Intermediate-risk Group

The IRS-IV study randomly assigned intermediate-risk patients to receive either standard VAC therapy or one of two other chemotherapy regimens using ifosfamide as the alkylating agent. This category includes patients with embryonal rhabdomyosarcoma at unfavorable sites (Stages 2 and 3) with gross residual disease (i.e., Group III), and patients with nonmetastatic alveolar rhabdomyosarcoma (Stages 2 and 3) at any site (Groups I, II, and III).[39]

The IRS-IV study randomly assigned intermediate-risk patients to receive either standard VAC therapy or one of two other chemotherapy regimens using ifosfamide as the alkylating agent. This category includes patients with embryonal rhabdomyosarcoma at unfavorable sites (Stages 2 and 3) with gross residual disease (i.e., Group III), and patients with nonmetastatic alveolar rhabdomyosarcoma (Stages 2 and 3) at any site (Groups I, II, and III).[39]

At 3 years, intermediate-risk patients had survival rates from 84% to 88%.[39]

The IRS-IV study randomly assigned intermediate-risk patients to receive either standard VAC therapy or one of two other chemotherapy regimens using ifosfamide as the alkylating agent. This category includes patients with embryonal rhabdomyosarcoma at unfavorable sites (Stages 2 and 3) with gross residual disease (i.e., Group III), and patients with nonmetastatic alveolar rhabdomyosarcoma (Stages 2 and 3) at any site (Groups I, II, and III).[39]

There was no difference in outcome between these three treatments. The VAC regimen was easier to administer, confirming VAC as the standard chemotherapy combination for children with intermediate-risk rhabdomyosarcoma.[39]

The IRS-IV study randomly assigned intermediate-risk patients to receive either standard VAC therapy or one of two other chemotherapy regimens using ifosfamide as the alkylating agent. This category includes patients with embryonal rhabdomyosarcoma at unfavorable sites (Stages 2 and 3) with gross residual disease (i.e., Group III), and patients with nonmetastatic alveolar rhabdomyosarcoma (Stages 2 and 3) at any site (Groups I, II, and III).[39]

Survival in patients with tumors of embryonal histology treated in the IRS-IV trial (who received higher doses of alkylating agents) was compared with similar patients treated in the IRS-III trial (who received lower doses of alkylating agents). A benefit was suggested 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.[178] For other groups of intermediate-risk patients, an intensification of cyclophosphamide was feasible but did not improve outcome.[179] A single-institution retrospective review of patients with head and neck rhabdomyosarcoma identified an increased risk of local failure with the use of reduced-dose cyclophosphamide.[180]

The COG has also evaluated whether the addition of topotecan and cyclophosphamide to standard VAC therapy improved 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.[181,182] Furthermore, the combination of cyclophosphamide and topotecan demonstrated substantial activity, both in patients with recurrent disease and in newly diagnosed patients with metastatic disease.[183,184]

The COG has also evaluated whether the addition of topotecan and cyclophosphamide to standard VAC therapy improved 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.[181,182] Furthermore, the combination of cyclophosphamide and topotecan demonstrated substantial activity, both in patients with recurrent disease and in newly diagnosed patients with metastatic disease.[183,184]

The COG-D9803 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.[185][Level of evidence A1]

The COG has also evaluated whether the addition of topotecan and cyclophosphamide to standard VAC therapy improved 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.[181,182] Furthermore, the combination of cyclophosphamide and topotecan demonstrated substantial activity, both in patients with recurrent disease and in newly diagnosed patients with metastatic disease.[183,184] › The COG-D9803 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.[185][Level of evidence A1]

Patients who received topotecan and cyclophosphamide fared no better than those treated with VAC alone. The 4-year FFS rate was 73% with VAC and 68% with VAC plus vincristine, topotecan, and cyclophosphamide.

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.[186][Level of evidence C1]

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.[186][Level of evidence C1]

The relative efficacy of this approach versus the standard approach requires further investigation.

A European trial (SIOP-MMT-95) included 457 patients with incompletely resected embryonal rhabdomyosarcoma, alveolar rhabdomyosarcoma, undifferentiated sarcoma, or soft tissue primitive neuroectodermal tumor. In this study, carboplatin, epirubicin, and etoposide was added to standard IVA therapy.[187]

A European trial (SIOP-MMT-95) included 457 patients with incompletely resected embryonal rhabdomyosarcoma, alveolar rhabdomyosarcoma, undifferentiated sarcoma, or soft tissue primitive neuroectodermal tumor. In this study, carboplatin, epirubicin, and etoposide was added to standard IVA therapy.[187]

The addition of carboplatin, epirubicin, and etoposide did not improve outcome. The 3-year OS rate was 82% for patients who received IVA and 80% for patients who received IVA plus carboplatin, epirubicin, and etoposide.

A European trial (SIOP-MMT-95) included 457 patients with incompletely resected embryonal rhabdomyosarcoma, alveolar rhabdomyosarcoma, undifferentiated sarcoma, or soft tissue primitive neuroectodermal tumor. In this study, carboplatin, epirubicin, and etoposide was added to standard IVA therapy.[187]

Toxicity was significantly worse for patients in the six-drug arm.

The COG reported a prospective randomized trial of two treatment strategies for patients with intermediate-risk rhabdomyosarcoma.[188][Level of evidence A1] Patients were randomly assigned to receive treatment with either VAC or VAC with half of the cyclophosphamide cycles replaced with vincristine/irinotecan (VAC/VI). All patients received a lower cumulative dose of cyclophosphamide and earlier introduction of RT than did patients who were treated in previous COG studies. Patients who were treated with VAC/VI received half as much cumulative cyclophosphamide than did patients who were treated with VAC.

The COG reported a prospective randomized trial of two treatment strategies for patients with intermediate-risk rhabdomyosarcoma.[188][Level of evidence A1] Patients were randomly assigned to receive treatment with either VAC or VAC with half of the cyclophosphamide cycles replaced with vincristine/irinotecan (VAC/VI). All patients received a lower cumulative dose of cyclophosphamide and earlier introduction of RT than did patients who were treated in previous COG studies. Patients who were treated with VAC/VI received half as much cumulative cyclophosphamide than did patients who were treated with VAC.

At a median follow-up of 4.8 years, the 4-year EFS was 63% with VAC and 59% with VAC/VI (P = .51), and the 4-year OS was 73% for VAC and 72% for VAC/VI (P = .80). The COG concluded that the addition of VI to VAC did not improve EFS or OS for patients with intermediate-risk rhabdomyosarcoma.

The COG reported a prospective randomized trial of two treatment strategies for patients with intermediate-risk rhabdomyosarcoma.[188][Level of evidence A1] Patients were randomly assigned to receive treatment with either VAC or VAC with half of the cyclophosphamide cycles replaced with vincristine/irinotecan (VAC/VI). All patients received a lower cumulative dose of cyclophosphamide and earlier introduction of RT than did patients who were treated in previous COG studies. Patients who were treated with VAC/VI received half as much cumulative cyclophosphamide than did patients who were treated with VAC.

Among patients with Group III embryonal tumors, local failure was higher in the ARST0531 (NCT00354835) trial than in the D9803 (NCT00003958) trial (27.9% vs. 19.4%) and was similar for the VAC and VAC/VI arms.

The COG reported a prospective randomized trial of two treatment strategies for patients with intermediate-risk rhabdomyosarcoma.[188][Level of evidence A1] Patients were randomly assigned to receive treatment with either VAC or VAC with half of the cyclophosphamide cycles replaced with vincristine/irinotecan (VAC/VI). All patients received a lower cumulative dose of cyclophosphamide and earlier introduction of RT than did patients who were treated in previous COG studies. Patients who were treated with VAC/VI received half as much cumulative cyclophosphamide than did patients who were treated with VAC.

After adjusting for other prognostic factors, OS was inferior in the ARST0531 trial.

The COG reported a prospective randomized trial of two treatment strategies for patients with intermediate-risk rhabdomyosarcoma.[188][Level of evidence A1] Patients were randomly assigned to receive treatment with either VAC or VAC with half of the cyclophosphamide cycles replaced with vincristine/irinotecan (VAC/VI). All patients received a lower cumulative dose of cyclophosphamide and earlier introduction of RT than did patients who were treated in previous COG studies. Patients who were treated with VAC/VI received half as much cumulative cyclophosphamide than did patients who were treated with VAC.

VAC/VI produced less hematologic toxicity, had a lower cumulative cyclophosphamide dose, and continues to be the backbone for the ARST1431 (NCT02567435) study.

The EpSSG performed a randomized phase III trial to test the addition of vinorelbine and low-dose cyclophosphamide as maintenance chemotherapy in patients with high-risk rhabdomyosarcoma.[189] The patients classified as high risk by the EpSSG had: These patients would be classified as intermediate risk by the COG.Patients received initial treatment with cycles of IVA—ifosfamide (6 g/m2), dactinomycin (1.5 mg/m2), and vincristine (1.5 mg/m2)—for 7 weeks, followed by randomization to continue IVA or IVA with doxorubicin (60 mg/m2). IVA represents a lower alkylating agent dose than the cyclophosphamide dose of 2.2 g/m2 used in COG rhabdomyosarcoma studies. Patients assessed to be in complete remission at the end of initial therapy were randomly assigned to either observation or the addition of six 4-week cycles of maintenance chemotherapy with vinorelbine (25 mg/m2) on days 1, 8, and 15 of each cycle with continuous daily cyclophosphamide (25 mg/m2/day).

The EpSSG performed a randomized phase III trial to test the addition of vinorelbine and low-dose cyclophosphamide as maintenance chemotherapy in patients with high-risk rhabdomyosarcoma.[189] The patients classified as high risk by the EpSSG had: These patients would be classified as intermediate risk by the COG.Patients received initial treatment with cycles of IVA—ifosfamide (6 g/m2), dactinomycin (1.5 mg/m2), and vincristine (1.5 mg/m2)—for 7 weeks, followed by randomization to continue IVA or IVA with doxorubicin (60 mg/m2). IVA represents a lower alkylating agent dose than the cyclophosphamide dose of 2.2 g/m2 used in COG rhabdomyosarcoma studies. Patients assessed to be in complete remission at the end of initial therapy were randomly assigned to either observation or the addition of six 4-week cycles of maintenance chemotherapy with vinorelbine (25 mg/m2) on days 1, 8, and 15 of each cycle with continuous daily cyclophosphamide (25 mg/m2/day).

Nonmetastatic incompletely resected embryonal rhabdomyosarcoma at unfavorable sites with unfavorable age (aged 10 years or older) or a tumor larger than 5 cm, or both;

The EpSSG performed a randomized phase III trial to test the addition of vinorelbine and low-dose cyclophosphamide as maintenance chemotherapy in patients with high-risk rhabdomyosarcoma.[189] The patients classified as high risk by the EpSSG had: These patients would be classified as intermediate risk by the COG.Patients received initial treatment with cycles of IVA—ifosfamide (6 g/m2), dactinomycin (1.5 mg/m2), and vincristine (1.5 mg/m2)—for 7 weeks, followed by randomization to continue IVA or IVA with doxorubicin (60 mg/m2). IVA represents a lower alkylating agent dose than the cyclophosphamide dose of 2.2 g/m2 used in COG rhabdomyosarcoma studies. Patients assessed to be in complete remission at the end of initial therapy were randomly assigned to either observation or the addition of six 4-week cycles of maintenance chemotherapy with vinorelbine (25 mg/m2) on days 1, 8, and 15 of each cycle with continuous daily cyclophosphamide (25 mg/m2/day).

Embryonal rhabdomyosarcoma with nodal involvement; or

The EpSSG performed a randomized phase III trial to test the addition of vinorelbine and low-dose cyclophosphamide as maintenance chemotherapy in patients with high-risk rhabdomyosarcoma.[189] The patients classified as high risk by the EpSSG had: These patients would be classified as intermediate risk by the COG.Patients received initial treatment with cycles of IVA—ifosfamide (6 g/m2), dactinomycin (1.5 mg/m2), and vincristine (1.5 mg/m2)—for 7 weeks, followed by randomization to continue IVA or IVA with doxorubicin (60 mg/m2). IVA represents a lower alkylating agent dose than the cyclophosphamide dose of 2.2 g/m2 used in COG rhabdomyosarcoma studies. Patients assessed to be in complete remission at the end of initial therapy were randomly assigned to either observation or the addition of six 4-week cycles of maintenance chemotherapy with vinorelbine (25 mg/m2) on days 1, 8, and 15 of each cycle with continuous daily cyclophosphamide (25 mg/m2/day).

Alveolar rhabdomyosarcoma without nodal involvement.

The EpSSG performed a randomized phase III trial to test the addition of vinorelbine and low-dose cyclophosphamide as maintenance chemotherapy in patients with high-risk rhabdomyosarcoma.[189] The patients classified as high risk by the EpSSG had: These patients would be classified as intermediate risk by the COG.Patients received initial treatment with cycles of IVA—ifosfamide (6 g/m2), dactinomycin (1.5 mg/m2), and vincristine (1.5 mg/m2)—for 7 weeks, followed by randomization to continue IVA or IVA with doxorubicin (60 mg/m2). IVA represents a lower alkylating agent dose than the cyclophosphamide dose of 2.2 g/m2 used in COG rhabdomyosarcoma studies. Patients assessed to be in complete remission at the end of initial therapy were randomly assigned to either observation or the addition of six 4-week cycles of maintenance chemotherapy with vinorelbine (25 mg/m2) on days 1, 8, and 15 of each cycle with continuous daily cyclophosphamide (25 mg/m2/day).

The 5-year DFS rate was 69.8% for patients in the observation group and 77.6% for patients in the maintenance chemotherapy group (P = .061).

The EpSSG performed a randomized phase III trial to test the addition of vinorelbine and low-dose cyclophosphamide as maintenance chemotherapy in patients with high-risk rhabdomyosarcoma.[189] The patients classified as high risk by the EpSSG had: These patients would be classified as intermediate risk by the COG.Patients received initial treatment with cycles of IVA—ifosfamide (6 g/m2), dactinomycin (1.5 mg/m2), and vincristine (1.5 mg/m2)—for 7 weeks, followed by randomization to continue IVA or IVA with doxorubicin (60 mg/m2). IVA represents a lower alkylating agent dose than the cyclophosphamide dose of 2.2 g/m2 used in COG rhabdomyosarcoma studies. Patients assessed to be in complete remission at the end of initial therapy were randomly assigned to either observation or the addition of six 4-week cycles of maintenance chemotherapy with vinorelbine (25 mg/m2) on days 1, 8, and 15 of each cycle with continuous daily cyclophosphamide (25 mg/m2/day).

The 5-year OS rate was 73.7% for patients in the observation group and 86.5% for patients in the maintenance chemotherapy group (P = .0097).

The EpSSG performed a randomized phase III trial to test the addition of vinorelbine and low-dose cyclophosphamide as maintenance chemotherapy in patients with high-risk rhabdomyosarcoma.[189] The patients classified as high risk by the EpSSG had: These patients would be classified as intermediate risk by the COG.Patients received initial treatment with cycles of IVA—ifosfamide (6 g/m2), dactinomycin (1.5 mg/m2), and vincristine (1.5 mg/m2)—for 7 weeks, followed by randomization to continue IVA or IVA with doxorubicin (60 mg/m2). IVA represents a lower alkylating agent dose than the cyclophosphamide dose of 2.2 g/m2 used in COG rhabdomyosarcoma studies. Patients assessed to be in complete remission at the end of initial therapy were randomly assigned to either observation or the addition of six 4-week cycles of maintenance chemotherapy with vinorelbine (25 mg/m2) on days 1, 8, and 15 of each cycle with continuous daily cyclophosphamide (25 mg/m2/day).

The addition of doxorubicin did not appear to confer any improvement in outcomes.[190]

The CWS conducted a phase III trial (RMS-96) in patients with high-risk nonmetastatic rhabdomyosarcoma and Ewing sarcoma recruited between 1995 to 2004 from the CWS and Italian Soft Tissue Sarcoma Committee institutions.[191] There were 557 evaluable patients with localized rhabdomyosarcoma. Patients were randomly assigned to receive either a four-drug regimen (vincristine, ifosfamide, doxorubicin, dactinomycin; 284 rhabdomyosarcoma patients) or six-drug regimen (carboplatin, epirubicin, vincristine, dactinomycin, ifosfamide, and etoposide; 273 rhabdomyosarcoma patients).

The CWS conducted a phase III trial (RMS-96) in patients with high-risk nonmetastatic rhabdomyosarcoma and Ewing sarcoma recruited between 1995 to 2004 from the CWS and Italian Soft Tissue Sarcoma Committee institutions.[191] There were 557 evaluable patients with localized rhabdomyosarcoma. Patients were randomly assigned to receive either a four-drug regimen (vincristine, ifosfamide, doxorubicin, dactinomycin; 284 rhabdomyosarcoma patients) or six-drug regimen (carboplatin, epirubicin, vincristine, dactinomycin, ifosfamide, and etoposide; 273 rhabdomyosarcoma patients).

The addition of etoposide and carboplatin and increased single-dose ifosfamide did not improve the EFS and overall outcome.

The CWS conducted a phase III trial (RMS-96) in patients with high-risk nonmetastatic rhabdomyosarcoma and Ewing sarcoma recruited between 1995 to 2004 from the CWS and Italian Soft Tissue Sarcoma Committee institutions.[191] There were 557 evaluable patients with localized rhabdomyosarcoma. Patients were randomly assigned to receive either a four-drug regimen (vincristine, ifosfamide, doxorubicin, dactinomycin; 284 rhabdomyosarcoma patients) or six-drug regimen (carboplatin, epirubicin, vincristine, dactinomycin, ifosfamide, and etoposide; 273 rhabdomyosarcoma patients).

Toxicities and secondary malignancies were identical in both treatment arms.

In a randomized, open-label, phase III COG trial (ARST1431), all patients received VAC/VI and a maintenance phase of therapy with vinorelbine and cyclophosphamide.[192] Patients were randomly assigned to receive or not to receive temsirolimus. Among 297 evaluable patients, 148 were assigned to VAC/VI alone and 149 were assigned to VAC/VI with temsirolimus.

In a randomized, open-label, phase III COG trial (ARST1431), all patients received VAC/VI and a maintenance phase of therapy with vinorelbine and cyclophosphamide.[192] Patients were randomly assigned to receive or not to receive temsirolimus. Among 297 evaluable patients, 148 were assigned to VAC/VI alone and 149 were assigned to VAC/VI with temsirolimus.

With a median follow-up of 3.6 years (interquartile range [IQR], 2.8–4.5), the 3-year EFS rate did not differ significantly between the two groups (64.8% [95% CI, 55.5%–74.1%] for the VAC/VI group vs. 66.8% [95% CI, 57.5%–76.2%] for the VAC/VI plus temsirolimus group; HR, 0.86 [95% CI, 0.58–1.26; log-rank P = .44]).