High-risk Group

A multinational pooled analysis included 788 patients with high-risk rhabdomyosarcoma who were treated with multiagent chemotherapy (all regimens used cyclophosphamide or ifosfamide plus dactinomycin and vincristine, with or without other agents), followed by local therapy (surgery with or without RT) within 3 to 5 months after starting chemotherapy.[197][Level of evidence C1] The analysis identified several adverse prognostic factors (Oberlin risk factors):The EFS rate at 3 years depended on the number of adverse prognostic factors:[197][Level of evidence C1]

A multinational pooled analysis included 788 patients with high-risk rhabdomyosarcoma who were treated with multiagent chemotherapy (all regimens used cyclophosphamide or ifosfamide plus dactinomycin and vincristine, with or without other agents), followed by local therapy (surgery with or without RT) within 3 to 5 months after starting chemotherapy.[197][Level of evidence C1] The analysis identified several adverse prognostic factors (Oberlin risk factors):The EFS rate at 3 years depended on the number of adverse prognostic factors:[197][Level of evidence C1]

Age at diagnosis younger than 1 year or 10 years and older.

A multinational pooled analysis included 788 patients with high-risk rhabdomyosarcoma who were treated with multiagent chemotherapy (all regimens used cyclophosphamide or ifosfamide plus dactinomycin and vincristine, with or without other agents), followed by local therapy (surgery with or without RT) within 3 to 5 months after starting chemotherapy.[197][Level of evidence C1] The analysis identified several adverse prognostic factors (Oberlin risk factors):The EFS rate at 3 years depended on the number of adverse prognostic factors:[197][Level of evidence C1]

Unfavorable primary site (all sites that are not orbit, nonparameningeal head and neck, genitourinary tract other than bladder/prostate, and biliary tract).

A multinational pooled analysis included 788 patients with high-risk rhabdomyosarcoma who were treated with multiagent chemotherapy (all regimens used cyclophosphamide or ifosfamide plus dactinomycin and vincristine, with or without other agents), followed by local therapy (surgery with or without RT) within 3 to 5 months after starting chemotherapy.[197][Level of evidence C1] The analysis identified several adverse prognostic factors (Oberlin risk factors):The EFS rate at 3 years depended on the number of adverse prognostic factors:[197][Level of evidence C1]

Bone and/or bone marrow involvement.

A multinational pooled analysis included 788 patients with high-risk rhabdomyosarcoma who were treated with multiagent chemotherapy (all regimens used cyclophosphamide or ifosfamide plus dactinomycin and vincristine, with or without other agents), followed by local therapy (surgery with or without RT) within 3 to 5 months after starting chemotherapy.[197][Level of evidence C1] The analysis identified several adverse prognostic factors (Oberlin risk factors):The EFS rate at 3 years depended on the number of adverse prognostic factors:[197][Level of evidence C1]

Three or more different metastatic sites or tissues.

A multinational pooled analysis included 788 patients with high-risk rhabdomyosarcoma who were treated with multiagent chemotherapy (all regimens used cyclophosphamide or ifosfamide plus dactinomycin and vincristine, with or without other agents), followed by local therapy (surgery with or without RT) within 3 to 5 months after starting chemotherapy.[197][Level of evidence C1] The analysis identified several adverse prognostic factors (Oberlin risk factors):The EFS rate at 3 years depended on the number of adverse prognostic factors:[197][Level of evidence C1]

The EFS rate was 50% for patients without any of these adverse prognostic factors.

A multinational pooled analysis included 788 patients with high-risk rhabdomyosarcoma who were treated with multiagent chemotherapy (all regimens used cyclophosphamide or ifosfamide plus dactinomycin and vincristine, with or without other agents), followed by local therapy (surgery with or without RT) within 3 to 5 months after starting chemotherapy.[197][Level of evidence C1] The analysis identified several adverse prognostic factors (Oberlin risk factors):The EFS rate at 3 years depended on the number of adverse prognostic factors:[197][Level of evidence C1]

The EFS rates were 42% for patients with one adverse prognostic factor, 18% for patients with two adverse prognostic factors, 12% for patients with three adverse prognostic factors, and 5% for patients with four adverse prognostic factors (P < .0001).

In the IRS-IV study, three combinations of drug pairs were studied in an up-front window: IE, vincristine/melphalan (VM),[198] and ifosfamide/doxorubicin (ID).[199] These patients received VAC after the up-front window agents were evaluated at weeks 6 and 12.

In the IRS-IV study, three combinations of drug pairs were studied in an up-front window: IE, vincristine/melphalan (VM),[198] and ifosfamide/doxorubicin (ID).[199] These patients received VAC after the up-front window agents were evaluated at weeks 6 and 12.

OS rates for patients treated with IE and ID were comparable (31% and 34%, respectively) and better than for those treated with VM (22%).[199]

In the IRS-IV study, three combinations of drug pairs were studied in an up-front window: IE, vincristine/melphalan (VM),[198] and ifosfamide/doxorubicin (ID).[199] These patients received VAC after the up-front window agents were evaluated at weeks 6 and 12.

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.[183,184]

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.[183,184]

Survival was not different from that seen with previous regimens.

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.[183,184]

An up-front window trial of topotecan in previously untreated children and adolescents with metastatic rhabdomyosarcoma showed similar results.[182]

Irinotecan and the VI combination have also been evaluated as up-front window trials by the COG-STS.[200]

Irinotecan and the VI combination have also been evaluated as up-front window trials by the COG-STS.[200]

The response rates were better when irinotecan was administered with vincristine than without it.

Irinotecan and the VI combination have also been evaluated as up-front window trials by the COG-STS.[200]

Survival in a preliminary analysis was not improved over previous experience.

In a French study, 20 patients with metastatic disease at diagnosis received window therapy with doxorubicin for two courses.[201]

In a French study, 20 patients with metastatic disease at diagnosis received window therapy with doxorubicin for two courses.[201]

Thirteen of 20 patients responded to therapy, and four patients had progressive disease.

A study from the SIOP demonstrated continued poor outcomes 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 (VDC) 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.[202]

A study from the SIOP demonstrated continued poor outcomes 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 (VDC) 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.[202]

No benefit was seen for the high-dose therapy arm.

A study of patients with previously untreated metastatic rhabdomyosarcoma from the COG-STS examined outcomes of 109 patients with the disease.[197] Several treatment strategies, all given over 54 planned weeks, were used:The following results were observed:

A study of patients with previously untreated metastatic rhabdomyosarcoma from the COG-STS examined outcomes of 109 patients with the disease.[197] Several treatment strategies, all given over 54 planned weeks, were used:The following results were observed:

A period of compressed (every 2 weeks) schedule of chemotherapy using VDC alternating with IE.

A study of patients with previously untreated metastatic rhabdomyosarcoma from the COG-STS examined outcomes of 109 patients with the disease.[197] Several treatment strategies, all given over 54 planned weeks, were used:The following results were observed:

The addition of VI, including during RT.

A study of patients with previously untreated metastatic rhabdomyosarcoma from the COG-STS examined outcomes of 109 patients with the disease.[197] Several treatment strategies, all given over 54 planned weeks, were used:The following results were observed:

A period of VDC therapy.

A study of patients with previously untreated metastatic rhabdomyosarcoma from the COG-STS examined outcomes of 109 patients with the disease.[197] Several treatment strategies, all given over 54 planned weeks, were used:The following results were observed:

Using Oberlin risk factors (age <1 or >10 years, unfavorable primary site, number of metastatic sites, and presence or absence of bone/bone marrow involvement), the strategy improved outcome compared with historical controls for patients with lower-risk disease. The 3-year EFS rates were 69% for those with an Oberlin risk factor score of zero or one and 60% for patients younger than 10 years with embryonal rhabdomyosarcoma.[203][Level of evidence C2]

A study of patients with previously untreated metastatic rhabdomyosarcoma from the COG-STS examined outcomes of 109 patients with the disease.[197] Several treatment strategies, all given over 54 planned weeks, were used:The following results were observed:

However, patients with more than two Oberlin risk factors had a 3-year EFS rate of 20%, comparable to historical outcomes. This intensive protocol did not appear to improve outcome for the highest-risk patients.

The EpSSG performed a randomized prospective phase III trial of patients with high-risk rhabdomyosarcoma. They compared a standard arm comprising nine cycles of IVA with an investigational arm comprising four cycles of IVA plus doxorubicin, followed by five cycles of IVA.[190][Level of evidence C1]

The EpSSG performed a randomized prospective phase III trial of patients with high-risk rhabdomyosarcoma. They compared a standard arm comprising nine cycles of IVA with an investigational arm comprising four cycles of IVA plus doxorubicin, followed by five cycles of IVA.[190][Level of evidence C1]

The investigational therapy was associated with increased toxicity, including treatment-related mortality, and was not associated with improvement in either EFS or OS.

The COG performed two nonrandomized pilot trials in patients with high-risk rhabdomyosarcoma. All patients received 54 weeks of chemotherapy, including VI, interval-compressed VDC alternating with IE, and vincristine/dactinomycin/cyclophosphamide.[204][Level of evidence C2]The following results were observed:

The COG performed two nonrandomized pilot trials in patients with high-risk rhabdomyosarcoma. All patients received 54 weeks of chemotherapy, including VI, interval-compressed VDC alternating with IE, and vincristine/dactinomycin/cyclophosphamide.[204][Level of evidence C2]The following results were observed:

In pilot 1, patients received intravenous cixutumumab (3, 6, or 9 mg/kg) once weekly throughout therapy. Cixutumumab is a monoclonal antibody against the insulin-like growth factor 1 receptor.

The COG performed two nonrandomized pilot trials in patients with high-risk rhabdomyosarcoma. All patients received 54 weeks of chemotherapy, including VI, interval-compressed VDC alternating with IE, and vincristine/dactinomycin/cyclophosphamide.[204][Level of evidence C2]The following results were observed:

In pilot 2, patients received oral temozolomide (100 mg/m2) daily for 5 days with irinotecan.

The COG performed two nonrandomized pilot trials in patients with high-risk rhabdomyosarcoma. All patients received 54 weeks of chemotherapy, including VI, interval-compressed VDC alternating with IE, and vincristine/dactinomycin/cyclophosphamide.[204][Level of evidence C2]The following results were observed:

With a median follow-up of 2.9 years, the 3-year EFS rate was 16% (95% CI, 7%–25%) for patients who received cixutumumab and 18% (95% CI, 2%–35%) for patients who received temozolomide.

The COG performed two nonrandomized pilot trials in patients with high-risk rhabdomyosarcoma. All patients received 54 weeks of chemotherapy, including VI, interval-compressed VDC alternating with IE, and vincristine/dactinomycin/cyclophosphamide.[204][Level of evidence C2]The following results were observed:

These results did not differ from the results observed in the ARST0431 (NCT00354744) trial that used the same chemotherapy regimen.

A European multinational collaboration investigated an intensive induction regimen followed by 1 year of maintenance therapy for patients with high-risk rhabdomyosarcoma who were aged 21 years or younger. Induction therapy consisted of four cycles of ifosfamide, vincristine, dactinomycin, and doxorubicin followed by five cycles of ifosfamide, vincristine, and dactinomycin. Maintenance therapy comprised 48 weeks of low-dose intravenous vinorelbine and low-dose oral cyclophosphamide. There were 270 evaluable patients.[205]

A European multinational collaboration investigated an intensive induction regimen followed by 1 year of maintenance therapy for patients with high-risk rhabdomyosarcoma who were aged 21 years or younger. Induction therapy consisted of four cycles of ifosfamide, vincristine, dactinomycin, and doxorubicin followed by five cycles of ifosfamide, vincristine, and dactinomycin. Maintenance therapy comprised 48 weeks of low-dose intravenous vinorelbine and low-dose oral cyclophosphamide. There were 270 evaluable patients.[205]

The 3-year EFS rate was 34.9% (95% CI, 29.1%–40.8%), and the OS rate was 47.9% (95% CI, 41.6%–53.9%).

A European multinational collaboration investigated an intensive induction regimen followed by 1 year of maintenance therapy for patients with high-risk rhabdomyosarcoma who were aged 21 years or younger. Induction therapy consisted of four cycles of ifosfamide, vincristine, dactinomycin, and doxorubicin followed by five cycles of ifosfamide, vincristine, and dactinomycin. Maintenance therapy comprised 48 weeks of low-dose intravenous vinorelbine and low-dose oral cyclophosphamide. There were 270 evaluable patients.[205]

The investigators simultaneously conducted a prospective randomized trial that tested the addition of bevacizumab to chemotherapy. In a subset of 102 patients, 50 were assigned to receive bevacizumab. The addition of bevacizumab did not improve EFS or OS.