatic workup generally includes a CT scan of the chest,

Rhabdomyosarcoma is classified into histologic subtypes that retroperitoneum and liver, a bone scan, and bilateral bone marroware of prognostic and therapeutic importance. These include the aspirates and biopsies. The role of positron emission tomographymore common and favorable embryonal form, which histological- scanning, including its value in assessing the extent of disease atly consists of spindle cells and simulates immature skeletal diagnosis, response to therapy, residual disease, and recurrence, ismuscle, and the unfavorable alveolar form with a tissue pattern under investigation.reminiscent of pulmonary alveoli lined by malignant small round The clinician should also be aware of patterns of spread that areblue cells.[12] The latter is often associated with either the uniquely associated with certain primary sites and modify thet(2;13)(q35;q14) or the t(1;13)(p36;q14) translocations that pro- initial evaluation accordingly. For example, a high incidence ofduce novel PAX-FKHR fusion proteins. Two variants of embryo- regional unilateral retroperitoneal lymph node spread occurs innal rhabdomyosarcoma, botryoid and spindle cell, have been boys, especially those aged >10 years, with paratesticular tu-defined histologically and account for <10% of all cases of mors.[14] Therefore, in addition to radiographic assessment of therhabdomyosarcoma. They have been associated with the most retroperitoneal lymph nodes, the STS COG recommends unilateralfavorable outcome. Some tumors demonstrate anaplasia, the clin- retroperitoneal lymph node dissections to assess nodal involve-ical significance of which is under investigation. ment for patients aged >10 years.[14] Similarly, the STS COG

Making these histologic distinctions is central to appropriate recommends surgical sampling to evaluate regional lymph nodesrisk group assignment (see section 4), and an experienced pediatric in children with extremity rhabdomyosarcoma (axillary nodes forpathologist should be consulted to correctly diagnose and classify upper extremity and inguinal nodes for lower) based on a highthe tumor. For example, alveolar histology alone is considered incidence of involvement.[15] For these and other sites, the sentinelsufficient to place a patient with a localized tumor in the inter- node most likely to contain tumor deposits can be identified bymediate risk group using current STS COG criteria and to receive injecting methylene blue dye and technetium-labeled colloid at theappropriately aggressive treatment. site of the primary tumor.[16] Evidence for involvement of regional

In the future, classification of rhabdomyosarcoma based on the lymph nodes will affect stage and group assignment and will alterpresence of chromosomal translocations or specific gene expres- radiation fields, since involved nodal groups require radiotherapy.



with tumors arising in unfavorable primary sites (includingparameningeal sites, bladder/prostate, extremities, and all othersites not included in stage 1), are classified as having either stage 2or 3 disease. Tumor size >5cm or clinical involvement of regionallymph nodes, as assessed by imaging, up-stages patients fromstage 2 to 3. Patients with metastatic disease at the time ofdiagnosis are classified as stage 4.

In addition to the preoperative stage, all patients receiving STSCOG recommended treatment are assigned an IRSG group basedon intraoperative findings and postoperative pathologic status todefine the extent of resection before chemotherapy is initiated(table III). This determination includes pathologic verification oftumor margins and lymph node involvement. Some Europeancooperative study groups have also utilized this system, althoughthey have sometimes referred to the groups as stages; therefore,care must be taken when comparing trials and treatments fromdifferent cooperative groups.[21]

4. General Management Principles for Patients

Table I. International Society of Pediatric Oncology-TNM-Union Internatio-nale Contre le Cancer (SIOP-TNM-UICC) soft tissue sarcoma clinical stag-ing system[18]

Stage Description

I T1

N0

M0

II T2

N0

M0

III T1 or T2

N1

M0

IV T1 or T2

N1 or N2

M1

T1 = tumor confined to the organ or tissue of origin; T2 = tumor involvingone or more contiguous organs or tissues or with adjacent malignanteffusion; N0 = no evidence of regional lymph node involvement; N1 =evidence of regional lymph node involvement; M0 = no evidence of distantmetastasis; M1 = evidence of distant metastasis.

with Rhabdomyosarcoma

In contrast, approximately 40% of patients with parameningealSince the tumor is relatively rare, requires highly specializedtumors have direct extension into the CNS, as demonstrated by

care, and important management questions remain to be answered,cranial nerve palsies, erosion of cranial bone, or direct intracranialoptimal management of rhabdomyosarcoma includes enrollmentgrowth.[17] Therefore, CT imaging of the head should be per-of patients in clinical trials whenever possible. Appropriate man-formed and cerebrospinal fluid obtained for cytology in theseagement begins with establishing the correct pathologic diagnosispatients.(see section 2), and the histologic subtype, primary site, extent of

Three staging systems are widely used for rhabdomyosarcoma,disease (stage), and extent of resection (group) [see section 3].

including the SIOP-TNM Union Internationale Contre le CancerCooperative groups throughout North America and Europe have

(TNM-UICC) soft tissue sarcoma clinical staging system,[18] thedefined risk-adapted treatment based on these factors. For exam-

IRSG staging system,[19] and the IRSG clinical grouping classifi-ple, the IRSG stage and group, and primary site were used to

cation.[19] Each of these systems has prognostic significance. define treatment in the IRS-IV study,[19] while the SIOP-TNM-The SIOP-TNM-UICC soft tissue sarcoma clinical staging UICC stage, extent of resection, primary site, age of the patient,

system is a TNM classification system (table I). Whether the and lymph node involvement were used in the SIOP-MMT (Ma-tumor is confined to the organ or tissue of origin or not (T1 vs T2) lignant Mesenchymal Tumor)-89 study.[22] Since the IRSG groupdistinguishes stages I and II. Evidence of regional lymph node and extent of resection are similar and the IRSG stage takes theinvolvement (N1) places the patient in stage III, and patients with primary site and lymph node involvement into account, the studiesmetastatic disease (M1) have stage IV disease. ultimately used similar data to define risk-adapted treatment. The

STS COG assigns patients to risk groups for the current generationBecause the primary site is of prognostic importance, the IRSGof studies based on the IRSG stage and group, and histology.[23]

developed a modified TNM staging system based on preoperativeimaging and physical findings that takes the primary site into Optimal management of rhabdomyosarcoma requires a coordi-account (table II). This system classifies patients with localized nated multidisciplinary management plan that includes surgery,tumors arising in favorable primary sites (the orbit, non-paramen- chemotherapy, and usually radiotherapy, to provide local controlingeal head and neck sites, and non-bladder/prostate genitourinary and systemic therapy; this highly specialized approach requiressites) as having stage 1 disease.[19] More recently, the biliary tract careful communication and consultation between experiencedhas also been considered as a favorable primary site.[20] Patients oncologists, surgeons, and radiation oncologists.



Table II. Intergroup Rhabdomyosarcoma Study Group staging system[19]

Stage Site Description

T sizea N M

1 Orbit T1 or T2 a or ba No, N1, or Nx Mo

Head and neck (non-parameningeal)

Genitourinary (non-bladder/non-prostate)

2 Bladder/prostate T1 or T2 aa No or Nx Mo

Extremity

Cranial parameningeal

Other

3 Bladder/prostate T1 or T2 aa N1 Mo

Extremity ba No, N1, or Nx Mo

Cranial parameningeal

Other

4 All T1 or T2 a or ba No or N1 M1

a a = ≤5cm in diameter; b = >5cm in diameter.

T = tumor invasiveness; T1 = tumor confined to anatomic site of origin; T2 = extension and/or fixation of tumor to surrounding tissue; N = regional nodes;N0 = regional nodes not clinically involved; N1 = regional nodes clinically involved; Nx = status of regional nodes unknown; M = metastasis; M0 = no distantmetastasis; M1 = metastasis present.

4.1 Surgery may eliminate the need for radiotherapy.[2,3,19,24] The surgeon canalso provide important insight into the site of origin of the tumor,which is not always clear by imaging or pathologic assessment butSurgery represents both a diagnostic and local control modality.is important to define as precisely as possible for staging andGenerally, the aim of surgery for rhabdomyosarcoma is to excisetreatment purposes.the primary tumor whenever possible without causing major func-

tional or cosmetic deficits. However, wide excision is difficult in The timing of definitive surgery differs to some extent amongsome primary sites and is complicated by the fact that the tumor the cooperative groups.[25] Generally, with IRSG/STS COG proto-grows in a locally infiltrative manner; complete resection of a cols, definitive surgery has been performed before beginningrhabdomyosarcoma is often neither possible nor medically indicat- chemotherapy to define the IRSG group and further treat-ed. Indeed, 62% of patients with localized tumors in the IRS-IV ment.[2,3,19,24] In contrast, with SIOP regimens, delayed primarystudy were classified as group III.[19] On the other hand, if the resection after the initiation of chemotherapy has been used moresurgeon feels a complete resection is possible but was not at- routinely as a definitive local control measure.[22] Postponingtempted or pathologic assessment of the tumor margins shows surgery until after chemotherapy has started may allow the sur-microscopic residual tumor, then consideration should be given to geon to completely resect a tumor that was initially consideredprimary re-excision of the area in order to obtain a complete unresectable, if there has been a good response to chemotherapy.resection. Complete resection of a tumor improves prognosis and The role of delayed primary resection to remove residual tumor

Table III. Intergroup Rhabdomyosarcoma Study Group clinical grouping system[2]

Group Description

I Localized disease, completely excised, regional lymph nodes not involved

II Total gross resection with evidence of regional spread

A. Grossly resected tumor with microscopic residual disease

B. Regional disease with involved nodes, completely resected with no microscopic residual disease

C. Regional disease with involved nodes, grossly resected, but with evidence of microscopic residual disease and/orhistologic involvement of the most distal regional node in the dissection

III Incomplete resection with gross residual disease

IV Distant metastatic disease present at onset



after the initiation of chemotherapy in conjunction with response- uterine tumors, who typically have excellent responses to chemo-adjusted doses of radiation is currently under investigation by the therapy, is based on the response to initial chemotherapy inSTS COG. conjunction with the ability to completely resect the tumor or

demonstrate a complete histologic response.[28] Assessment ofLastly, it remains controversial whether a residual mass seen bydose reductions for patients with the most favorable disease char-imaging at the end of treatment should be assessed by biopsy oracteristics, such as patients with IRSG stage 1, group III orbitwhether an attempt at resection should be made.[26,27] The benefitprimaries, group II embryonal tumors without regional lymphof such procedures remains unclear, since the biopsies may benode involvement, or patients undergoing delayed primary resec-difficult to interpret and evidence suggests that patients withtions for group III tumors is ongoing.residual masses do not have an increased risk of subsequent tumor

recurrence compared with other patients. Results of the SIOP MMT-89 trial[22] suggested that avoidanceof radiotherapy is justified for some patients who would receiveradiotherapy if treated according to STS COG guidelines. How-4.2 Radiotherapyever, further work is needed to identify those patients for whomthis is most applicable. In the SIOP MMT-89 trial, radiotherapyRadiotherapy represents an important component of treatmentwas generally not given to patients who had gross residual tumorfor the majority of children with rhabdomyosarcoma. Indeed,at the time that chemotherapy was started and subsequentlyfailure of local control is the major reason for treatment failure. Inachieved complete local tumor control with chemotherapy and/orthe IRS-IV study, 14% of patients had locoregional relapses,delayed primary resection. The remaining patients received radio-accounting for 68% of all relapses,[19] while in the MMT-89 study,therapy at a dose of 45Gy to the initial tumor volume, with a 5Gy34% of patients had locoregional relapses, accounting for 84% ofboost permitted depending on age, treatment volume, and extent ofall relapses.[22]

residual disease.The cooperative groups agree on the importance of radiother-Studies conducted by the German Cooperative Soft Tissueapy for rhabdomyosarcoma and define radiation fields by the

Sarcoma Group have also stratified the use of radiotherapy accord-initial presurgical tumor volume. However, there are importanting to tumor response after initiating chemotherapy.[21] Patientsdifferences in radiation administration guidelines.[25] For example,with gross residual tumor at the time of initiating chemotherapy inSIOP guidelines allow radiation dose reductions or sometimesthe CWS-86 study received no radiotherapy if there was a com-elimination of radiotherapy based on the amount of tumor remain-plete response following 7–9 weeks of chemotherapy, radiother-ing after the initiation of chemotherapy with or without a delayedapy at a dose of 32Gy for a good response (tumor volume regres-primary resection. In contrast, the STS COG generally basession ≥two-thirds), and 54.4Gy for a poor response (tumor volumeradiation doses on the amount of tumor that remains after initialregression <two-thirds and ≥one-third). The 5-year event-freesurgery before beginning chemotherapy. Therefore, patients treat-survival and overall survival rates in this study were 59% ± 3%ed according to STS COG guidelines are more likely to receiveand 69% ± 3%, respectively.radiotherapy and to receive a higher dose. This approach appears

to optimize cure rates; however, this is potentially at a cost of Newer radiotherapy modalities that may be associated withhigher toxicity.[25] reduced bone growth arrest and muscle atrophy in young children

The only patients in current STS COG trials who do not receive may be applicable and include intensity modulated radiation ther-radiotherapy are patients with completely resected embryonal apy, which is already widely utilized for rhabdomyosarcoma;tumors. For other patients, radiotherapy generally begins between brachytherapy, which may be appropriate for all or part of theweeks 3 and 15 of chemotherapy. Doses of 36–41.4Gy are gener- radiotherapy in some patients; and proton radiation, which willally used for microscopic disease (group II), depending on the likely play an increasing role in the future.[29-31] Twice dailypresence of regional node involvement, and 45–50.4Gy for gross hyperfractionated radiotherapy administration, used to escalate thedisease (group III), depending on the primary site.[19] Special dose of radiotherapy (total dose of 59.4Gy) and potentially preventconsideration is given only to patients with parameningeal tumors late effects from being worse, was compared with conventionalwith evidence of intracranial extension and girls with vaginal or daily administration (total dose of 50.4Gy) in a randomized trial asuterine tumors. Patients with parameningeal tumors and evidence part of the IRS-IV study for patients with group III rhabdomy-of intracranial extension are at risk for early CNS dissemination, osarcoma. In this study, 239 patients <22 years of age werewhich can be reduced by earlier administration of radiotherapy;[17] randomized to hyperfractionated radiotherapy and 251 to conven-therefore, these patients begin radiotherapy in week 1 of treatment. tional fractionation.[32] In this trial, hyperfractionated administra-In contrast, the need for radiotherapy in girls with vaginal or tion was not advantageous in terms of local tumor control. Optimal



approaches to local control for patients aged <1–2 years remain to using upfront phase II window studies in high-risk patients (pa-be defined.[33] tients with metastatic disease at diagnosis) and randomized trials

in intermediate risk patients (patients with stage 2 and 3 tumors ofembryonal histology with gross residual disease and localized4.3 Chemotherapytumors of alveolar histology) for agents showing activity in thephase II window setting.[19,35-38] Most recently, the topoisomerase IAll patients with rhabdomyosarcoma require chemotherapy,inhibitors, topotecan in combination with cyclophosphamide, andwhich provides local and systemic treatment. Standard chemother-irinotecan in combination with vincristine, have been tested in thisapy based on IRSG/STS COG trials in North America consists ofsetting. Although activity can be demonstrated for several agentsthe combination of vincristine, dactinomycin, and cyclophospha-in the window setting, improved survival over that with VAC formide (VAC).[2,3,19,24] Randomized trials have shown comparableintermediate-risk patients has not yet been achieved.[2,3,19,24,35-38]

but not superior outcomes for other combinations of active agents,VAC can be associated with considerable acute toxicity. Somesuch as VAC plus vincristine, ifosfamide, and etoposide (VIE) or

of the more common and important toxicities include myelosup-vincristine, dactinomycin, and ifosfamide (VAI) in the IRS-IVpression, febrile neutropenia, and hepatopathy.[19] Hepatopathy,trial, and doxorubicin in combination with VAC in the IRS-I, II,characterized by hepatomegaly, right upper quadrant pain,and III trials.[2,3,19,24] Based on the toxicity profile and the fact thathyperbilirubinemia, weight gain or ascites, thrombocytopenia, andVAC can be administered in a single day, VAC has, therefore,sometimes reversal of portal venous flow by ultrasound, occursremained the ‘standard’ treatment in North America for the pastmore frequently in young patients (aged <36 months) and usuallyseveral decades.within the first 12 weeks of beginning therapy.[34] The rate ofHowever, the manner in which VAC has been administeredchemotherapy-induced hepatopathy appears to decrease if age-during this time has changed considerably and continues to bedependent dactinomycin and cyclophosphamide administrationmodified and studied by the STS COG. For example, in the IRS-guidelines are used. Vincristine-induced peripheral neuropathyIV study, VAC included weekly vincristine (1.5 mg/m2/dose;can also be significant for these patients.maximum 2mg) for up to 13 consecutive weeks at a time, daily

In contrast, European trials (CWS, ICG, and MMT) havedactinomycin for 5 days (0.015 mg/kg/day; maximum single doserecently used ifosfamide as the alkylator in combination with0.5mg) every 3 weeks, and high-dose intravenous cyclophospha-vincristine and dactinomycin (IVA), with or without an anthra-mide (2.2 g/m2/dose) every 3 weeks with mesna uroprotection,cycline (VAIA).[21,22,39,40] Overall, this provides a backbone offollowed by myeloid growth factor support.[19] The treatmentchemotherapy that is comparable to the STS COG protocols.duration was approximately 43 weeks. Earlier trials included theSimilar to the STS COG protocols, patients with the mostuse of oral cyclophosphamide, lower doses of intravenous cyclo-favorable disease characteristics in these trials (SIOP-TNM-UICCphosphamide, and a duration of treatment of 2 years for somestage I, completely excised) received VA only, although the dura-patients.[2,3] More recently, dactinomycin has been administered astion of therapy (10–22 weeks) was somewhat shorter than used bya single dose (0.045 mg/kg/dose; maximum single dose 2.5mg)the STS COG. In the MMT-89 trial, the number of IVA coursesevery 3 weeks, the intravenous cyclophosphamide dose has beenwas determined for higher risk patients based on the SIOP-TNM-reduced (1.2 g/m2/day), and VAC administration guidelines areUICC stage, primary site, and the extent of resection, with a totalnow based on age, in part because of a higher rate of hepatopathyof 4–6 courses given.[22] In contrast with recent STS COG trials,in young children aged <36 months.[34] Myeloid growth factorsecond-line chemotherapy for patients with a poor response tosupport may be necessary and Pneumocystis carinii prophylaxisinitial chemotherapy has been more widely utilized in Europeanshould be administered.trials, which is consistent with an approach to avoid local therapyUsing risk-adapted treatment, patients with low risk disease asin responding patients.[21,22] The second-line chemotherapy combi-defined by the STS COG (patients with stage 1 tumors and grosslynation in the MMT-89 trial[22] included vincristine, carboplatin,resected stage 2 and 3 tumors of embryonal histology) haveand epirubicin. In addition to myelosuppression, hepatopathy, andreceived vincristine and dactinomycin (VA) with no cyclophos-peripheral neuropathy that may be observed with VAC, ifos-phamide or reduced-dose cyclophosphamide in an attempt tofamide-associated acute neurologic complications and Fanconimaintain excellent outcomes while minimising toxicity from therenal tubular nephrotoxicity may also occur with these chemother-administration of high-dose cyclophosphamide.[24] Reduction inapy combinations.the duration of therapy is currently under investigation for these

patients. For higher risk patients, the STS COG has systemically Currently, the European Pediatric Soft Tissue Sarcoma Studyintroduced additional and newer agents into the VAC regimen, Group (EpSSG), which represents the combined efforts of the



major European cooperative groups, is conducting a randomized pre-cooperative group era of the 1960s to >70% in more recenttrial to assess the value of adding dose-intense doxorubicin (30 trials.[2,3,19,22,24] Patients with localized embryonal rhabdomy-mg/m2 days 1 and 2 for courses 1–3 of induction treatment) to the osarcoma have benefited the most; patients with alveolar rhabdo-IVA backbone (IVADo) and of adding maintenance therapy con- myosarcoma or metastatic disease have demonstrated less im-sisting of intravenous vinorelbine (25 mg/m2 given for 3 of 4 provement.weeks) and oral cyclophosphamide (25 mg/m2/day) in patients The STS COG risk categories used for current studies are basedwith localized rhabdomyosarcoma.[41,42] on outcomes from the IRS-III and IV trials.[19,23,24] Patients in the

The novel use of existing agents and the continued introduction low risk category (patients with stage 1 tumors and grossly re-of newer agents represent ongoing strategies to improve outcomes sected stage 2 and 3 tumors of embryonal histology) had a 5-yearfor higher risk patients. The STS COG is not only introducing failure-free survival of approximately 85% in these trials. Patientsirinotecan into front-line therapy for rhabdomyosarcoma but also in the intermediate risk category (patients with stage 2 and 3using this agent as a radiation sensitizing agent in current trials. In tumors of embryonal histology with gross residual disease andaddition, the STS COG is testing interval compression of vincris- localized tumors of alveolar histology) had a 5-year failure-freetine-doxorubicin-cyclophosphamide and ifosfamide-etoposide survival of approximately 65%. The high-risk category includeschemotherapy courses with the use of granulocyte colony-stimu- patients with metastatic disease; the 4-year failure-free survival forlating factor for patients with metastatic rhabdomyosarcoma.[43] these patients remains at approximately 20%.[38]

The EpSSG is currently studying the concept of maintenance The debate surrounding response-adjusted radiation adminis-therapy for rhabdomyosarcoma to treat minimal residual disease tration with or without delayed primary resections continues. Thefollowing conventional treatment; this maintenance therapy in- more conservative approach to response-adjusted radiation admin-troduces vinorelbine into front-line therapy for rhabdomy- istration used in the IRS-IV study compared with the MMT-89osarcoma.[42] study produced superior event-free survival (78% in IRS-IV vs

Identification of newer active agents requires ongoing phase I 57% in MMT-89) and somewhat better overall survival rates (84%and II clinical trials, which depend on preliminary basic research. in IRS-IV vs 71% in MMT-89), although presumably at the cost ofTo help prioritize which agents to advance to clinical trials for higher toxicity.[25] The effect was more pronounced for somechildhood cancers, the National Cancer Institute in the US is primary sites (i.e. extremity and non-parameningeal head andsupporting the Pediatric Preclinical Testing Program (PPTP).[44] neck) than others (i.e. genitourinary).[25] Long-term effects ofThe PPTP conducts in vitro and in vivo testing of novel agents therapy and their impact on quality of life have not been rigorouslyagainst panels of childhood cancer xenografts and cell lines, compared for these two studies.including rhabdomyosarcoma. It is hoped that the PPTP will The optimal management approach for patients with metastaticexpedite the discovery of effective new therapies. Expression of disease at diagnosis and for patients with recurrent rhabdomy-vascular endothelial growth factor (VEGF) and its tyrosine kinase osarcoma remains to be defined and enrollment of these patients inreceptors in rhabdomyosarcoma has raised interest in testing clinical trials should be encouraged whenever possible. Unfortu-agents such as bevacizumab, an anti-VEGF monoclonal antibody, nately, the introduction of newer chemotherapeutic agents andand cediranib, a VEGF receptor inhibitor, against rhabdomy- high-dose chemotherapy followed by autologous stem cell rescueosarcoma cell lines.[45-48] There is now some evidence that these has not improved the outcomes for these patients.[51-54] Successfulagents have activity against rhabdomyosarcoma in vitro and in therapy for patients with metastatic rhabdomyosarcoma will likelyvivo. In addition, survival of rhabdomyosarcoma cells has been depend on a better understanding of tumor biology and the devel-linked to the mammalian target of rapamycin pathway, and inhibi- opment of therapies based specifically on molecular genetic de-tors of this pathway, such as rapamycin and its analog tem- fects in the tumors.sirolimus, have been shown to inhibit the growth of rhabdomy- Finally, the physician should be aware of possible long-termosarcoma xenografts.[49,50] Use of these newer agents in the relapse consequences of therapy and monitor for them. Total cumulativesetting is under investigation. doses of cyclophosphamide of >7.5 g/m2 have been associated

with infertility in males.[55] Total cumulative cyclophosphamide5. Outcomes for Patients with Rhabdomyosarcoma doses associated with infertility in females and ifosfamide doses

associated with infertility in either sex remain to be defined. LateBy applying the principles and approaches discussed in section effects in girls treated for pelvic rhabdomyosarcoma using current

4 in a systematic way through clinical trials, the 5-year survival for treatment strategies can be particularly significant and illustraterhabdomyosarcoma has increased from approximately 25% in the the need for long-term medical and psychosocial follow-up as well



13. Breneman JC, Lyden E, Pappo AS, et al. Prognostic factors and clinical outcomesas refinement of the treatment approach.[56] Second malignantin children and adolescents with metastatic rhabdomyosarcoma: a report from

neoplasms have been reported at a rate of 2.9% at 10 years, which the Intergroup Rhabdomyosarcoma Study IV. J Clin Oncol 2003 Jan 1; 21 (1):78-84is comparable to the rate in other long-term survivors of childhood

14. Wiener ES, Anderson JR, Ojimba JI, et al. Controversies in the management ofcancers, and generally include alkylator-induced leukemias, radia-paratesticular rhabdomyosarcoma: is staging retroperitoneal lymph node dis-

tion-induced sarcomas and carcinomas, and tumors associated section necessary for adolescents with resected paratesticular rhabdomy-osarcoma? Semin Pediatr Surg 2001 Aug; 10 (3): 146-52with cancer predisposition syndromes.[57] Long-term conse-

15. Neville HL, Andrassy RJ, Lobe TE, et al. Preoperative staging, prognostic factors,quences related to bone growth arrest, muscle atrophy, and bladderand outcome for extremity rhabdomyosarcoma: a preliminary report from the

dysfunction following radiotherapy can also be significant.[58] Intergroup Rhabdomyosarcoma Study IV (1991-1997). J Pediatr Surg 2000Feb; 35 (2): 317-21

16. Neville HL, Andrassy RJ, Lally KP, et al. Lymphatic mapping with sentinel node6. Conclusions biopsy in pediatric patients. J Pediatr Surg 2000 Jun; 35 (6): 961-4

17. Michalski JM, Meza J, Breneman JC, et al. Influence of radiation therapy para-Optimal management of rhabdomyosarcoma continues to pre- meters on outcome in children treated with radiation therapy for localized

parameningeal rhabdomyosarcoma in Intergroup Rhabdomyosarcoma Studysent many challenges and requires carefully planned, coordinatedGroup trials II through IV. Int J Radiat Oncol Biol Phys 2004 Jul 15; 59 (4):

care by an experienced team. Enrollment in clinical trials should 1027-38be encouraged whenever possible. It is hoped that advances in our 18. Rodary C, Flamant F, Donaldson SS. An attempt to use a common staging system

in rhabdomyosarcoma: a report of an international workshop initiated by theunderstanding of the underlying biology of rhabdomyosarcomaInternational Society of Pediatric Oncology (SIOP). Med Pediatr Oncol 1989;

will lead to newer therapies that will benefit all patients with 17 (3): 210-5

rhabdomyosarcoma in the future. 19. Crist WM, Anderson JR, Meza JL, et al. Intergroup rhabdomyosarcoma study-IV:results for patients with nonmetastatic disease. J Clin Oncol 2001 Jun 15; 19(12): 3091-102

Acknowledgments20. Spunt SL, Lobe TE, Pappo AS, Aggressive surgery is unwarranted for biliary tract

rhabdomyosarcoma. J Pediatr Surg 2000 Feb; 35 (2): 309-16Dr Walterhouse is a member of the Soft Tissue Sarcoma Committee of the

21. Koscielniak E, Harms D, Henze G, et al. Results of treatment for soft tissueChildren’s Oncology Group (STS COG) and study chair for COG ARST0331. sarcoma in childhood and adolescence: a final report of the German Coopera-No sources of funding were used to assist in the preparation of this review. The tive Soft Tissue Sarcoma Study CWS-86. J Clin Oncol 1999 Dec; 17 (12):

3706-19authors have no conflicts of interest that are directly relevant to the content of22. Stevens MC, Rey A, Bouvet N, et al. Treatment of nonmetastatic rhabdomy-this review.

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Optimal Management Strategies for Rhabdomyosarcoma in Children