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Multidisciplinary Management of Pediatric Soft-Tissue Sarcoma

Multidisciplinary Management of Pediatric Soft-Tissue Sarcoma

The article by Drs. Neville, Raney, and Andrassy is a well-written and informative review of salient issues in the diagnosis and treatment of pediatric soft-tissue sarcomas. Not surprisingly, given the senior author’s acknowledged expertise in the field of surgical management of pediatric tumors, the article is heavily weighted toward the surgical perspective, and consequently, offers only a superficial treatment of the role of radiation therapy in the local control of these tumors.

Each year in the United States, approximately 350 children and adolescents are diagnosed with rhabdomyosarcoma, and a slightly greater number are diagnosed with tumors that are collectively referred to as nonrhabdomyosarcoma soft-tissue sarcomas.[1] Over the past 3 decades, largely as a result of the lessons learned from the sequential, multi-institution Intergroup Rhabdomyosarcoma Studies (IRS), a consensus, risk-based treatment approach has been developed.[2-5]

Unfortunately, due to the relative rarity of this disease, there have been few prospective, cooperative-group trials in children with nonrhabdomyosarcoma soft-tissue sarcomas. Their management is, therefore, to a much greater degree, based upon extrapolation from the approach to the adult patient.

Initial Work-up

Virtually all patients with rhabdomyosarcoma will have micrometastatic disease at diagnosis. Thus, local measures almost never constitute adequate therapy. The initial work-up must define both the local extent of the primary tumor, as well as document all sites of radiographically detectable regional nodal and/or distant metastatic disease.

In addition to the staging studies described by Neville et al, all patients should undergo bilateral bone marrow aspirates and biopsies, and patients with parameningeal primary tumors should have a lumbar puncture performed for cytologic evaluation of the cerebrospinal fluid. It is imperative that adequate imaging studies (computed tomography and/or magnetic resonance imaging) of the primary site be performed before the initial diagnostic biopsy.

Given the locations at which these tumors present, the relatively young age of patients who get these tumors, and their uniform degree of chemosensitivity, only a small minority of patients will have tumors for which an initial attempt at complete surgical resection is warranted. The guiding principles of the initial biopsy should, therefore, be (1) to place the biopsy incision in a fashion that will not compromise subsequent attempts at complete surgical resection; (2) to obtain enough tissue to submit for routine processing, as well as for freezing for subsequent molecular genetic analyses (generally not possible with fine-needle aspiration); and (3) to avoid functionally and cosmetically impairing procedures.

The role of lymphatic mapping with sentinel node biopsy is far from clear; the authors’ enthusiasm for this procedure notwithstanding, its utility in the surgical staging of rhabdomyosarcoma remains, at best, unclear.[6] Although IRS V encourages the evaluation of this approach in the surgical staging of appropriate patients, it should be combined with—rather than replace—the age- and site-specific recommendations for lymph node dissection that constitute the “gold standard” for defining the extent of nodal disease.

Identification of Subtype

Once the histologic diagnosis of rhabdomyosarcoma has been confirmed, it is critical that the subtype be accurately determined. Although the authors were correct to state that alveolar subhistology was not identified as an independent, adverse prognostic factor in patients with extremity tumors treated in IRS IV, the overwhelming body of literature supports the view that alveolar rhabdomyosarcomas behave more aggressively and have a worse prognosis than embryonal rhabdomyosarcomas.[7,8]

More than 80% of patients with alveolar rhabdomyosarcomas will have a characteristic translocation between the long arm of chromosome 2 and the long arm of chromosome 13—referred to in shorthand notation as t(2;13)(q35;q14).[9,10] This translocation juxtaposes the PAX3 gene (or, rarely, the PAX7 gene located at chromosome 1p36), believed to regulate transcription during early neuromuscular development, and the FKHR gene (a member of the forkhead family of transcription factors). Presumably, this “oncogenic” fusion transcription factor then abnormally activates the transcription of one or more genes that contribute to the transformed phenotype.

Although the precise consequence of this tumor-specific translocation remains to be elucidated, cDNA microarray analyses have shown that the PAX-FKHR fusion expressed in fibroblasts specifically turns on an array of myogenic factors. Every effort should be made to submit fresh, frozen tumor material for polymerase chain reaction testing to precisely confirm a diagnosis of alveolar rhabdomyosarcoma. This is particularly important in light of data suggesting that patients with the “variant” PAX7-FKHR translocation may have a more favorable prognosis than patients with the more common t(2;13).[11,12]

Chemotherapy Treatment Guidelines

As summarized by the authors, for any given stage and group tumor classification, current chemotherapy treatment guidelines differ significantly based upon histologic subtype. Given the failure of IRS IV to improve outcome among patients with unresectable stage II or III embryonal rhabdomyosarcomas, as well as patients with alveolar rhabdomyosarcomas, our current treatment strategy at Memorial Sloan-Kettering Cancer Center (MSKCC) for this high-risk group of patients combines the following measures: As both “window” and subsequent “maintenance” therapy, irinotecan (Camptosar)—which, unlike topotecan (Hycamtin), appears to have extremely promising activity in patients with relapsed rhabdomyosarcoma—is added to a more intensive, high-dose alkylator and doxorubicin-based chemotherapy “backbone.” Concurrently, we incorporate the more aggressive use of second-look surgery and novel radiation techniques (see below). Following a period of 9 to 12 weeks of neoadjuvant chemotherapy (during which time, prompt and dramatic tumor regression is the norm), local control measures need to be initiated.

Radiation Therapy

Radiation therapy is an important component of the multidisciplinary management of pediatric soft-tissue sarcomas. Unfortunately, the article by Neville and colleagues provides inadequate, and in some cases, inaccurate information about the role of radiation therapy.

According to the current standard of care for rhabdomyosarcoma, as defined by the IRS Group, the need for radiation therapy depends upon the clinical group assigned prior to the initiation of chemotherapy. Patients who have a complete resection up front with negative surgical margins (group I) do not require radiotherapy unless they have alveolar or undifferentiated histologic subtypes.[13] In general, patients with lymph node involvement, microscopically positive margins (group II), or gross disease (group III) before chemotherapy, will require radiotherapy, regardless of their response to chemotherapy and/or subsequent surgery.[14]

The recommended radiation dose varies according to specific clinical details. IRS V is currently investigating dose reductions for some groups of patients. Radiation therapy is also necessary for involved lymph node regions and sites of distant metastases.

Ewing’s Sarcoma/PNET

In this article, extraosseous Ewing’s sarcoma/primitive neuroectodermal tumor (PNET) is included with other nonrhabdomyosarcoma soft-tissue sarcomas. This entity deserves separate consideration since its biology, natural history, and treatment options differ significantly from the other sarcomas.

As in rhabdomyosarcoma, systemic chemotherapy is the backbone of therapy for Ewing’s sarcoma. This tumor is also very radioresponsive, and thus, should be managed with definitive radiotherapy for local control when surgery would result in loss of form or function. Conversely, outside of a clinical trial, there is no proven role for the use of systemic chemotherapy in the other pediatric nonrhabdomyosarcoma soft-tissue sarcomas, except in patients who present with either unresectable or metastatic disease.

Most of our understanding of the role of radiation therapy for nonrhabdomyosarcoma soft-tissue sarcomas is derived from trials conducted in adult patients. A landmark study by the National Cancer Institute prospectively randomized patients to receive or not receive adjuvant radiation therapy following complete resection of extremity sarcomas.[15] Local control was significantly improved for those patients who were treated with radiotherapy.

Similarly, a prospective, randomized trial of adjuvant brachytherapy for soft-tissue sarcomas was conducted at MSKCC.[16] Patients with high-grade tumors who were treated with adjuvant brachytherapy after complete resection experienced significantly improved local control. The vast majority of patients in both trials had negative surgical margins. Radiotherapy did not impact overall survival in these studies.

Patients with positive margins or unresectable disease obviously require radiotherapy. Adjuvant radiation therapy is also recommended for patients with large (> 5 cm) or high-grade tumors when margins of resection are clear.


Brachytherapy is highlighted in this article as a desirable method for delivering radiation. We agree with the authors that this technique is often optimal for sparing normal tissues—an especially important goal in children. Data are not yet sufficient to prove that brachytherapy has equivalent efficacy to external-beam radiation for pediatric soft-tissue sarcomas, and therefore, it should only be used for carefully selected patients.

The authors suggest that brachytherapy be used as a sole radiation modality when surgical margins are positive. This statement should be interpreted with caution, however, since a report from MSKCC showed that patients with positive surgical margins had better local control when external-beam radiation was used in conjunction with brachytherapy, rather than brachytherapy alone.[17]

In closing, new technologies in radiation oncology promise to improve the outcome for children with soft-tissue sarcomas by increasing the dose to the target and decreasing doses to normal tissues. These advances include intraoperative radiation therapy (IORT) and intensity-modulated radiation therapy (IMRT).[18,19]


1. Gurney JG, Young JL Jr, Roffers SD, et al, in Ries LAG, Smith MA, Gurney JG, et al (eds): Cancer Incidence and Survival Among Children and Adolescents: United States SEER Program 1975-1995. National Cancer Institute, SEER Program. NIH Pub No. 99-4649. 111, 1999.

2. Maurer HM, Beltangady M, Gehan EA, et al: The Intergroup Rhabdomyosarcoma Study I: A final report. Cancer 61:209, 1988.

3. Maurer HM, Gehan EA, Beltangady M, et al: The Intergroup Rhabdomyosarcoma Study II. Cancer 71:1904, 1993.

4. Crist W, Gehan EA, Ragab AH, et al: The Third Intergroup Rhabdomyosarcoma Study. J Clin Oncol 13:610, 1995.

5. Baker KS, Anderson JR, Link MP, et al: Benefit of intensified therapy for patients with local or regional embryonal rhabdomyosarcoma: Results from the Intergroup Rhabdomyosarcoma Study IV. J Clin Oncol 18:2427, 2000.

6. Neville HL, Andrassy RJ, Lally KP, et al: Lymphatic mapping with sentinel node biopsy in pediatric patients. J Pediatr Surg 35:961, 2000.

7. Tsokos M, Webber BL, Parham DM, et al: Rhabdomyosarcoma: A new classification scheme related to prognosis. Arch Pathol Lab Med 116:847, 1992.

8. Newton WA Jr, Gehan EA, Webber BL, et al: Classification of rhabdomyosarcoma and related sarcomas: Pathologic aspects and proposal for a new classification—An Intergroup Rhabdomyosarcoma Study. Cancer 76:1073, 1995.

9. Shapiro DN, Sublett JE, Li B, et al: Fusion of PAX3 to a member of the forkhead family of transcription factors in human alveolar rhabdomyosarcoma. Cancer Res 53:5108, 1993.

10. Davis RJ, D’Cruz CM, Lovell MA, et al: Fusion of PAX7 to FKHR by the variant t(1;13)(p36;q14) translocation in alveolar rhabdomyosarcoma. Cancer Res 54:2869, 1994.

11. Kelly KM, Womer RB, Sorensen PH, et al: Common and variant gene fusions predict distinct clinical phenotypes in rhabdomyosarcoma. J Clin Oncol 15:1831, 1997.

12. Lynch JC, Triche TJ, Qualman SJ, et al: Prognostic significance of PAX3-FKHR and PAX7-FKHR gene fusions in alveolar rhabdomyosarcoma (abstract). Proc Am Soc Clin Oncol 19:584a, 2000.

13. Wolden SL, Anderson JR, Crist WM, et al: Indications for radiotherapy and chemotherapy after complete resection in rhabdomyosarcoma: A report from the Intergroup Rhabdomyosarcoma Studies I to III. J Clin Oncol 17:3468, 1999.

14. Godzinski J, Flamant F, Rey A, et al: Value of postchemotherapy bioptical verification of complete clinical remission in previously incompletely resected (stage I and II pT3) malignant mesenchymal tumors in children: International Society of Pediatric Oncology 1984 Malignant Mesenchymal Tumors Study. Med Pediatr Oncol 22:22, 1994.

15. Yang JC, Chang AE, Baker AR, et al: Randomized, prospective study of the benefit of adjuvant radiation therapy in the treatment of soft-tissue sarcomas of the extremity. J Clin Oncol 16:197, 1998.

16. Pisters PW, Harrison LB, Leung DH, et al: Long-term results of a prospective, randomized trial of adjuvant brachytherapy in soft-tissue sarcoma. J Clin Oncol 14:859, 1996.

17. Alekhteyar KM, Leung DH, Brennan MF, et al: The effect of combined external-beam radiotherapy and brachytherapy on local control and wound complications in patients with high-grade soft-tissue sarcomas of the extremity with positive microscopic margin. Int J Radiat Oncol Biol Phys 36:321, 1996.

18. Merchant TE, Zelefsky MJ, Sheldon JM, et al: High-dose rate intraoperative radiation therapy for pediatric solid tumors. Med Pediatr Oncol 30:34, 1998.

19. Miralbell R, Cella L, Weber D, et al: Optimizing radiotherapy of orbital and paraorbital tumors: Intensity-modulated x-ray beams vs intensity-modulated proton beams. Int J Radiat Oncol Biol Phys 47:1111, 2000.

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