Previously Untreated Childhood Rhabdomyosarcoma

Surgical Management Treatment Options
        Head and neck
        Extremity sites
        Truncal sites
        Genitourinary system
        Unusual primary sites
        Metastatic sites
Chemotherapy Treatment Options
         Low-risk patients
        Intermediate-risk patients
        High-risk patients
Radiation Therapy Management Options
        Standard treatment options
        Treatment options under clinical evaluation
Current Clinical Trials

Note: Some citations in the text of this section are followed by a level of evidence. The PDQ Editorial Boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence ¹.)

Surgical Management Treatment Options

The basic principle for the initial surgical treatment of children with rhabdomyosarcoma is complete resection of the primary tumor with a surrounding margin of normal tissue, along with sampling lymph nodes in the draining nodal basin, provided that major functional/cosmetic impairment will not result.[1][Level of evidence: 3iii] Important exceptions to the rule of normal margins exist (e.g., tumors of the orbit and of the genitourinary region).[2,3] The principle of wide and complete resection of the primary tumor is less applicable to patients known to have metastatic disease at the initial operation, but it is a reasonable concept if easily accomplished. Patients with microscopic residual tumor following their initial excisional procedure appear to have improved prognoses if a second operative procedure to re-excise the primary tumor bed before beginning chemotherapy can achieve complete removal of tumor.[4] There is little evidence that debulking surgery that leaves macroscopic residual tumor improves outcome, compared with biopsy alone.[5][Level of evidence: 2A] Second-look procedures can show whether there is viable tumor after starting treatment; patients with viable tumor had shorter event-free survival (EFS) rates than did those without viable tumor, but there was no effect on overall survival (OS).[6] The exact role of second-look surgery remains undefined in rhabdomyosarcoma. Because rhabdomyosarcoma can arise from multiple sites, surgical care must be tailored to the unique aspects of each site. Surgical management of the more common primary sites is provided below.

Head and neck

If the tumors are parameningeal (in the middle ear/mastoid, nasopharynx/nasal cavity, paranasal sinus, parapharyngeal region, or pterygopalatine/infratemporal fossa), a magnetic resonance imaging (MRI) scan with contrast of the primary site and brain should be obtained to check for presence of base-of-skull erosion and possible extension through the dura. If skull erosion and/or transdural extension is equivocal, a computed tomography (CT) scan of the same regions with contrast is indicated. If there is any suspicion of extension down the spinal cord, an MRI scan with contrast of the entire cord should be obtained. The cerebrospinal fluid (CSF) should be examined for malignant cells in all patients with parameningeal tumors. Despite its parameningeal site, middle ear rhabdomyosarcoma has a favorable prognosis.[7]

Rhabdomyosarcomas of the orbit should not undergo exenteration, but biopsy is needed for diagnosis.[8,9] Biopsy is followed by chemotherapy and RT, with orbital exenteration reserved for the small number of patients with locally persistent or recurrent disease.[10,11]

For nonparameningeal and nonorbital head and neck tumors, wide excision of the primary tumor (when feasible) and ipsilateral neck lymph node sampling of clinically involved nodes are appropriate.[12] Narrow resection margins (<1 mm) are acceptable because of anatomic restrictions. Cosmetic and functional factors should always be considered, but with modern techniques, complete resection in patients with superficial tumors need not be inconsistent with good cosmetic and functional results. Specialized, multidisciplinary surgical teams also have performed resections of anterior skull-based tumors in areas previously considered inaccessible to definitive surgical management, including the nasal areas, paranasal sinuses, and temporal fossa. These procedures should only be considered, however, in children with recurrent locoregional disease or residual disease following chemotherapy and radiation therapy (RT). For patients with head and neck primary tumors that are considered unresectable, chemotherapy and RT are the mainstay of primary management.[7,10,13-16]

Extremity sites

The definitive surgical procedure involves wide local excision with en bloc removal of a cuff of normal tissue.[2] Complete tumor removal from the hand or foot is not feasible in most cases because of functional impairment.[17][Level of evidence: 3iiA] Primary re-excision may be appropriate in patients whose initial surgical procedure leaves microscopic residual disease that is resectable by a second procedure.[4] Amputation should be avoided because primary RT results in excellent local control.[18][Level of evidence: 3iiiA]

Because of the significant incidence of nodal spread for extremity primary tumors (often without clinical evidence of involvement) and because of the prognostic and therapeutic implications of nodal involvement, extensive pretreatment assessment for regional nodal involvement is warranted.[19-22] The Children's Oncology Group Soft Tissue Sarcoma Committee (COG-STS) recommends systematic aggressive axillary node sampling for patients with upper-extremity primary tumors, even with clinically and radiographically negative nodes. The COG-STS also recommends inguinal and femoral triangle node sampling for patients with lower-extremity primary tumors, even with clinically and radiographically negative nodes. If clinically positive nodes are present, biopsy of more proximal nodes is recommended prior to sampling of the involved nodal region. Sentinel lymph node (SLN) mapping is employed at some centers to identify the regional nodes that are the most likely to be involved.[22-25] The contribution of SLN mapping is not yet clearly defined in pediatric patients.

Truncal sites

The surgical management of patients with lesions of the chest wall or abdominal wall should follow the same guidelines as those used for lesions of the extremities (i.e., wide local excision and an attempt to achieve negative microscopic margins). These resections may require use of prosthetic materials. Very large truncal masses should be biopsied initially. Chemotherapy, with or without RT, is then given. Initial surgery is performed if there is a realistic expectation of achieving negative margins. However, most patients who present with large tumors in these sites have localized disease that becomes amenable to complete resection with negative margins after preoperative therapy and is therefore associated with excellent long-term survival.[26-29]

Intrathoracic or intraabdominal sarcomas may not be resectable at diagnosis because of the massive size of the tumor and extension into vital organs or vessels.[30] For patients with initially unresectable retroperitoneal/pelvic tumors, complete surgical removal following chemotherapy, with or without RT, offers a significant survival advantage (73% vs. 34% to 44% without removal).[30]

With rhabdomyosarcoma of the biliary tree, total resection is rarely feasible. Outcome is good despite residual disease after surgery. External biliary drains significantly increase the risk of postoperative infectious complications. Thus, external biliary drainage is not warranted.[31]

Patients with rhabdomyosarcoma arising from tissue around the perineum or anus usually have advanced disease. These patients have a high likelihood of regional lymph node involvement, and about half of the tumors have alveolar histology. The current recommendation is to sample the lymph nodes. When feasible, without unacceptable morbidity, removing all gross tumor before chemotherapy is begun improves the likelihood of cure. In Intergroup Rhabdomyosarcoma Study Group (IRSG) Protocols I through IV, the OS after aggressive therapy for tumors in this location was 49%.[32]

Genitourinary system

Primary sites for childhood rhabdomyosarcoma within the genitourinary system include the paratesticular area, bladder, prostate, kidney, vagina, uterus, and vulva. Specific considerations for the surgical management of tumors arising at each of these sites are discussed in the paragraphs below.[33]

Lesions occurring adjacent to the testis or spermatic cord and up to the internal inguinal ring should be removed by orchiectomy with resection of the entire spermatic cord, utilizing an inguinal incision with proximal vascular control (i.e., radical orchiectomy).[34] Resection of hemiscrotal skin is required when there is tumor fixation or invasion, or when a previous transscrotal biopsy has been performed. Paratesticular tumors have been found to have a relatively high incidence of lymphatic spread (26% in IRS-I and IRS-II [POG-7898] ²),[19] and all patients with paratesticular primary tumors should have thin-cut abdominal and pelvic CT scans with contrast to evaluate nodal involvement. For patients who are younger than 10 years and who have Group I disease, and whose CT scans show no evidence of lymph node enlargement, retroperitoneal node biopsy/sampling is unnecessary, but a repeat CT scan every 3 months is recommended.[35,36] For patients with suggestive or positive CT scans, retroperitoneal lymph node sampling (but not formal node dissection) is recommended, and treatment is based on the findings of this procedure.[3,37,38] A staging ipsilateral retroperitoneal lymph node dissection is currently required for all children 10 years and older with paratesticular rhabdomyosarcoma on IRSG and COG-STS studies. Node dissection is not routine in Europe for adolescents with resected paratesticular rhabdomyosarcoma. European investigators tend to rely on radiographic rather than surgico-pathologic assessment of retroperitoneal lymph node involvement.[34,35] It appears, however, that the ability of the CT scan to predict the presence of lymph node involvement needs further study.[39] For patients with incompletely removed paratesticular tumors that require radiation therapy, temporarily repositioning the contralateral testicle into the adjacent thigh prior to scrotal radiation therapy may preserve hormone production.[40][Level of evidence: 3iiiC]

Bladder salvage is a major goal of therapy for patients with tumors arising in the prostate and bladder. An important review providing information about historical, current, and future treatment approaches for prostate and bladder rhabdomyosarcomas has been published.[41] In rare cases, the tumor is confined to the dome of the bladder and can be completely resected. Otherwise, to preserve a functional bladder in patients with gross residual disease, chemotherapy and RT have been used to reduce tumor bulk,[42,43] followed, when necessary, by a more limited surgical procedure such as partial cystectomy.[44] Early experience with this approach was disappointing, with only 20% to 40% of patients with bladder/prostate tumors remaining alive and with functional bladders 3 years following diagnosis (3-year OS was 70% in IRS-II [POG-7898] ²).[44,45] The more recent experience from IRS-III ³ and IRS-IV-STAGE- 1 ⁴, which used more intensive chemotherapy and RT, showed 55% of patients alive with functional bladders at 3 years postdiagnosis, with 3-year OS exceeding 80%.[43,46,47] Thus, this approach to therapy remains generally accepted, with the belief that more effective chemotherapy and RT will continue to increase the frequency of bladder salvage. The initial surgical procedure in most patients consists of a biopsy, which often can be performed using ultrasound guidance or cystoscopy, or by a direct-vision transanal route. For patients with biopsy-proven, residual malignant tumor following chemotherapy and RT, appropriate surgical management may include partial cystectomy, prostatectomy, or exenteration (usually approached anteriorly with preservation of the rectum). Very few studies have objective long-term assessments of bladder function, and urodynamic studies are important to obtain accurate evaluation of bladder function.[48]

In patients who have been treated with chemotherapy and RT for rhabdomyosarcoma arising in the bladder/prostate region, the presence of well-differentiated rhabdomyoblasts in surgical specimens or biopsies obtained after treatment does not appear to be associated with a high risk of recurrence and is not an indication for a surgical procedure such as total cystectomy.[46,49,50] One study suggested that in patients with residual bladder tumors with histologic evidence of maturation, additional courses of chemotherapy should be given before cystectomy is considered.[46] Surgery should be considered only if malignant tumor cells do not disappear over time following initial chemotherapy and RT. Because of very limited data, it is unclear whether this situation is analogous for patients with rhabdomyosarcoma arising in other parts of the body.

For patients with genitourinary primary tumors of the vagina/vulva/uterus, the initial surgical procedure is usually a transvaginal biopsy. Initial radical surgery is not indicated for rhabdomyosarcoma of the vagina/vulva/uterus.[3] Conservative surgical intervention for vaginal rhabdomyosarcoma, with primary chemotherapy and adjunctive radiation (often brachytherapy) for residual disease (Group IIA or III), results in excellent disease-free survival.[51,52] Because of the smaller number of patients with uterine rhabdomyosarcoma, it is difficult to make a definitive treatment decision, but chemotherapy or RT is also effective.[51,53] Exenteration is usually not required for primary tumors at these sites, but if needed it may be done, with rectal preservation possible in most cases.

Unusual primary sites

Rhabdomyosarcoma occasionally arises in sites other than those discussed above. Patients with localized primary rhabdomyosarcoma of the brain can occasionally be cured using a combination of tumor excision, RT, and chemotherapy.[54][Level of evidence: 3iiiDiii]

Patients with laryngeal rhabdomyosarcoma will usually be treated with chemotherapy and RT after biopsy in an attempt to preserve the larynx.[55]

Patients with diaphragm tumors often have locally advanced disease that is not grossly resectable initially because of fixation to adjacent vital structures such as the lung, great vessels, pericardium, and/or liver. In such circumstances, chemotherapy should be initiated after diagnostic biopsy, with the intent to try to remove residual tumor at a later date.[56]

The kidney is occasionally the primary site for rhabdomyosarcoma or undifferentiated sarcoma; ten cases have been identified from among 5,746 eligible patients (0.17%) enrolled on IRSG protocols. The tumors were large (median diameter, 12 cm), and anaplasia was present in 60% of patients. Six patients with grossly complete tumor removal at diagnosis survived; the four with incomplete removal and gross or metastatic disease died of infection or metastatic tumor.[57]

Two well-documented cases of primary ovarian rhabdomyosarcoma (one stage III and one stage IV) have been reported to supplement the eight previously reported patients. These two cases were alive at 20 and 8 months after diagnosis. Six of the previously reported eight patients had died of their disease.[58][Level of evidence: 3iiiDiii] Treatment with combination chemotherapy followed by removal of the residual mass or masses can sometimes be successful.[58]

Metastatic sites

Primary resection of metastatic disease is rarely indicated.[59] The European Cooperative Rhabdomyosarcoma Study Group reviewed four consecutive trials and identified 29 patients with embryonal rhabdomyosarcoma and metastasis limited to the lung. They reported approximately 40% 5-year EFS for the cohort and did not identify any benefit for local control of the pulmonary metastasis.[60][Level of evidence: 3iiiA]

Chemotherapy Treatment Options

All children with rhabdomyosarcoma should receive chemotherapy. The intensity and duration of the chemotherapy are dependent on the Risk Group assignment.[61] See Table 4 ⁵ in the Staging Information section for more information on Risk Groups.

Low-risk patients

Standard treatment options

• Low-risk patients have localized (nonmetastatic) embryonal histology tumors in favorable sites that have been grossly resected (Groups I and II), embryonal tumors that have not been completely resected in the orbit (Group III), and localized tumors in an unfavorable site that have been grossly resected (Groups I and II). (See Table 3 ⁶ in the Staging Information section of this summary.) Certain subgroups of low-risk patients have achieved survival rates higher than 90% when treated with a two-drug chemotherapy regimen that includes vincristine and dactinomycin (VA) plus RT for residual tumor. See Table 5 below.

Table 5. Characteristics of Low-Risk Patients with High Survival Rates Using Two-Drug Therapy with VA ± RT (Stratum I)

Site	Size	Group	Nodes
Favorable	Any	I, IIA	N0
Orbital	Any	I, II, III	N0
Unfavorable	≤5 cm	I, IIA	N0

The COG-D9602 ⁸ study of the Children's Oncology Group stratified 388 patients with low-risk embryonal rhabdomyosarcoma into two groups.[62] Treatment for subgroup A patients (n = 264; stage 1 group I/IIA, stage 2 group I, and stage 1 group III orbit) consisted of VA with or without RT for 48 weeks. Patients with subgroup B disease (n = 78; stage 1 group IIB/C, stage I group III nonorbit, stage 2 group II, and stage 3 group I/II disease) received VA plus cyclophosphamide (total dose 28.6 g/m²). Radiation doses were reduced from 41.4 Gy to 36 Gy for stage 1 group IIA patients and from 50 Gy or 59 Gy to 45 Gy for group III orbit patients. At 5 years for subgroup A patients, the overall failure-free survival (FFS) rate was 88% and the OS rate was 97%. For subgroup B patients, the 5-year FFS rate was 85% and the OS rate was 93%.

Other subgroups of low-risk patients have achieved survival rates higher than 90% by undergoing three-drug chemotherapy with VA and cyclophosphamide (VAC) plus RT for residual tumor. The total cyclophosphamide dose used in completed COG protocols was 28.6 g/m². See Table 6 below.

Table 6. Characteristics of Low-Risk Patients with High Survival Rates Using Three-Drug Therapy with VAC ± RT (Stratum II)

Site	Size	Group	Nodes
Favorable (orbital or non-orbital)	Any	IIB, IIC, III	N0, N1
Unfavorable	≤5 cm	II	N0
Unfavorable	>5 cm	I, II	N0, N1

Intermediate-risk patients

Standard treatment options

• Intermediate-risk patients have survival rates ranging from 55% to 70%. This category includes patients with embryonal rhabdomyosarcoma at unfavorable sites who have gross residual disease (i.e., Group III), and patients with nonmetastatic alveolar rhabdomyosarcoma at any site. For intermediate-risk patients, vincristine, dactinomycin, and cyclophosphamide (VAC) is the standard chemotherapy treatment.[63-65] The IRS-IV-STAGE-1 ⁴ study randomly assigned patients to receive either standard VAC therapy or one of two other chemotherapy regimens. One regimen combined vincristine and dactinomycin with ifosfamide (VAI),[66] based on the activity of ifosfamide against rhabdomyosarcoma.[67,68] The other regimen combined vincristine with ifosfamide and etoposide.[69] The combination of ifosfamide and etoposide had previously demonstrated substantial activity against rhabdomyosarcoma in phase II trials.[70] In the IRS-IV-STAGE-1 study, there was no difference in outcome between these three treatments, confirming that VAC remains the standard chemotherapy combination for children with intermediate-prognosis rhabdomyosarcoma.[38]

  A comparison of survival in patients with tumors of embryonal histology treated on IRS-IV-STAGE-1 (who received higher doses of alkylating agents) compared with similar patients treated on IRS-III ³ (who received lower doses of alkylating agents) suggested a benefit with the use of higher doses of cyclophosphamide for certain groups of intermediate-risk patients. These included patients with tumors at favorable sites and positive lymph nodes, patients with gross residual disease, or patients with tumors at unfavorable sites who underwent grossly complete resections, but not patients with unresected embryonal rhabdomyosarcoma at unfavorable sites.[71] For other groups of intermediate-risk patients, an intensification of cyclophosphamide was feasible but did not improve outcome.[72]

• The COG has also evaluated whether the addition of topotecan and cyclophosphamide to standard VAC therapy improves outcome for children with intermediate-risk rhabdomyosarcoma. Topotecan was prioritized for evaluation on the basis of its preclinical activity in rhabdomyosarcoma xenograft models as well as its single agent activity in previously untreated children with rhabdomyosarcoma, particularly those with alveolar rhabdomyosarcoma.[73,74] Furthermore, the combination of cyclophosphamide and topotecan demonstrated substantial activity both in the recurrent disease setting and in newly diagnosed patients with metastatic disease.[75,76] The COG clinical trial for newly diagnosed patients with intermediate-risk disease randomly assigned patients to receive either VAC therapy or VAC therapy with additional courses of topotecan and cyclophosphamide. However, patients who received topotecan and cyclophosphamide fared no better than those treated with VAC alone.[77][Level of evidence: 1A]

• In a limited-institution pilot study, a combination of vincristine/doxorubicin/cyclophosphamide (VDC) alternating with ifosfamide/etoposide (IE) was used to treat patients with intermediate-risk rhabdomyosarcoma. The relative efficacy of this approach versus the standard approach would require further investigation.[78][Level of evidence: 3iiiA]

• For Group III patients, approximately 20% of patients will have a residual mass at the completion of therapy. The presence of a residual mass had no adverse prognostic significance. Aggressive alternative therapy may not be warranted for rhabdomyosarcoma patients with a residual mass at the end of planned therapy. For Group III patients, best response to initial chemotherapy had no impact on overall outcome.[79]

Treatment options under clinical evaluation

The following are examples of national and/or institutional clinical trials that are currently being conducted. Information about ongoing clinical trials is available from the NCI Web site ¹⁰.

• COG-ARST0531 ¹¹ (Combination Chemotherapy and Radiation Therapy in Treating Patients With Newly Diagnosed Rhabdomyosarcoma): The COG intermediate-risk rhabdomyosarcoma protocol is comparing standard VAC chemotherapy versus VAC alternating with vincristine and irinotecan (VI). RT begins at week 4 in conjunction with VI to determine the potential benefit of early local therapy in this group of patients.

High-risk patients

Standard treatment options

• High-risk patients have metastatic disease in one or more sites at diagnosis (stage IV). These patients continue to have a relatively poor prognosis (5-year survival rate of 50% or lower) with current therapy, and new approaches to treatment are needed to improve survival in this group.[65,80,81]

  In a pooled analysis of high-risk rhabdomyosarcoma patients treated with multiagent chemotherapy (all chemotherapy regimens used a cyclophosphamide or ifosfamide plus dactinomycin and vincristine-based backbone with variation as to the use of additional chemotherapy agents) followed by local therapy (surgery with or without RT) within 3 to 5 months of starting chemotherapy, adverse prognostic factors in patients presenting with metastatic disease included: age younger than 1 year or age 10 years or older, unfavorable primary site, bone and/or bone marrow involvement, and three or more metastatic sites. The EFS rate at 3 years was 50% for patients without any of these adverse prognostic factors. The EFS rates were 42% for patients with one adverse prognostic factor, 18% for patients with two adverse prognostic factors, 12% for patients three adverse prognostic factors, and 5% for patients with four adverse prognostic factors.[82][Level of evidence: 3iiiA]

  The standard systemic therapy for children with metastatic rhabdomyosarcoma is the three-drug combination of VAC. Despite many clinical trials attempting to improve outcome by adding additional agents to standard VAC chemotherapy (or substituting new agents for one or more components of VAC chemotherapy), to date, no chemotherapy regimens have been shown to be more effective than VAC, including the following:

  • In the IRS-IV-STAGE-1 ⁴ study, three combinations of drug pairs were studied in an up-front window: IE, vincristine/melphalan (VM),[83] and ifosfamide/doxorubicin (ID).[84] These patients received VAC after the up-front window agents were evaluated at weeks 6 and 12. OS for patients treated with IE and ID was comparable (31% and 34%, respectively) and better than those treated with VM (22%).[84] However, results with VAC chemotherapy for stage IV rhabdomyosarcoma in the North American experience are similar.
  • Results from a phase II window trial of patients with metastatic disease at presentation and treated with topotecan and cyclophosphamide showed activity for this two-drug combination, but survival was not different from that seen with previous regimens.[75,76] An up-front window trial of topotecan in previously untreated children and adolescents with metastatic rhabdomyosarcoma gave similar results.[74]
  • Irinotecan and irinotecan with vincristine [85] have also been evaluated as up-front windows by the COG-STS; the response rates were better when irinotecan was administered with vincristine than without it, but again, survival in a preliminary analysis was not improved over prior experience.[85]
  • In a French study, 20 patients with metastatic disease at diagnosis received window therapy with doxorubicin for two courses. Thirteen of 20 patients responded to therapy, and four patients had progressive disease.[86]
  • A study from the International Society of Pediatric Oncology (SIOP) demonstrated continued poor outcome for patients with high-risk features such as age 10 years and older or bone/bone marrow involvement. This study compared a standard six-drug combination followed by vincristine, doxorubicin, cyclophosphamide (VAC) maintenance versus an arm that evaluated a window of single-agent doxorubicin or carboplatin followed by sequential high-dose monotherapy courses including cyclophosphamide, etoposide, and carboplatin followed by maintenance VAC. No benefit was seen for the high-dose therapy arm.[87]

Alternative Therapies

• High-dose chemotherapy with stem cell rescue has been evaluated in a limited number of patients with rhabdomyosarcoma.[88,89]; [90][Level of evidence: 3iiiA] The use of high-dose chemotherapy with stem cell rescue has failed to improve the outcome of patients with newly diagnosed or recurrent rhabdomyosarcoma.

Treatment options under clinical evaluation

The following are examples of national and/or institutional clinical trials that are currently being conducted. Information about ongoing clinical trials is available from the NCI Web site ¹⁰.

• COG-ARST08P1 ¹² (Temozolomide, Cixutumumab, and Combination Chemotherapy in Treating Patients With Metastatic Rhabdomyosarcoma): COG-ARST08P1 evaluates the addition of novel therapeutic agents to the intensive chemotherapy used in the COG study COG-ARST0431 ¹³. Newly diagnosed patients with metastatic rhabdomyosarcoma (excluding patients younger than 10 years with embryonal rhabdomyosarcoma) who have an expected FFS of less than 20% are eligible. The study consists of the following three sequential pilots:
  • Pilot 1 assesses the feasibility of adding IMC-A12, a fully human IgG1 monoclonal antibody targeting the insulin-like growth factor-I receptor (IGF-IR), to most known effective chemotherapy agents in rhabdomyosarcoma.

  • Pilot 2 assesses the feasibility of adding temozolomide, an alkylating agent, to vincristine/irinotecan cycles, based on the synergistic activity of temozolomide when added to irinotecan.

  • Pilot 3 will assess the feasibility of adding both agents to the COG-ARST0431 backbone, provided that pilot studies 1 and 2 have not shown unexpected toxicity.

• The NCI's intramural Pediatric Oncology Branch is conducting a study of consolidative immunotherapy incorporating T-cell reconstitution followed by a dendritic-cell plus tumor-peptide vaccine that could be given with little toxicity to patients with translocation-positive metastatic or recurrent Ewing sarcoma and alveolar rhabdomyosarcoma.[91][Level of evidence: 3iiiA]

Radiation Therapy Management Options

RT is an effective method for achieving local control of tumor for patients with microscopic or gross residual disease following biopsy, initial surgical resection, or chemotherapy. In Group II rhabdomyosarcoma patients, over 50% experienced local recurrence associated with noncompliance or omission of RT.[92] Patients with completely resected tumors (Group I) of embryonal histology do well without RT,[63,64] but RT benefits patients with Group I tumors with alveolar or undifferentiated histology.[93] A review of European trials conducted by the Cooperative Soft Tissue Sarcoma Study Group between 1981 and 1998 in which RT was omitted for some Group II patients demonstrated a benefit to using RT as a component of local tumor control for all Group II patient subsets (defined by tumor histology, tumor size, and tumor site).[94] Local failure is the predominant type of relapse for patients with Group III disease. Patients with tumor-involved regional lymph nodes at diagnosis have a higher risk of local and distant failure compared with patients whose lymph nodes are negative.[95] As with the surgical management of patients with rhabdomyosarcoma, recommendations for RT depend on the site of primary tumor and on the amount of residual disease, if any, following surgical resection. For patients with head and neck rhabdomyosarcoma, four studies reported excellent local control in patients treated with intensity-modulated radiation therapy (IMRT) or fractionated stereotactic radiation therapy and chemotherapy over a 4-year period. Further study is needed, but the use of IMRT and chemotherapy in patients with head and neck rhabdomyosarcoma may result in less severe late effects.[96-99]; [100][Level of evidence: 3iiiA]

For optimal care of pediatric patients undergoing radiation treatments, it is imperative to have a radiation oncologist, radiation technicians, and nurses who are experienced in treating children. An anesthesiologist may be necessary to help sedate and immobilize young patients. The facility should be equipped with a linear accelerator and have the capabilities to administer electron beam therapy. Computerized treatment planning with a three-dimensional planning system should be available. Techniques to deliver radiation specifically to the tumor while sparing normal tissue (e.g., conformal radiation therapy, IMRT, proton-beam therapy [charged-particle radiation therapy], or brachytherapy) should be considered (see below).[101-103]

Standard treatment options

• The RT dose depends predominantly on the amount of residual disease, if any, following the primary surgical resection. In general, patients with microscopic residual disease (Group II) receive RT to approximately 41 Gy,[93,104] though doses from 30 Gy to 40 Gy may be adequate in patients receiving effective multiagent chemotherapy.[105] IRS-II (POG-7898) ² study patients with gross residual disease (Group III) who received 40 Gy to more than 50 Gy had locoregional relapse rates greater than 30%; higher doses of radiation (>60 Gy) have been associated with unacceptable long-term toxic effects.[106,107] Group III patients on the IRS-IV-STAGE-1 ¹⁴ standard treatment arm received 50.4 Gy.[108]

• The treated volume should be determined by the extent of tumor at diagnosis prior to surgical resection and prior to chemotherapy. A margin of 2 cm is generally used, including clinically involved regional lymph nodes.[93] While the volume irradiated may be modified on the basis of guidelines for normal tissue tolerance, gross residual disease at the time of radiation should receive full-dose treatment.

• The timing of RT generally allows for chemotherapy to be given for 1 to 3 months before RT is initiated. In COG protocols, patients with parameningeal disease who have evidence of intracranial extension start radiation therapy at the beginning of treatment.[64,109,110] A prospective trial of 26 patients with Group III parameningeal rhabdomyosarcoma achieved good local control and survival with RT administered at the conventional time.[111] RT is usually given for 5 to 6 weeks (e.g., 1.8 Gy per day for 28 treatment days), during which time chemotherapy is usually modified to avoid the radiosensitizing agents dactinomycin and doxorubicin.

The IRSG conducted a randomized study within the IRS-IV-STAGE-1 ¹⁴ protocol and showed that giving RT twice a day, 6 to 8 hours apart, at 1.1 Gy per dose (hyperfractionated schedule), 5 days per week was feasible but difficult to accomplish in small children who required sedation twice daily. Patients with localized, gross residual tumors were randomly assigned to receive conventional RT (50.4 Gy vs. 59.4 Gy) given by the twice-daily hyperfractionated schedule. There was no demonstrated advantage in terms of local control.[112] Therefore, conventional RT remains the standard for treating patients with rhabdomyosarcoma and gross residual disease.[38]

Among the modifications of RT for specific primary sites recommended for IRS-IV-STAGE-1 patients were the following:[38,108]

• For patients with orbital tumors, precautions should be taken to limit the dose to the lens, cornea, lacrimal gland, and optic chiasm.

• Patients with bladder/prostate primary tumors who present with a large pelvic mass resulting from a distended bladder caused by outlet obstruction receive treatment to a volume defined by imaging studies following initial chemotherapy.

• Girls with genitourinary primary tumors should have their ovaries shielded or possibly moved, in an effort to preserve fertility when they are receiving RT to the lower abdomen and pelvis. In a retrospective review of 41 patients on two sequential studies for patients with low-risk embryonal rhabdomyosarcoma conducted by IRSG/COG, 33 girls with Group IIA or III N0 localized vaginal tumors received no primary irradiation and 12 (36%) recurred locally after VA (4 out of 6), VAC (2 out of 14), or VAc ([c, low-dose cyclophosphamide] 6 out of 13) chemotherapy. All survived. For the 25 patients with vaginal rhabdomyosarcoma treated on COG-D9602 ⁸, the estimated 5-year FFS was 70% and OS rate was 100%. However, for the 16 patients with Group III vaginal tumors treated on COG-ARST0331 ¹⁵, the estimated 2-year FFS rate was 42% and OS rate was 88%. Thus, a response-based approach that eliminates RT in children with vaginal tumors treated with VA or low-dose VAC appears to increase the rate of local recurrences. Based on this evidence, patients choosing to not undergo therapy have a 50% chance risk of needing intensive chemotherapy followed by RT.[52][Level of evidence: 3iiiDiii]

• Patients with parameningeal disease with intracranial extension in contiguity with the primary tumor, and/or cranial base bone erosion, and/or cranial nerve palsy do not require whole-brain irradiation or intrathecal therapy, unless tumor cells are present in the CSF at diagnosis.[109] Patients should receive RT to the site of primary tumor with a 2-cm margin to include the meninges adjacent to the primary tumor [110] and the region of intracranial extension, if present, again with a 2-cm margin. Patients with intracranial extension should begin receiving RT within 2 weeks after diagnosis.[110]

• Rarely, children can present with tumor cells in the CSF, have other evidence of diffuse meningeal disease, and/or have multiple intraparenchymal brain metastases from a distant primary tumor. They should be treated with central nervous system-directed irradiation in addition to chemotherapy/RT for the primary tumor. Spinal irradiation may also be indicated.

Very young children (age <36 months or younger) diagnosed with rhabdomyosarcoma pose a therapeutic challenge because of their increased risk for treatment-related morbidity. Recent experience [113] supports using a somewhat reduced dose of RT in settings where surgery alone is insufficient to provide a high likelihood of local control. For children with initially unresectable tumors, delayed gross total resection followed by 36 Gy beam RT provides an excellent likelihood of local control. For infants with unresectable tumors, higher doses of RT remain appropriate. Radiation techniques are designed to maximize normal tissue sparing, and should include conformal approaches, often with intensity-modulated techniques.

Treatment options under clinical evaluation

The following are examples of national and/or institutional clinical trials involving RT that are currently being conducted. Information about ongoing clinical trials is available from the NCI Web site ¹⁰.

• Brachytherapy: Brachytherapy, using either intracavitary or interstitial implants, is another method of local control and has been used in selected situations for children with rhabdomyosarcoma, especially those with primary tumors at vaginal or vulvar sites,[114-118] and selected bladder/prostate sites.[100] In small series from one or two institutions, this treatment approach was associated with a high survival rate and with retention of a functional organ or tissue in most patients.[115,119] Other sites, especially head and neck, have also been treated with brachytherapy.[120] Patients with initial Group III disease who later have microscopic residual disease after chemotherapy with or without delayed surgery are likely to achieve local control with RT at doses of 40 Gy or more.[121]

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with previously untreated childhood rhabdomyosarcoma ¹⁶. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site ¹⁰.

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82. Oberlin O, Rey A, Lyden E, et al.: Prognostic factors in metastatic rhabdomyosarcomas: results of a pooled analysis from United States and European cooperative groups. J Clin Oncol 26 (14): 2384-9, 2008.  [PUBMED Abstract]
    
    
83. Breitfeld PP, Lyden E, Raney RB, et al.: Ifosfamide and etoposide are superior to vincristine and melphalan for pediatric metastatic rhabdomyosarcoma when administered with irradiation and combination chemotherapy: a report from the Intergroup Rhabdomyosarcoma Study Group. J Pediatr Hematol Oncol 23 (4): 225-33, 2001.  [PUBMED Abstract]
    
    
84. Sandler E, Lyden E, Ruymann F, et al.: Efficacy of ifosfamide and doxorubicin given as a phase II "window" in children with newly diagnosed metastatic rhabdomyosarcoma: a report from the Intergroup Rhabdomyosarcoma Study Group. Med Pediatr Oncol 37 (5): 442-8, 2001.  [PUBMED Abstract]
    
    
85. Pappo AS, Lyden E, Breitfeld P, et al.: Two consecutive phase II window trials of irinotecan alone or in combination with vincristine for the treatment of metastatic rhabdomyosarcoma: the Children's Oncology Group. J Clin Oncol 25 (4): 362-9, 2007.  [PUBMED Abstract]
    
    
86. Bergeron C, Thiesse P, Rey A, et al.: Revisiting the role of doxorubicin in the treatment of rhabdomyosarcoma: an up-front window study in newly diagnosed children with high-risk metastatic disease. Eur J Cancer 44 (3): 427-31, 2008.  [PUBMED Abstract]
    
    
87. McDowell HP, Foot AB, Ellershaw C, et al.: Outcomes in paediatric metastatic rhabdomyosarcoma: results of The International Society of Paediatric Oncology (SIOP) study MMT-98. Eur J Cancer 46 (9): 1588-95, 2010.  [PUBMED Abstract]
    
    
88. Admiraal R, van der Paardt M, Kobes J, et al.: High-dose chemotherapy for children and young adults with stage IV rhabdomyosarcoma. Cochrane Database Syst Rev (12): CD006669, 2010.  [PUBMED Abstract]
    
    
89. Peinemann F, Kröger N, Bartel C, et al.: High-dose chemotherapy followed by autologous stem cell transplantation for metastatic rhabdomyosarcoma--a systematic review. PLoS One 6 (2): e17127, 2011.  [PUBMED Abstract]
    
    
90. Klingebiel T, Boos J, Beske F, et al.: Treatment of children with metastatic soft tissue sarcoma with oral maintenance compared to high dose chemotherapy: report of the HD CWS-96 trial. Pediatr Blood Cancer 50 (4): 739-45, 2008.  [PUBMED Abstract]
    
    
91. Mackall CL, Rhee EH, Read EJ, et al.: A pilot study of consolidative immunotherapy in patients with high-risk pediatric sarcomas. Clin Cancer Res 14 (15): 4850-8, 2008.  [PUBMED Abstract]
    
    
92. Million L, Anderson J, Breneman J, et al.: Influence of noncompliance with radiation therapy protocol guidelines and operative bed recurrences for children with rhabdomyosarcoma and microscopic residual disease: a report from the Children's Oncology Group. Int J Radiat Oncol Biol Phys 80 (2): 333-8, 2011.  [PUBMED Abstract]
    
    
93. 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 (11): 3468-75, 1999.  [PUBMED Abstract]
    
    
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95. Wharam MD, Meza J, Anderson J, et al.: Failure pattern and factors predictive of local failure in rhabdomyosarcoma: a report of group III patients on the third Intergroup Rhabdomyosarcoma Study. J Clin Oncol 22 (10): 1902-8, 2004.  [PUBMED Abstract]
    
    
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100. Martelli H, Haie-Meder C, Branchereau S, et al.: Conservative surgery plus brachytherapy treatment for boys with prostate and/or bladder neck rhabdomyosarcoma: a single team experience. J Pediatr Surg 44 (1): 190-6, 2009.  [PUBMED Abstract]
     
     
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