Previously Untreated Childhood Rhabdomyosarcoma
Primary resection of metastatic disease is rarely indicated. Persistent metastatic disease in the lung following RT and chemotherapy should be resected when possible to render patients disease free, provided that adequate pulmonary function can be preserved.
Chemotherapy Treatment Options
All children with rhabdomyosarcoma should receive chemotherapy. The intensity and duration of the chemotherapy are dependent on the Risk Group assignment.See Table 4 in the Staging Information section for more information on Risk Groups.
Standard treatment options
- Low-risk patients have a localized (nonmetastatic) embryonal histology tumor in a favorable site, or a localized embryonal rhabdomyosarcoma in an unfavorable site that has been grossly resected (Surgico-pathologic Groups I and II). (See Table 3 in the Staging Information section of this summary.) Certain subgroups of low-risk patients have achieved survival rates higher than 90% by undergoing two-drug chemotherapy with 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)
|Orbital||Any||I, II, III||N0|
|Unfavorable||?5 cm||I, IIA||N0|
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)
|Favorable (orbital or non-orbital)||Any||IIB, IIC, III||N0, N1|
|Unfavorable||?5 cm||II ||N0|
|Unfavorable||>5 cm||I, II||N0, N1|
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.
- COG-ARST0331: The COG low-risk embryonal rhabdomyosarcoma regimen includes four initial courses of cyclophosphamide given every 3 weeks, using a historically modest dose of 1.2 g/m2 /per course (total dose, 4.8 g/m2), with vincristine, and dactinomycin, followed by RT at week 13 for patients with microscopic, locoregional, or gross residual tumor. Subsequently, patients receive four (Stratum I) or 12 (Stratum II) further courses of VA, depending on the tumor stage and Group. The protocol is designed to increase efficacy of treatment while shortening the duration of treatment for a subset of low-risk patients and reducing both acute toxicity (myelosuppression) and long-term toxicity (impaired fertility) from cyclophosphamide. Stratum I closed to patient accrual in August 2010.
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.[60,61,62] The IRS-IV-STAGE-1 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), based on the activity of ifosfamide against rhabdomyosarcoma.[64,65] The other regimen combined vincristine with ifosfamide and etoposide. The combination of ifosfamide and etoposide had previously demonstrated substantial activity against rhabdomyosarcoma in phase II trials. 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.
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 (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. For other groups of intermediate-risk patients, an intensification of cyclophosphamide was feasible but did not improve outcome.
- 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.[70,71] Furthermore, the combination of cyclophosphamide and topotecan demonstrated substantial activity both in the recurrent disease setting and in newly diagnosed patients with metastatic disease.[72,73] 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.[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.[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.