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Rhabdomyosarcoma

Lead contributors:Andrea Ferrari, MD

Christina Meazza, MDMichela Casanova, MDPediatric Oncology Unit

Fondazione IRCCS Istituto Nazionale TumoriMilan, Italy

A. Introduction

Soft tissue sarcomas are a very heterogeneous group of non-epithelial

extraskeletal malignancies that are classified on a histogenic basis according to

the adult tissue they resemble. Overall, soft tissue sarcomas are rare, with an

annual incidence of approximately 2–3 cases in 100,000, they account for less

than 1% of all malignant tumors and are responsible for 2% of the total cancer-

related mortality.1 However, these tumors are relatively more common in

children, accounting for 8% of all pediatric tumors.

Rhabdomyosarcomas (RMSs) represents more than 50% of soft tissue

sarcomas occurring in childhood and adolescence (annual incidence, 4.3 cases

per million people under 20 years of age). Although RMS is a rare tumor, it is

one of the typical pediatric cancers. It can occur at any age, but its incidence

decreases significantly with increasing age: about 3 out of 4 cases occur in

children under 10 years, with a peak incidence in children between 3 and 5

years old and, as well as a second, smaller peak in adolescents).2,3

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A. Figure 1

A. References1Wexler LH, Crist WM, Helman LJ. Rhabdomyosarcoma and the undifferentiated sarcomas. In:Pizzo PA, Poplack DG, ed. Principles and Practice of Pediatric Oncology, 4th ed. Philadelphia,PA: Lippincott Williams & Wilkins, 2002: 939-971.2Gurney JG, Young GL Jr, Roffers SD, et al. Soft tissue sarcomas. In: Ries LAG, Smith MA, GurneyJG, et al., eds. Cancer Incidence and Survival among Children and Adolescents: United StatesSEER program 1975-1995, National Cancer Institute, SEER Program. NIH Pub. No. 99-4649.Bethedsa, MD, 1999;111: //seer.cancer.gov/publications/childhood/softtissue.pdf.3Gatta G, Capocaccia R, Stiller C, et al. Childhood cancer survival trends in Europe: A EUROCAREWorking Group study. J Clin Oncol.2005; 23(16):3742-3751.

B. Biological and Pathological Aspects

As in most soft tissue sarcomas, the pathogenesis of RMS is still

unknown, and there are no well-established risk factors. Ionizing radiations,

chemical carcinogens, and oncogenic viruses have been variously associated

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with the development of some types of sarcomas, but the etiology remains

unclear. Clinical evidence of a genetic predisposition to RMS is rare. Studies

have shown that neurofibromatosis type 1, Li Fraumeni syndrome, Costello

syndrome, and other genetic diseases may be rarely associated with RMS. RMS

is reported to be associated with an increased incidence of congenital

anomalies, particularly those involving the genitourinary and central nervous

systems.1-5

RMS arises from immature mesenchymal cells committed to skeletal

muscle differentiation, therefore, it can develop anywhere in the body,

including sites in which striated muscle tissue is normally absent. RMS is a

highly malignant tumor that is characterized by local aggressiveness and a

propensity to metastasize; it differs from typical adult soft tissue sarcomas in

terms of its etiology and greater sensitivity to chemo- and radiotherapy.9

Two classic histological subtypes of RMS have been described, the

embryonal subtype and the alveolar subtype. A third form, the pleomorphc

RMS, should be considered separately from the other RMS subtypes. In fact,

pleomorphic RMS is very rare in pediatric populations (incidence, less than 1%)

and in among adolescents and young adults. It typically occurs in the deep soft

tissues of the extremities in individuals older than 45–50 years (with a higher

incidence in males). In the past, pleomorphic RMS was often frequently

diagnosed, however, it gradually came to be regarded as a variant of malignant

fibrous histiocytoma (and its existence as a separate type put in doubt). More

recently, the criteria for diagnosis have been refined with advances in the

techniques for ultrastructural, immunohistochemical, and molecular analyses.6,7

Different data suggest that pleomorphic RMS is probably biologically and

clinically closer to high-grade spindle-cell sarcoma in adults than to pediatric

RMS.8

An international consensus meeting proposed a new International system

for the classification of RMS based on the relationship between histological

findings and prognosis. In this system the subtypes associated with a

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favourable prognosis are the 2 embryonal variants, the botryoid and spindle-

cell (or leiomyomatous) variants. The classic embryonal subtype, is considered

to be an intermediate prognosis; and alveolar RMS, as well as the recently

described solid variant, has unfavorable prognosis. Diagnostic tests for the

alveolar subtype should be performed if there is any degree of alveolar

architecture or cytology.10-12 RMS cells can be recognized by their expression of

myosin and MyoD protein family antigens; myoglobin, desmin, and muscle-

specific actin are also useful diagnostic markers.13 Cytogenetic and molecular

analyses may be useful for the diagnosis of RMS and for defining subtypes

because cytogenetic abnormalities are well-known in these tumors. Most

alveolar RMSs display a specific translocation, t(2;13)(q35;q14), involving the

PAX3 and FKHR genes;14,15 another variant, t(1;13)(p36;q14), has been less

frequently reported. Embryonal RMSs lack a tumor-specific translocation but

generally exhibit loss of heterozygosity at chromosome 11p, which could

inactivate tumor-suppressor genes.16-19

A pattern of association between the histotypes and clinical features of

RMS has been described. The spindle-cell variant typically occurs in the

paratesticular region, while the botryoid variant is usually associated with the

mucosa of the genitourinary tract or the head and neck region, and occurs in

young children. The alveolar histiotype is more frequently localized at the

extremities and in the trunk, and is typically found in adolescents and young

adults.

B. References

1Ruymann FB, Maddux HR, Ragab A, et al. Congenital anomalies associated withrhabdomyosarcoma: An autopsy study of 115 cases. A report from the IntergroupRhabdomyosarcoma Study Committee (representing the Children's Cancer Study Group, thePediatric Oncology Group, the United Kingdom Children's Cancer Study Group, and the PediatricIntergroup Statistical Center). Med Pediatr Oncol. 1988; 16(1):33-39.2Diller L, Sexsmith E, Gottlieb A, et al. Germline p53 mutations are frequently detected in youngchildren with rhabdomyosarcoma. J Clin Invest.1995; 95:1606.

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3Sung L, Anderson JR, Arndt C, et al. Neurofibromatosis in children with rhabdomyosarcoma: Areport from the Intergroup Rhabdomyosarcoma Study IV. J Pediatr, 2004; 144:666-668.4Gripp KW, Scott CI, Jr, Nicholson L, et al. Five additional Costello syndrome patients withrhabdomyosarcoma: Proposal for a tumor screening protocol. Am J Med Genet.2002; 108:80-87.5Ferrari A, Bisogno G, Macaluso A, et al. Soft tissue sarcomas in children and adolescents withneurofibromatosis type 1. Cancer, 2007; 109(7):1406-1412.6Gaffney EF, Dervan PA, Fletcher CDM. Pleomorphic rhabdomyosarcoma in adulthood: Analysisof 11 cases with definition of diagnostic criteria. Am J Surg Pathol, 1993; 17:601-609.7Schurch W, Bégin LR, Seemayer TA, et al. Pleomorphic soft tissue myogenic sarcomas ofadulthood: A reappraisal in the mid-1990s. Am J Surg Pathol, 1996; 20:131-147.8Ferrari A, Dileo P, Casanova M, et al. Rhabdomyosarcoma in adults: A retrospective analysis of171 patients treated at a single institution. Cancer, 2003; 98:571-580.9Wexler LH, Crist WM, Helman LJ. Rhabdomyosarcoma and the undifferentiated sarcomas. In:Pizzo PA, Poplack DG, ed. Principles and Practice of Pediatric Oncology, 4th ed. Philadelphia, PA:Lippincott Williams & Wilkins, 2002: 939-971.10Newton WA, Gehan EA, Webber BL, et al. Classification of rhabdomyosarcomas and relatedsarcomas. Pathologic aspects and proposal for a new classification - An IntergroupRhabdomyosarcoma Study. Cancer, 1995; 70:1073-1085.11Asmar L, Gehan EA, Newton WA, et al. Agreement among and within groups of pathologists inthe classification of rhabdomyosarcoma and related childhood sarcomas. Report of aninternational study of four pathology classifications. Cancer.1994; 1;74(9):2579-2588.12Qualman SJ, Coffin CM, Newton WA, et al. Intergroup rhabdomyosarcoma study: Update forpathologists. Pediatr Dev Pathol, 1998; 1(6):550-561.13Sebire NJ, Malone M. Myogenin and MyoD1 expression in paediatric rhabdomyosarcoma. J ClinPathol, 2003; 56:412-416.14Barr FG. Gene fusions involving PAX and FOX family members in alveolar rhabdomyosarcoma.Oncogene, 2001; 20(40):5736-5746.15Sorensen PH, Lynch JC, Qualman SJ, et al. PAX3-FKHR and PAX7-FKHR gene fusions areprognostic indicators in alveolar rhabdomyosarcoma: A report from the children's oncologygroup. J Clin Oncol 20(11):2672-2679, 2002.16Parham DM. Pathologic classification of rhabdomyosarcomas and correlations with molecularstudies. Mod Pathol 14(5):506-514, 2001.17Pappo AS, Shapiro DN, Crist WM, Maurer HM. Biology and therapy of pediatricrhabdomyosarcoma. J Clin Oncol 13:2123-2139, 1995.18Barr FG. Molecular genetics and pathogenesis of rhabdomyosarcoma. J Pediatr Hematol Oncol19:483-491, 1997.19Linardic CM, Downie DL, Qualman S, et al. Genetic modeling of human rhabdomyosarcoma.Cancer Res. 65(11):4490-4495, 2005.

C. Clinical Findings

RMSs can arise anywhere in the body, although the most common sites

are the head and neck region (parameningeal and orbital sites) and the

genitourinary tract (the bladder, prostate, vagina, or paratesticular region).

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C. Figure 1

Like other soft tissue sarcomas, an enlarging soft tissue mass is the usual

expression of the primary tumor, but in deep sites (the pelvis, or trunk) the

clinical evidence of the mass could appear relatively late. Therefore, the

presenting symptoms depend on the site of origin. Pain can be associated with

RMS at various sites. Proptosis, nasal obstruction, hemorrhagic discharge, and

cranial nerve palsies are typical symptoms of RMS in the head and neck.

Hematuria, polypoid vaginal extrusion of mucosanguineous tissue, and a

painless scrotal mass are the typical presenting signs of genitourinary RMS,

while ascites and gastrointestinal or urinary tract obstruction may be

associated with intra-abdominal RMS.

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Ultrasonography is often the first diagnostic modality used in diagnosis.

Computed tomography (CT) scans or magnetic resonance imaging (MRI) of the

primary site improve the first local evaluation of the site and are mandatory for

assessing local tumor extension before any treatment is given. MRI could be

considered to be superior to CT for defining tumor extension into the soft

tissue.1

After evidence of a suspected soft part lesion is obtained, pathological

assessment is necessary to identify the histological nature of the tumor. An

initial biopsy is performed to establish a diagnosis, as well as to provide

enough material for immunochemical, cytogenetic, and biological studies and

for eventual central pathology review for patients who can be included in

multicentre trials.2 Biopsy should be the initial surgical procedure in all

patients. When primary excision with adequate margins seems possible, the

biopsy could be considered to avoid inadequate surgery (except perhaps in

cases of solid masses with paratesticular sites, which should be directly

resected via an inguinal approach). Core needle biopsy or aspiration can help in

detecting malignancy although it is not very effective for subtype identification

and does not provide adequate tissue for additional studies. Most RMS trials

require an incisional biopsy, which is to be considered the standard option.

Experienced surgeons should carefully plan the surgical procedure, taking into

account the definitive surgery that may subsequently be required as well as the

scar that will remain and the biopsy tract. For example, in RMS of the

extremities, the incision must be longitudinal to the limb and should not

traverse multiple compartments. Careful hemostasis should be carried out to

avoid postsurgical hematoma and drains. Ultrasound-guided core needle

biopsy (tru-cut) guided by ultrasound or CT scan may be appropriate in cases

of inaccessible tumor sites.

After the histological diagnosis, staging investigations must be

performed to detect possible regional and distant metastases. RMS is a very

aggressive tumor that tends to invade not only contiguous structures but also

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disseminates along both lymphatic and hematogenous routes. About 20% of

patients have distant metastases detected at the time of diagnosis, with the

lungs being the most common site of metastasis. Dissemination to the regional

lymph nodes is present in 10–20% of cases. This incidence depend on the

primary site (the incidence of such dissemination is higher in RMS of the

extremities, genitourinary tract, and pelvis). It is of note that the frequency

with which positive lymph nodes are reported depends on the diagnostic

approach adopted. The diagnostic approach could be a clinical or radiological

assessment. Local extent of disease should be assessed by the best

radiological resources available. It is recommended that either CT scan and MRI

be employed to assess disease. Distant assessment requires, chest CT, bone

scanning with technetium (with plain x-rays of abnormal sites), abdominal

ultrasound, and bone marrow aspiration plus trephine biopsy should be

performed to identify dissemination to the lungs, bone, abdomen, and bone

marrow dissemination, respectively, for all RMS patients. Positron emission

tomography (PET) is not considered a standard technique for staging RMS.

RMS of special sites requires particular evaluation procedures:

1) for parameningeal RMS, cerebrospinal fluid cytology is required for the risk

of meningeal dissemination

2) for RMS of the extremities, due to the higher risk of dissemination to the

lymph nodes,3-5 careful radiological evaluation of the regional nodes as well as

biopsy is suggested, even in cases with clinically uninvolved nodes.6,7 However,

the possible role of sentinel node biopsy is still unclear8,9

3) for paratesticular RMS, adequate staging of the retroperitoneal lymph nodes

is strongly recommended.

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While European research groups consider thin-cut CT scan as a sufficient

procedure,10-12 North American groups recommend surgical assessment in

patients older than 10 years, given the higher risk of nodal dissemination is

higher in these patients than in younger children.13-16

C. References1McHugh K, Boothroyd AE. The role of radiology in childhood rhabdomyosarcoma. Clin Radiol,1999; 54:2-10.2Qualman SJ, Bowen J, Parham DM, et al. Protocol for the examination of specimens frompatients (children and young adults) with rhabdomyosarcoma. Arch Pathol Lab Med, 2003;127(10):1290-1297.3Lawrence W, Hays DM, Heyn R, et al. Lymphatic metastases with childhood rhabdomyosarcoma.A report from the Intergroup Rhabdomyosarcoma Study. Cancer, 1987; 60:910-915.4LaQuaglia MP, Ghavimi F, Penenberg D, et al. Factors predictive of mortality in pediatricextremity rhabdomyosarcoma. J Pediatr Surg,1990; 25:238-244.5Andrassy RJ, Corpron CA, Hays D, et al. Extremity sarcomas: An analysis of prognostic factorsfrom the Intergroup Rhabdomyosarcoma Study III. J Pediatr Surg, 1996; 31:191-196.6Heyn R, Beltangady M, Hays D, et al. Results of intensive therapy in children with localizedalveolar extremity rhabdomyosarcoma: A report from the Intergroup Rhabdomyosarcoma Study.J Clin Oncol, 1989; 7:200-207.7Neville HL, Andrassy RJ, Lobe TE, et al. Preoperative staging, prognostic factors, and outcomefor extremity rhabdomyosarcoma: A preliminary report from the IntergroupRhabdomyosarcoma Study IV (1991-1997). J Pediatr Surg, 2000; 35:317-321.8Neville HL, Andrassy RJ, Lally KP, et al. Lymphatic mapping with sentinel node biopsy inpediatric patients. J Pediatr Surg, 2000; 35:961-964.9McMulkin HM, Yanchar NL, Fernandez CV, Giacomantonio C. Sentinel lymph node mapping andbiopsy: A potentially valuable tool in the management of childhood extremityrhabdomyosarcoma. Pediatr Surg Int, 2003; 19(6):453-456.10Olive D, Flamant F, Zucker JM, et al. Paraaortic lymphadenectomy is not necessary in thetreatment of localized paratesticular rhabdomyosarcoma. Cancer, 1984; 54(7):1283-1287.11Ferrari A, Bisogno G, Casanova C, et al. Paratesticular rhabdomyosarcoma: Report from theItalian and German Cooperative Group. J Clin Oncol, 2002; 20:449-455.12Stewart RJ, Martelli H, Oberlin O, et al. Treatment of children with nonmetastatic paratesticularrhabdomyosarcoma: Results of the Malignant Mesenchymal Tumors studies (MMT 84 and MMT89) of the International Society of Pediatric Oncology. J Clin Oncol,2003; 19:793-798.13Wiener ES, Lawrance W, Hayes D, et al. Retroperitoneal node biopsy in paratesticularrhabdomyosarcoma. J Pediatr Surg, 1994; 29:171-177.14Wiener ES, Grier H, Breneman J, et al. Changing pattern of relapse with localized paratesticularrhabdomyosarcoma in the Intergroup Rhabdomyosarcoma Study Group trials. Proc Am Soc ClinOncol 16, abstract 1865, 1997.15Wiener ES, Anderson JR, Ojimba JI, et al. Controversies in the management of paratesticularrhabdomyosarcoma: Is staging retroperitoneal lymph node dissection necessary for adolescentswith resected paratesticular rhabdomyosarcoma? Semin Pediatr Surg, 2001;10(3):146-152.16Crist WM, Anderson JR, Meza JL, et al. Intergroup Rhabdomyosarcoma Study-IV: Results forpatients with nonmetastatic disease. J Clin Oncol,2001; 19:3091-3102.

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D. Prognosis

In the past 30 years, the cure rate for RMS has dramatically improved

from 25–30% (before the modern chemotherapy era) to approximately 70% 1

This success is due to the development of multidisciplinary and risk-adapted

treatment approaches developed by international cooperative groups.

D. Table 1.Event free survival (EFS) and overall survival (OS) at 5 year in the internationalcooperative studies over the years (localized RMS).

5yr EFS 5yr OSItalian Cooperative Group - Associazione ItalianaEmatologia Oncologia Pediatrica (ICG-AIEOP)

RMS79 55% 62%RMS88 63% 72%RMS96 67% 81%

International Society of Pediatric OncologyMalignant Mesenchymal Tumour Committee (SIOP-MMT)

MMT84 52% 72%MMT98 57% 71%

German Soft Tissue Sarcoma Cooperative Group(Co-operative Weichteilsarkomen Studie – CWS)

CSW81 70% 71%CWS86 79% 84%CWS95 67% 81%

Intergroup Rhabdomyosarcoma Study (IRS)IRS I(1972-1978)

- 55%

IRS II(1978-1984)

55% 63%

IRS III(1984-1990)

65% 71%

IRS IV(1991-1997)

78% 84%

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North American and European trials form the basis of every study

concerning pediatric RMS. In particular, studies coordinated by the Intergroup

Rhabdomyosarcoma Study (IRS) group (currently known as the Soft Tissue

Sarcoma Committee of the Children’s Oncology Group (COG)) represent

successful clinical models of coordinated in the study of a rare disease.2-5 In

Europe, 3 independent cooperative groups have coordinated studies of

pediatric soft tissue sarcomas: the International Society of Pediatric Oncology-

Malignant Mesenchymal Tumor Committee (SIOP-MMT),6,7 the German Soft

Tissue Sarcoma Cooperative Group (Cooperative Weichteilsarkomen Studie

(CWS)),8,9 and, the Italian Cooperative Group (ICG; Associazione Italiana

Ematologia Oncologia Pediatrica-Soft Tissue Sarcoma Committee (AIEOP-

STSC)).10-14 Early in the present century, these groups joined forces to create a

pan-European group—the European pediatric Soft Tissue Sarcoma Study Group

(EpSSG).15-17

The overall outcome of RMS patients with localized disease is around

70%, but is strictly correlated to the risk group. Several prognostic factors have

been identified over the years and are used for risk stratification and for

developing risk-adapted treatment strategies that aims to improve the cure

rates in patients with a less favorable disease by using more intensive therapy,

while avoiding over-treatment and containing side effects, without jeopardizing

the results in cases where the prognosis is more favorable. Historically, stage

classification was based on the IRS post-surgical grouping system, which

classifies patients according to the amount and extent of residual tumor

detected after the initial surgery,3 and on the pre-treatment clinical tumor-

node-metastases (TNM) classification system.18 The IRS system represents the

quality of the primary surgical procedure and correlates with outcomes.

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D. Table 2Staging systems

TNM classificationT1 tumor confined to organ or tissue of origin

T1A - tumor 5 cmT1B - tumor > 5 cm

T2 tumor not confined to organ or tissue of origin

T2A - tumor 5 cm

T2B - tumor > 5 cm

N0 no evidence of lymph node involvement

N1 regional lymph node involvement

M0 no evidence of distant metastases

M1 distant metastases

IRS staging system

group I completely-excised tumors with negative microscopicmargins

group II grossly-resected tumors with microscopic residual diseaseand/or regional lymph nodal spread

groupIII

gross residual disease after incomplete resection or biopsy

groupIV

metastases at onset

LegendTNM - Tumor-Nodes-Metastases classificationIRS - Intergroup Rhabdomyosarcoma Study staging system

In the ICG RMS-88 protocol, 5-year overall survival (OS) rate was 93% for

IRS group I patients, 77% for group II patients, and 65% for group III patients. In

contrast, the OS rate is generally less than 30% for patients with metastases at

the time of diagnosis.14

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The TNM system correlates with the tumor burden at the time of diagnosis.

Patients with tumors measuring less than 5 cm generally have worse outcomes

than patients with smaller tumors (in the ICG RMS-88 study, the 5-year OS rates

were 67% and 82%, respectively), as well as patients with T2 tumors versus

those with T1 tumors (5-year OS rates, 64% and 81% respectively). However, as

expected, the presence of regional spread represents a significant predictor of

an adverse outcome (5-year OS rates, 60% in N1 patients and 76% in N0 tumors

respectively).

With the recognition of different prognostic factors, risk assessment has

become more complex but also more careful.

D. Figure 3

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In particular, histology is a main variable: the alveolar subtype is generally

associated with a worse outcome (in the ICG RMS-88 study, the 5-year OS rate

was 61% for alveolar RMS and 79% for non-alveolar RMS subtypes),14 although

recent data suggest it does not maintain this adverse prognostic role in RMS

arising in paratesticular sites.19 The tumor site is another significant factor:

tumors arising in the extremities, trunk, parameningeal sites, bladder, and

prostate have worse outcomes than those arising in the orbit, paratesticular

regions, and vagina20

D. Figure 4

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Finally, age has recently been identified as a major prognostic factor, with

infancy and adolescence being the unfavorable age periods.13,21 In the ICG RMS-

88 study, the 5-year OS rate was 35% in children aged less than 1 year, 80% in

patients aged 1–10 years, and 70% in older patients. Similarly, the last IRS-IV

study reported a 3-year failure-free survival rate of 55% for infants, 83% for

children aged 1–10 years, and 68% for patients aged more than 10 years.14

These prognostic factors are often interdependent. For example, the alveolar

subtype is more frequent in tumors of the extremities and in adolescents.

In combining of these factors, the risk-stratification of the new EpSSG protocol

for localized RMS identifies 4 groups (low, standard, high, and very high risk)

and 8 subgroups (from A to H), each with its own recommended treatment.17

D. Figure 5

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In the IRS-V study, classifies patients along much the same lines, identifying 3

groups (low, intermediate, and high risk) and 17 subgroups.1

D. Figure 6*

*From Raney RB, Anderson JR, Barr FG, et al.1

D. References

1Raney RB, Anderson JR, Barr FG, et al. Rhabdomyosarcoma and undifferentiated sarcoma in firsttwo decades of life: A selective review of Intergroup Rhabdomyosarcoma Study Groupexperience and rationale for Intergroup Rhabdomyosarcoma Study V. J Pediatr Hematol Oncol,2001; 23(4):215-220.2Crist WM, Anderson JR, Meza JL, et al. Intergroup Rhabdomyosarcoma Study-IV: Results forpatients with non-metastatic disease. J Clin Oncol, 2001; 19:3091-3102.3Maurer HM, Beltangady M, Gehan EA, et al. The Intergroup Rhabdomyosarcoma Study-I. A finalreport. Cancer, 1988; 61:209-220.4Maurer HM, Gehan EA, Beltangady M, et al. The Intergroup Rhabdomyosarcoma Study-II.Cancer, 1993; 71:1904-1922.5Crist WM, Gehan EA, Ragab AH, et al. The third Intergroup Rhabdomyosarcoma Study. J ClinOncol, 1995; 13:610-630, 1995.6Flamant F, Rodary C, Rey A, et al. Treatment of non-metastatic rhabdomyosarcomas inchildhood and adolescence. Result of the second study of the International Society of PaediatricOncology: MMT84. Eur J Cancer, 1998; 34(7):1050-1062.

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7Stevens MC, Rey A, Bouvet N, et al. Treatment of non-metastatic rhabdomyosarcoma inchildhood and adolescence: Third study of the International Society of Paediatric Oncology--SIOPMalignant Mesenchymal Tumor 89. J Clin Oncol, 2005; 23:2618-2628.8Koscielniak E, Jurgens H, Winkler K, et al. Treatment of soft tissue sarcoma in childhood andadolescence: A report of the German Cooperative Soft Tissue Sarcoma Study. Cancer, 1992;70(10):2557-2567.9Koscielniak E, Harms D, Henze G, et al. Results of treatment for soft tissue sarcoma inchildhood and adolscence: A final report of the German Cooperative Soft Tissue Sarcoma StudyCWS-86. J Clin Oncol , 1999; 17:3706-3719.10Cecchetto G, Carli M, Sotti G, et al. Importance of local treatment in pediatric soft tissuesarcomas with microscopic residual after primary surgery: Results of the Italian CooperativeStudy RMS-88. Med Pediatr Oncol, 2000; 34:97-101.11Cecchetto G, Guglielmi M, Inserra A, et al. Primary re-excision: The Italian experience inpatients with localized soft tissue sarcomas. Pediatr Surg Int, 2001; 17(7):532-534.12Carli M, Passone E, Perilongo G, Bisogno G. Ifosfamide in pediatric solid tumors. Oncology,2003; 65(Suppl2):99-104.13Ferrari A, Casanova M, Bisogno G, et al. Rhabdomyosarcoma in infants younger than one yearold: A report from the Italian Cooperative Group. Cancer , 2003; 97(10):2597-2604.14Carli M, Bisogno G, Guglielmi M, et al. Improved outcome for children with embryonalrhabdomyosarcoma: Results of the Italian Cooperative Study. International Society of PaediatricOncology SIOP XXXII Meeting. Med Pediatr Oncol, 2000; 35(3): abstract O-87.15Casanova M, Ferrari A, Bisogno G, et al. Vinorelbine and low-dose cyclophodphamide in thetreatment of pediatric sarcomas. Pilot study for the upcoming European RhabdomyosarcomaProtocol. Cancer, 2004; 101(7):1664-1671.16Bisogno G, Ferrari A, Bergeron C, et al. The IVADo regimen, a pilot study with ifosfamide,vincristine, actinomycin and doxorubicin in children with metastatic soft tissue sarcoma. A pilotstudy by the European pediatric Soft Tissue Sarcoma Study Group. Cancer, 2005; 103(8):1719-1724.17Ferrari A, Casanova M. Current chemotherapeutic strategies for rhabdomyosarcoma. ExpertRev Anticancer Ther, 2005; 5(2):283-294.18Harmer MH. TNM Classification of pediatric tumors. Geneva, Switzerland, UICC InternationalUnion against Cancer, 1982, pp 23-28.19Ferrari A, Bisogno G, Casanova M, et al. Is alveolar histotype a prognostic factor inparatesticular rhabdomyosarcoma? The experience of Italian and German Soft Tissue SarcomaCooperative Group. Pediatr Blood Cancer, 2004; 42(2):134-138.20Crist WM, Garnsey L, Beltangady MS, et al. Prognosis in children with rhabdomyosarcoma: Areport of the Intergroup Rhabdomyosarcoma Studies I and II. J Clin Oncol , 1990; 8:443-452.21Joshi D, Anderson JR, Paidas C. Age is an independent prognostic factor inrhabdomyosarcoma: A report from the Soft Tissue Sarcoma Committee of the Children'sOncology Group. Pediatr Blood Cancer, 2004; 42(1):64-73.

E. Treatment

RMS is a rare tumor, and its treatment is necessarily multidisciplinary and

complex. Patients should be referred to select institutions with staff that have

adequate experience in treating pediatric tumors and multidisciplinary skills for

enrolling patients in clinical trials.

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Patients with RMS are treated within pediatric trials. This is true not only

for children and adolescents but also for adults. Although rare, RMS can occur

in adults and is usually associated with a worse outcome than RMS in children

(OS rate, 20–50%), raising doubts that adult RMS is a completely different

disease from childhood RMS. 1-5 Recent findings (from a large-scale

retrospective study conducted by the Istituto Nazionale Tumori of Milan, which

stratified patients in relation to the appropriateness of the treatment according

to current treatment guidelines for childhood RMS) have suggested that the

outcomes in adults might be more like the those in children when adult

patients are treated according to treatment strategies like the one adopted for

children.6

Of course, various factors may contribute to the globally unsatisfactory

outcomes of adult RMS. First, the clinical presentation is unfavorable in adults,

because the incidence of the alveolar subtype and of large invasive tumors is

greater in adults and also because it is known that age itself is a prognostic

factor. Second, adults are less tolerant of intensive treatment. Finally, the more

pronounced expression of multidrug resistance proteins is stronger in adult

RMS than in childhood RMS. The medical oncologist’s attitude toward a tumor

that occurs so rarely in adulthood may also play a role, at least in part, in the

treatment outcomes. All possible efforts should be made to increase the

number of adult RMS patients given adequate treatment, either within pediatric

trials or with therapies in line with those treatment strategies.6

E.1 Overall treatment strategy

Multimodality therapy involving surgery, radiotherapy, and chemotherapy

is necessary for RMS.7,8-11 The optimal intensity and timing of these treatment

modalities must be planned with regard to the patient’s risk stratification and

the late effects of treatment. RMS can be distinguished from other soft tissue

sarcomas that occur in children and adults, because RMS is generally a highly

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chemosensitive tumor. Although local control is essential for the successful

treatment of RMS (because local progression or relapse is the main cause of

treatment failure),12,13 surgery and radiotherapy need to be used with caution,

given the important sequelae of these treatments in children. The efficacy of

chemotherapy permits a less aggressive use of these modalities. Debate on the

possible different approaches to, intensity, and timing of local therapies, and

the indications for radiotherapy in particular (in patients who achieve complete

remission after chemotherapy) have given rise to the concept of the “total

burden of therapy” experienced by a patient and the predicted sequelae that

different treatments may have. In particular, the philosophy behind the SIOP-

MMT studies has pointed to a lesser use of radiotherapy. Although this

produced generally worse local relapse rates than those reported elsewhere,

the OS rates could be super imposable, at least for some subgroups of

patients, since a significant number of patients with local relapse were cured by

salvage treatment. On the other hand, a proportion of patients could be cured

without aggressive local treatment and therefore without sequelae. In other

words, this strategy demands that the outcome be measured on the basis of a

combination of OS and the “cost” of survival in terms of sequelae, rather than

on the basis of disease-free survival alone.14,15-17

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E. Figure 1*

*From Oberlin O, Rey A, Anderson J, et al.42

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E. Figure 2*

*From Donaldson SS, Anderson JR.17

The possible complications associated with different treatment strategies

should always balanced with the beneficial effects, and functional and cosmetic

damage should be minimized without jeopardizing the outcome. Late

complications may be related to chemotherapy: cyclophosphamide may cause

infertility,18 ifosfamide-based regimens may cause long-term renal damage,19,20

and doxorubicin when given at a high cumulative dose is known to cause

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cardiotoxicity.21 Moreover, the continuing use of high doses of alkylating

agents (and the use of etoposide), together with radiotherapy, contributes to a

significantly increased risk of secondary malignancies in long-term survivors of

childhood cancer.22-24 Compared to chemotherapy, radiotherapy carries a high

risk of severe late sequelae, particularly when delivered to young children.

Survivors of head and neck RMS, particularly those with parameningeal RMS

(requiring full doses and large volumes of radiotherapy) a high risk of

developing significant sequelae: the most common and evident late side effect

is facial growth retardation (bone and soft tissue hypoplasia and facial

asymmetry), followed by dental abnormalities, neuroendocrine dysfunction

(growth hormone deficiency and hypothyroidism), visual problems, hearing

loss, and intellectual delay.25-28

E.2 Surgery

Local treatment is essential in RMS because local progression or relapse

is the major cause of treatment failure.12,13,29 Surgery for RMS has evolved over

the years from the primary treatment modality (prior to the introduction of

effective antineoplastic agents) to one component of a multidisciplinary

approach, and the associated approach has evolved from an aggressive surgery

to a more conservative and organ sparing procedures.30,31 It is noteworthy that

chemotherapy and radiotherapy permit in some cases to cure the disease,

without the need for surgery.32

Primary en bloc resection should be performed only if complete resection

is possible (i.e., with histologically detected free margins) and if non-mutilating

excision is considered feasible, otherwise, a biopsy should be recommended.

In cases where surgery is associated with the risk of anatomic or functional

impairment, are not a recommended as first surgical approach and should be

considered only as salvage treatment, after the failure of other procedures.30,33-35

In fact, many tumors considered unresectable at diagnosis can be

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conservatively and completely resected in a large percentage of cases after

tumor shrinkage achieved by primary chemotherapy. However, a possible role

for debulking procedure has been suggested for large retroperitoneum and

pelvis.36 Initial wide resections are generally considered to be adequate to

obtain local control of RMS,37,40 differently from adult sarcomas that in generally

should require compartmental resection or wide excision followed by

radiotherapy. In cases of primary marginal resection, primary reoperation (prior

to any other treatment) is recommended when feasible, to achieve complete

resection without doubtful microscopic residues, and to eliminate the need for

radiation.38,39,41

In addition to the surgeon’s judgment and experience, other factors that

largely determine the feasibility of surgery are the tumor size, local

invasiveness, and especially the tumor site strongly affected the feasibility of

surgery, that is also influenced by the surgeon’s own judgment and

experience.

Special surgical guidelines are usually given for tumors at specific sites.

For orbital RMS, for instance, the surgical approach is usually limited to biopsy,

and enucleation or exenteration is considered only after the failure of

chemotherapy and radiotherapy.42 In case of head and neck tumors, surgical

resection is rarely feasible (in particular for parameningeal RMS), but in some

cases, major resection combined with brachytherapy and reconstruction may

be appropriate after primary chemotherapy.43 Paratesticular RMS should be

resected, associated with orchidectomy via an inguinal excision, although

recent data suggests that a transscrotal approach may not cause contamination

as the generally considered.44 The superficial location of these tumors usually

permit complete resection at diagnosis, and this leads the usually favorable

prognosis of patients with paratesticular RMS.45 European groups do not

require surgical evaluation of the retroperitoneal lymph nodes in paratesticular

RMS,45-47 while biopsy is recommended in IRS study in patients aged more than

10 years old, considered at major risk of nodal involvement. 48-50

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In RMS of the bladder and prostate RMSs, therapeutic efforts should be

directed toward avoiding cystectomy. The treatment approach adopted for

these tumors usually includes partial cystectomy and partial prostatectomy in

conjunction with brachytherapy and external beam irradiation, after tumor

shrinkage obtained with primary chemotherapy.51,52

Surgery on involved regional lymph nodes should be considered as a

diagnostic procedure. Involved lymph nodes require radiotherapy, and

therefore initial radical lymphadenectomy with high risk of morbidity are not

necessary.

Finally, surgery seems to have a limited role in patients with metastatic

RMS. When, in cases where the primary tumor has to be resected (if feasible),

the surgical removal of metastases seems to add few chances of cure. 53

E.3 Radiotherapy

Radiotherapy is a mainstay of therapy for RMS.54 Considering the risk

caused by radiation (together with the effectiveness of systemic treatment), the

role of radiotherapy has partially diminished over the years and it is now

recommended with more caution.27,28 Early experience with high-dose

radiotherapy ( 60 Gy) and the use of wide fields to achieve local control in a

high percentage of cases (90%) has been associated with subsequent severe

long-term morbidity. Currently, radiotherapy is delivered at doses ranging from

40 to 55 Gy, depending on the patient’s age, the tumor size and site, the

patient’s response to primary chemotherapy, the tumor histology, and the

extent of residual tumor detected after surgery.40,41,57-59,69,76,-78 Radiotherapy is

particularly important for RMSs localized in the parameningeal region, the

trunk (i.e., pelvis), and the alveolar region, however, use of radiotherapy must

be limited in younger children.

Careful planning is mandatory in the use of techniques such as three-

dimensional conformal radiotherapy, which might improve the therapeutic

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index and reduce radiation-related late effects. Radiotherapy administered

using megavoltage equipment allows the use of wide margins (2–3 cm) around

the tumor.60 Although involved lymph nodes should be irradiated, prophylactic

irradiation of uninvolved lymph nodes adjacent to the disease site is not

recommended.57-59,85,86

As for the timing of radiation therapy, it is generally accepted that

radiotherapy should be given within the 12th week from the start of treatment.57-

59,85,86 For patients with parameningeal RMS, radiotherapy is proposed in IRS

trials (but not in European studies) at the first week of treatment, in

combination with chemotherapy.59,60-62 For parameningeal RMS patients, whole-

brain irradiation (as well as intrathecal chemotherapy, both adopted in the first

trials to reduce the risk of meningeal spread) has been abandoned and it is

currently indicated only for cases of intracranial extension and malignant cells

in the cerebrospinal fluid at onset of the disease.32,103

Although interesting suggestions have been derived from

hyperfractionated and accelerated schedules32,77,63-65 the conventional

fractionation scheme currently remains the standard choice.66 Interstitial

radiotherapy can be useful in specific situations, for small tumors in the head

and neck region or in genitourinary sites).52,67,68

The indications for radiotherapy can be described, as follows, according

to the stage of the disease. IRS group I patients (initial complete resection),

radiotherapy can be omitted in patients with favorable histology, whereas it is

required for alveolar histotype.40,57-59 For IRS group II patients (microscopic

residual disease after surgery), there are some debates on the indications for

radiotherapy are debated: a recent report from the CWS group showed that

local control after 5 years was better in patients treated with radiotherapy when

compared to those who did not (83% versus 65%), and no subgroup could be

defined for which the omission of radiotherapy produced an outcome

equivalent to that noted in patients who received radiotherapy.70 However, it is

noteworthy that in view of the concept of the total burden of therapy and the

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predicted sequelae that treatments are predicted to have, the SIOP-MMT group

tends to limit the indications for radiotherapy in IRS group II patients,

particularly in those who have favorable clinical features.16,69

Another issue of concern is the indication of radiotherapy in IRS group III

patients (patients with initial resection). In patients who cannot receive

secondary complete surgery, radiotherapy is the only available local therapy

and it is recommended.61,71 An exception could be partially represented by

embryonal RMS arising in favorable site (e.g., the orbit), for which the SIOP-

MMT group considered avoiding irradiation in case of complete response to

primary chemotherapy.42 In the case of group III patients for whom secondary

complete resection is an option, the debate on the indications of radiotherapy

remains open, although radiotherapy is generally delivered even after delayed

complete resection,61.71 it may be omitted in select patients with favorable

findings (e.g., tumors of embryonal histology or vaginal tumors).34,35

E.4 Chemotherapy

RMS is a chemosensitive tumor (more than 80% cases of newly diagnosed

cases of RMS respond to currently available chemotherapy regimens), and the

role of multiagent chemotherapy in its treatment been clearly demonstrated.

Moreover, all RMS patients are virtually considered to have micro metastatic

disease at the time of diagnosis, and therefore chemotherapy is recommended

for all patients affected by RMS.8,10,15,59,73,74

E.5 Standard chemotherapy

The standard chemotherapy for RMS is a multiagent regimen including

an alkylating agent plus vincristine and actinomycin D. Numerous

chemotherapeutic regimens have been tested in cooperative trials over the

years. Currently, the VAC regimen (a combination of vincristine, actinomycin D,

and cyclophosphamide) is considered the mainstay of chemotherapy in IRS

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trials,38,112 whereas the IVA regimen (ifosfamide, vincristine, and actinomycin D),

which differs in the alkylating agent selected is considered the gold standard in

Europe.14,55,73 The duration of treatment has progressively been reduced over

the years, from the 2 years of the first IRS protocol, and it currently lasts

between 6 to 12 months, according to the treatment protocol selected and the

patient’s risk group.

In the current standard regimen, actinomycin D is currently scheduled as

a single dose (an Italian randomized study showed that a 5-day course of

actinomycin D produced the same results but with greater toxicity),79 and

vincristine is usually administered on a weekly basis during the initial phase of

treatment.

Although ifosfamide is unquestionably effective against RMS (achieving a

response rate of up to 86% when administered in up-front window therapy for

previously untreated patients),80 the European groups’ preference for

ifosfamide over cyclophosphamide is not supported by any randomized

studies. Although a German group reported that better responses were

achieved in the ifosfamide-based CWS-86 trial than in the cyclophosphamide-

based CWS-81 study, ifosfamide did not afford any clear benefit in terms of

survival rates.81 On the other hand, the IRS-IV study compared the VAC regimen

with the IVA regimen in a prospective randomized trial (with a third arm

including ifosfamide in combination with etoposide) and found no differences

in the survival rates.57 The VAC and IVA regimens can probably be considered

to have similar efficacy.59,82 Ifosfamide may offer some advantages in terms of

myelotoxicity and gonadal toxicity but is associated with a higher risk of renal

toxicity (although this toxicity is limited when the cumulative dose is lower

than 60 mg/m2 and when the drug is administered via short-term infusion, e.g.,

over 3 hours).83 However, both drugs, require hyperhydration and concurrent

Mesna administration are essential to prevent hemorrhagic cystitis.

Cyclophosphamide may be selected because it is cheaper and can be

administered over the course of 1 day rather than the 2–5 days needed to

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administer ifosfamide.19,20,59,82

European groups, in their latest trials, experimented with intensifying the

ifosfamide dosage within the IVA regimen. No apparent advantage was noted

on increasing the dose intensity to 9 g·m-2·course-1; hence, IVA chemotherapy

with a dose intensity of 6 g·m-2/course-1 remains the reference regimen in

Europe.69,78,84,85 Similarly, the cumulative dose of cyclophosphamide was

increased from the one used in the VAC regimen of the IRS-I study to the dose

used in the pulse VAC regimen of the IRS-II and IRS-III studies with a parallel

improvement in survival rate.86-89 Consequently, in the IRS-IV study, the drug

was consequently delivered as a single dose of 2.2 g·m-2·course-1 (considered to

be equivalent to 9 g·m-2·course-1 of ifosfamide). When compared with these

results the previous studies (which used 10 mg·kg-1·day-1 for 3 days and

approximately 1 g·m-2·course-1) revealed that this dose intensification proved

beneficial only for certain subgroups of intermediate-risk patients.57 A

subsequent study of cyclophosphamide conducted by the COG revealed that

further dose intensification (3.6 g·m-2·course-1) did not improve the outcome

and that the use of a higher dose (4.5 g·m-2·course-1) resulted in extremely

severe toxicity.90

E.6 Chemotherapy for low-risk patients

Both North American and European studies have explored over the years,

the chances of reducing the intensity of chemotherapy, without jeopardizing

the results, in patients considered to be at low risk of failure, without

jeopardizing the results. Currently, a 22-week chemotherapy regimen lacking

an alkylating agent and anthracyclines, the VA regimen (vincristine and

actinomycin), is considered effective for low-risk patients.40,45,59,69,75,87 However,

the debate concerns which patients can be defined at low-risk: the EpSSG RMS

protocol restricted the definition to a very select group of patients (IRS group I,

embryonal histotype, tumor size < 5 cm, and patient age < 10 years; mainly

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children with paratesticular RMS), whose cases account for about 6% of all

cases and are characterized by an estimated 5-year event-free survival (EFS)

rate of approximately 90% and an OS rate of approximately 95%.53

E.7 Chemotherapy for high-risk patients

The prognosis for high-risk patients is still unsatisfactory, and effective

drugs must be found for new intensive regimens for these patients remain to

be identified.

In pediatric oncology, the most traditional approach for the inclusion of

new agents into standard treatment regimens involves 3 steps: a phase I safety

study in multiple relapsing patients (with no other therapeutic options), a

phase II activity study of patients with relapse (usually at the first relapse), and

finally a phase III randomized study in newly diagnosed patients, by adding the

new agent to the standard multimodality therapy. The primary limitation of this

approach is that the effectiveness of new agents may be underestimated in

classic phase II trials testing drugs in previously treated patients who may have

lower tolerance to further chemotherapy and whose tumors may have

developed multidrug resistance.91

An alternative approach, explored in the last 15 years by the IRS-COG

investigators, is the up-front phase-II window study, wherein the new agent (or

new combination) is tested in newly diagnosed patients with poor predicted

outcomes (stage IV) or in previously untreated patients whose tumors are less

likely to exhibit multidrug resistance. If a response is noted (evaluated after 6

weeks of therapy), the new agent is incorporated into the subsequent

treatment, together with the standard chemotherapy.91 In fact, drugs that

yielded limited results in the treatment of refractory RMS (melphalan or

topotecan alone) proved effective for newly diagnosed patients.91-93 Various

chemotherapy regimens have been tested by this approach.

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E. Figure 3*

*From Breitfeld PP 91

In recent years, topoisomerase I inhibitors have been considered the

most attractive drugs. The use of topotecan alone yielded poor results in the

treatment of refractory RMS94,95 but achieved a good response rate in up-front

window studies (with a better response in alveolar tumors than in the

embryonal subtype with a response rate 65% versus 28%).96 When combined

with cyclophosphamide, topotecan showed a marked degree of activity both in

cases of previously treated recurrent RMS (10 responders out of 15 in a phase

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II study of the Pediatric Oncology Group)97 and in up-front window studies.98 In

a recent study, the COG evaluated the response to the subsequently-

administered VAC chemotherapy administered after the failure of window

therapy had failed: the response rate was 24% in patients whose window

combination included an alkylating agent (i.e., melphalan or ifosfamide) the

response to VAC was 24%, but it was 53% when window therapy regimen

included topotecan. These data would suggest a basic lack of cross resistance

to VAC and topotecan, supporting the possibility of combining topotecan with

alkylating agents.91,92

Irinotecan activity was investigated when the drug was administered

alone 99,100 and in combination with vincristine: the combination of irinotecan

and vincristine proved to be the most effective combination when tested in

window studies, achieving a response rate of 70% and, more importantly, a

progression rate of only 8% (these rates are significantly better than those

achieved with irinotecan alone, topotecan alone, or topotecan combined with

cyclophosphamide).101 Moreover, this regimen resulted in a relatively high

response rate in patients with refractory disease (in the COG-ARST 0121 study,

the response rate was 25% when a regimen of 20 mg for 10 days was used and

37% when one of 50 mg for 5 days was used).

In light of these findings, the topotecan and cyclophosphamide

combination was studied in the IRS-V protocol (intermediate-risk patients were

randomized to receive standard VAC chemotherapy plus radiotherapy or VAC

alternated with topotecan, cyclophosphamide, and vincristine plus

radiotherapy). The recently reported results of this trial showed no significant

improvement in the outcomes after the introduction of topotecan-based

chemotherapy.102

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E. Figure 4

* From Arndt CA, Donaldson SS, Anderson JR, et al.35

These findings were consistent with those of various early randomized

trials conducted by cooperative groups, wherein different drugs (namely,

doxorubicin, carboplatin, cisplatin, etoposide, and melphalan) were combined

with standard chemotherapeutic agents but did not reveal any definite

advantage over the standard combinations.

The role of cisplatin and etoposide in combination with VAC was explored

in the IRS-III protocol, in a 3-way randomized trial that compared the standard

regimen against VAC plus doxorubicin and cisplatin and against VAC plus

doxorubicin, cisplatin, and etoposide. The results revealed that adding new

drugs increased the toxicity of the treatment and did not offer any advantage in

terms of survival.87

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The IRS-IV study investigated the role of the ifosfamide-etoposide

combination.135 A randomized study revealed that inpatients with localized

disease, the survival rates did not vary with the VAC, IVA, and VIE (vincristine,

ifosfamide, and etoposide) regimens.57 Patients with metastatic disease were

randomized to receive the vincristine-melphalan combination,104 the ifosfamide-

etoposide combination, or the ifosfamide-doxorubicin combination: the best

survival rate was achieved in the ifosfamide-etoposide arm, whereas the

melphalan-vincristine combination produced the worst results, probably

because of the lower dose intensity secondary to its greater myelotoxicity.

Moreover, a higher rate of second malignancy was also reported among

patients receiving melphalan.105

These studies showed the difficulties encountered in clinical trials

designed to find a new regimen that is more effective than the standard

regimen for treating RMS. If it is true that classic phase II trials on recurrent

patients may underestimate the effectiveness of new agents, on the other hand

it is evident that most (or all) drugs proven effective in up-front window studies

do not prove to be advantageous over standard regimens in phase III studies.

This may be because the spectrum of tumor cells killed by the new agent

overlaps with the spectrum of tumor cells killed by standard agents. In other

words, it may be possible that any antitumor activity observed in previously

treated patients with relapse is potentially more significant than that assessed

in window studies, because in the former case, the real target that has to be

destroyed by the new drug to improve outcome is the recurrent, treatment-

resistant tumor cells.73

Another drug generally considered effective against RMS is doxorubicin

(adriamycin):106 high activity (65% response rate) was obtained with doxorubicin

alone in a recent window study conducted by the Société Française d’Oncologie

Pediatrique (SFOP),107 Nevertheless, the role of anthracyclines as components of

multidrug regimens is controversial, and different randomized studies have

failed to demonstrate any improvement in survival when doxorubicin is

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included in the established VAC or IVA regimens could improve survival.

However, it is important to note that these trials involved alternating

administration of doxorubicin and actinomycin D, i.e., VAC alternated with

VAdrC (vincristine, doxorubicin, and cyclophosphamide) or IVA alternated with

IVAd (ifosfamide, vincristine, and doxorubicin), so, there was a lengthy interval

between doxorubicin courses and consequently a lower anthracycline dose

intensity 69,84-87 Following suggestions emerging from experience on Ewing

sarcoma, which showed that induction treatment that included doxorubicin in

every course were more effective than those with alternating courses),108 the

EpSSG hypothesized that RMS patients may benefit from a greater doxorubicin

dose intensity during the initial part of the treatment. In an Italian pilot study,

full-dose doxorubicin was added to the well-established IVA regimen, and this

new regimen, called IVADo (ifosfamide, vincristine, actinomycin D, and

doxorubicin52), proved feasible and efficacious, prompting the exploration of

the anthracycline question in the new EpSSG randomized trial for localized RMS

patients with localized disease (wherein high-risk patients were randomized to

receive IVA or IVADo chemotherapy for the first 4 cycles).75

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E. Figure 5

E. Figure 6

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E.8 High-dose chemotherapy

The prognosis for patients with metastatic RMS has shown very limited

progress in the last decade, and similar considerations are suitable patients

with relapsing disease. The chances of cure are relatively high (5-year OS rate,

approximately 45–50%) in a small subset of these patients, namely, children

under 10 years of age with tumors of embryonal histology and lung metastases

(or with only 1 site of metastases)109-112 as well as patients who relapsed with

none or 1 of the following risk factors: (a) tumor of the alveolar subtype, (b) an

unfavorable tumor site, (c) systemic recurrence, and (d) recurrence after

therapy.13 For all other patients, the outcome remains dismal, with a survival

rate of approximately 25%.

High-dose, myeloablative chemotherapy (followed by autologous stem

cell rescue) is considered a potential treatment strategy on the basis of the

following hypothesis: given the high chemosensitivity of RMS and the dose-

response relationship, the use of higher doses and greater dose intensities

could improve the outcome. Some single-institutional series that involved very

few patients have suggested the possible benefits of high-dose therapy, but the

major studies did not clearly identify any advantage of high-dose consolidation

therapy over the conventional approach in terms of survival.110-116 Definite

conclusions regarding high-dose chemotherapy cannot easily be drawn from

studies conducted thus far because of several factors, such as the small

number of patients considered, the variable eligibility criteria adopted, and the

different cytoreductive regimens used (melphalan was the agent adopted for

myeloablative consolidation in most cases). Only a large, cooperative, multi-

institutional randomized trial could provide definitive data in this regard.

Therefore, high-dose chemotherapy is still being investigated and should be

recommended only within clinical trials.115,116

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A new hypothesis under discussion for increasing chemotherapy dosages

is “dose compression” (increasing the dose intensity of chemotherapy), wherein

chemotherapy cycles are administered at intervals of 1–2 weeks (instead of the

usual 3 weeks).117 However, new strategies are clearly needed to improve the

overall cure rates of patients with metastatic (and relapsing) disease, and RMS

experts and investigators currently find it very difficult to design a

comprehensive and promising treatment approach.

E. Figure 7

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E.9 Maintenance therapy

A potentially interesting treatment strategy is maintenance therapy.

Despite the high rate of complete responses, most attempts to intensify

chemotherapy in high-risk patients have failed to significantly improve the

outcomes; this suggests that once complete remission has been achieved, the

main obstacle to improving cure rates would be minimal residual disease that is

resistant to short-term high-dose treatment. In light of this consideration, an

alternative method for improving the results of chemotherapy may involve the

use of maintenance “metronomic” therapy (regular, frequent administration of

low doses of the drug with the aim of achieving an antiangiogenic effect) at the

end of conventional chemotherapy.

Several studies have suggested that prolonged continuous chemotherapy

might have different mechanisms of action from those of standard

chemotherapy, including the antiangiogenic effects (related to “collateral

damage” to the tumor vasculature).118-122 The CWS group explored the role of

oral maintenance chemotherapy (trofosfamide plus etoposide and trofosfamide

plus idarubicin) in treating metastatic RMS and reported interesting preliminary

results.123 This hypothesis will be one of the premises of the new EpSSG

protocol for RMS, in which the role of 6-month maintenance therapy comprising

of a combination of vinorelbine and low-dose cyclophoshamide will be

evaluated in a randomized trial involving patients with high-risk features.75

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E. Figure 8

Laboratory and clinical studies have suggested that vinorelbine may have

potentially antiangiogenic effects123-125 and exhibits some activity in vascular

sarcomas;158 moreover, this drug has proven to be effective in already heavily-

treated patients with recurrent RMS (particularly tumors of the alveolar

histotype) who have already been extensively treated.127,128 Cyclophoshamide has

been variously indicated as a possible anti-angiogenic effects when given at

continuous low doses, and this drug has proved to be one of the most active

agents against RMS. A pilot study with vinorelbine and low-dose

cyclophosphamide has been conducted, showing that the combination is

feasible and potentially effective.129

E.10 Targeted therapy

More than new cytotoxic drugs novel therapeutic approaches and novel

mechanisms of action are needed. In particular, expectations of a focus on new

molecular therapies specifically designed for targets critical to a tumor’s

biology. For this purpose, the primary challenge at hand for pediatric

oncologists is to improve cooperation among researchers, the pharmaceutical

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industry, and regulatory authorities in order to increase the number of new

agents available for pediatric oncology trials and to overcome some of the

numerous difficulties that prevent the development of new drugs specifically for

RMS and, more generally, for pediatric cancers .75

Noteworthy steps in this direction have been the actions of the COG

Phase I Consortium in collaboration with the Cancer Therapy Evaluation

Program of the National Cancer Institute, which defined a systematic program

for predictive preclinical models, as well as the creation of the European Project,

Innovative Therapies for Children with Cancer (ITCC).130-133

Various agents for RMS are under investigation for RMS, and the number

of new targets for therapy will increase in the near future thanks to the

mapping of protein signaling networks within RMS cell.:, Targeted therapies

under investigation include: (a) multireceptor tyrosine kinase inhibitors (e.g.

sunitinib), (b) tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)

receptor 2 agonists (e.g., lexatumumab),133 (c) mammalian target of rapamycin

(m-TOR) inhibitors (e.g., temsirolimus—CCI-779; AP23537—Ariad),166-168 (d)

insulin-like growth factor-I receptor kinase (IGF1R) inhibitors (e.g., R1760),138

and (e) vascular endothelial growth factor (VEGF) receptor antibodies (e.g.,

bevacizumab).139,140

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F. Considerations for developing countries

Improvements in the economic status and health conditions in countries

with limited resources and a reduction in mortality from infection-related

mortality, these countries have begun to recognize childhood cancers as a

major cause of mortality in children.

RMS is a heterogeneous entity whose treatment should be necessarily

multidisciplinary and be performed at centers whose staff have adequate

relevant experience. The therapeutic standards that have been established in

developed countries are unlikely to be reproduced in low-income countries, due

to the differences in health infrastructure and training, the limited availability of

some active drugs, and supportive care to overcome the life-threatening toxic

effects of modern chemotherapy, and the poor treatment compliance of

patients.

In order to identify the specific factors that limit patient outcomes in

developing countries, a recent interesting study compared the clinical findings

and treatment outcomes of RMS patients treated in Guatemala with those of

patients treated in Europe and North America. In conclusion, our study is the

first series on soft tissue sarcoma in Central America. This study revealed that

the treatment outcomes in developing countries are considerably inferior to

those in developed countries that use established standards, and multiple

factors seem to affect patient outcomes.

In addition to the general socioeconomic factors that adversely affect the

care of children with cancer in countries with limited resources, factors that

may be more specific for RMS are as follows: 1) the problem of delayed

diagnosis and advanced disease at diagnosis; 2) the high percentage of

abandonment of treatment prior to its completion, probably due to refusal to

radical local control; and 3) the quality of local control.

Many initiatives and intervention programs are being considered in order

to improve early diagnosis and decrease the rate at which treatment is

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discontinued; these include public information and education programs

designed to increase awareness at various levels (among patients, communities,

and health care workers) as well as programs designed to facilitate early patient

referrals to medical care, empower socials workers to strongly support patients’

families, provide financial assistance, and develop satellite pediatric oncology

units for treating patients in rural areas.

The poor quality of local control achieved may be related, in principle, to

the quality of available radiotherapy, the experience of surgeons, and the

interaction between radiotherapists and surgeons for defining locally adopted

procedures.

The implementation of programs that build partnerships among groups

of health care providers, similar to those available in developed countries, may

prospectively improve the quality of health care in countries with limited

resources.

F. ReferencesAntillon F, Castellanos M, Valverde P, et al. Treating pediatric soft tissue sarcomas in a countrywith limited resources: The experience of the Unidad Nacional de Oncologia Pediatrica inGuatemala. Ped Blood Cancer 51(6):760-764, 2008.

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